• ribosome inhibiting proteins (RIPs) are a group of proteins that inhibit protein synthesis of a ribosome
• class I RIPs consist of a single polypeptide chain with molecular weight 25-30 kDa
• ebulin
• dianthin 29
• saporin S6
• saporin L1
• pokeweed antiviral protein (PAP) a
• bryodin
• momordin I / a-momorcharin
• b-momorcharin
• a-trichosanthin
• gelonin
• class II RIPs consist of 2 chains linked with a disulphide bond: an enzyme A-chain and a lectin B-chain
• abrin
• ricin
• mistletoe lectins
Type-I RIPs and the A-chains of type-II RIPs share sequence and structural homology and inhibit protein synthesis by cleaving the N-glycosidic bond in adenosine A4324 in 28S eukaryotic rRNA or the one in the equivalent position of rRNA in other organization by hydrolysis, which prevents the binding of elongation factor-2 and arrests the elongation step of protein synthesis. The B-chain binds to carbohydrate moieties of the cell surface and triggers the internalization of the entire toxin into the cell. Because of the lack of this internalization facility, type-I RIPs exhibit low toxicity to a whole cell system. Recent studies have demonstrated that RIPs not only release adenine from rRNA, but both type-I and type-II RIPs release adenine from DNA, and many type-I RIPs can release adenine from poly-(A).

• Embryophyta
• Tracheophyta
• Euphyllophyta
• Moniliformopses
• Equisetophyta
• Sphenopsida
• Equisetales
• Equisetaceae
• Equisetum
• Equisetum arvense (common or field horsetail) : sterols (b-sitosterol (60.0%), campesterol (32.9%), isofucosterol (5.9%) and cholesterol (trace amounts)^ref) and isoquercitroside : antinociceptive and anti-inflammatory effects^ref; dicaffeoyl-m-tartaric acid has vasorelaxant activity^ref, antioxidant^ref
• Lycopodiophyta
• Lycopodiopsida
• Lycopodiales
• Lycopodiaceae
• Huperzia
• Huperzia dalhousieana
• Huperzia serrata
=> huperzineA (9-amino-13-ethylidene-11-methyl-4-azatricyclo[7.3.1.0(3.8)]trideca-3(8),6,11-trien-5-one), s-(-)-3-n-butylphthalide (s-(-)-3-butyl-1(3H)-isobenzofuranone) is a putative nootropic AChE inhibitor used to treat Alzheimer's disease
• Spermatophyta
• Coniferopsida
• Coniferales
• Cupressaceae
• Juniperus
• Juniperus sabina

=> savin oil : an acrid oil from the fresh tops, the chief constituent of which is sabinol; it has been used in folk medicine as an emmenagogue, anthelmintic, and antirheumatic, and is used in perfumery. It may cause hematuria and violent gastrointestinal irritation when administered internally; fatal poisoning has resulted from its use as an abortifacient.
• Juniperus virginiana (a.k.a. red cedar)

=> cedar oil / cedarwood oil / oil of cedar wood : a volatile oil from the wood used as a clearing agent in microscopical techniques; the thicker fraction is used as the immersion medium with oil-immersion objectives
• Pinaceae
• Pinus
• Pinus
• Pinus palustris (a.k.a. longleaf pine)

=> pine oil : the volatile oil obtained by steam distillation of the wood; used as a deodorant and disinfectant.
=> rectified tar oil : the volatile rectified by steam distillation; in veterinary medicine, administered internally as a stimulant expectorant and externally as an antipruritic, antiseptic, and stimulant for skin diseases. Also used as a disinfectant and deodorizer
• Pinus mugo (a.k.a. mugo pine, Swiss mountain pine)
• Pinus mugo var. pumilio
=> dwarf pine needle oil : the volatile oil distilled with steam from the fresh leaf, used as a perfume and flavoring agent
• Taxaceae
• Taxus
• Taxus brevifolia

=> taxol
• Ginkgophyta
• Ginkgoales
• Ginkgoaceae
• Ginkgo
• Ginkgo biloba (maidenhair tree)

=> flavonoid glycosides and terpenic lactones => increased cerebral blood flow.
Americans consumed nearly $250 million of this herbal product in 2000. The literature shows no evidence that it improves cognition, but it may decrease the risk of dementia.
• Gnetophyta
• Gnetopsida
• Ephedrales
• Ephedraceae
• Ephedra (a.k.a. ma huang)
• Ephedra spp.
• Ephedra sinica (a.k.a. Chinese ephedra, cao ma-huang)
=> ephedrine
• herbal ecstasy is an alternative drug of abuse usually containing both ephedrine and caffeine => perceptual disturbances, anorexia, inability to sleep, dizziness, palpitations and paresthesia^ref, cardiovascular toxicity^ref
=> pseudoephedrine (enantiomer)
• Magnoliophyta
• eudicotyledons
• core eudicots
• Asteridae (asterids)
• campanulids
• Apiales; Apiaceae; Apioideae; apioid superclade; Angelica + Arracacia clade
• Peucedanum
• Peucedanum oreoselinum (a.k.a. oreoselinum) : a plant used in homeopathic practice as a diuretic.
• Asterales
• Asteraceae
• Asteroideae
• Astereae
• Aster
• Aster tataricus

=> astins : antitumour pentapeptides consisting of a 16-membered ring system containing a unique b,g-dichlorinated proline [Pro(Cl)₂], other non-coded amino acid residues and a cis conformation in one of the peptide bonds
• Plucheeae
• Sphaeranthus
• Sphaeranthus indicus is a rice weed commonly found in India, Sri Lanka, Africa and Australia, whose extract inhibits TNF-a and has been proposed as a treatment for rheumatoid arthritis
• Dipsacales
• Valerianaceae
• Valeriana
• Valeriana officinalis (a.k.a. common valerian) is used to treat insomnia

=> 6-methylapigenin, a GABA_A ligand
• Cornales
• Cornaceae
• Nyssoideae
• Camptotheca
• Camptotheca acuminata

=> camptothecin
• Ericales
• Ericaceae
• Ericoideae
• Rhodoreae
• Rhododendron spp.

=>
•  Phyllodoceae
• Kalmia
• Kalmia angustifolia
• Kalmia latifolia
• Vaccinioideae
• Gaultherieae
• Leucothoe
• Leucothoe grayana
=> grayanotoxins : they bind to site 4 on voltage-gated Na⁺ channels and block Na⁺ flux.
• Sapotaceae
• Palaquium
• Palaquium gutta
• Payena
=> gutta-percha [Malay getah perca sap of the percha tree] : the coagulated, dried, and purified latex of trees; used in orthopedics for fracture splints, in surgery for temporary sealing of cavities, and in dentistry in the form of cones for filling the root canal and in the form of sticks for sealing cavities over treatment.
• Styracaceae
• Styrax
• Styrax benzoin

=> benzoin
• Theaceae
• Camellia
• Camellia sinensis

The beverage tea, from the top leaves, is one of the most widely used beverages in the world, second only to water.
• non-fermented tea : green tea has a higher content of catechins (EGCG is 5 times higher in green than in black tea : old leaves > young leaves) and low caffeine
• semi-fermented tea : red tea (oolong tea) : the fermentation process during tea manufacturing reduces the levels of catechins and caffein significantly
• fermented teas
• black tea has higher caffeine and gallic acid levels
• Chinese pu-erh tea
=> theophylline inhibits phosphodiesterases, and acts as an antagonist A₁, A_2a, A_2b, and A₃ receptors.
=> antioxidants : green tea polyphenols (GTP) down-regulate the IGF-1-driven molecular pathway (including PI3K, Akt and Erk1/2) and indirectly down-regulating plasma VEGF in prostate tumor cells. GTP inhibited the levels of urokinase plasminogen activator as well as MMP2 and MMP9, cellular molecules linked to the metastasis.
• catechins
• (-)-epigallocatechin gallate (EGCG) binds to the metastasis-associated 67-kDa laminin receptor with a nanomolar K_d value
• (-)-epigallocatechin (EGC)
• (-)-epicatechin gallate (ECG)
• (-)-epicatechin (EC)
The tea leaf polyphenol oxidase mediated oxidation to oolong and black tea, yielding other polyphenols :
• theaflavins
• theaflavin (TF-1)
• theaflavin-3-gallate
• theaflavin-3'-gallate
• theaflavin-3,3'-digallate (TF-3)
• thearubigins
• gallic acid (GA)
• teine / caffeine / 1,3,7-trimethylxanthine / 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6- dione / methyltheobromine / guaranine : there is 40-50 mg caffeine in a 160-ml cup of tea
=> Kombucha mushroom tea / Manchurian tea / Kargasok tea is not actually derived from a mushroom, but from the fermentation of various yeasts and bacteria. A starter culture is added to a mixture of black tea and sugar, and the resulting mix is allowed to ferment for a week or more. The culture grows to form a mushroom-shaped colony, the derivation of its name. Through the process of fermentation, the product comes to contain considerable quantities of acids commonly found in some foods such as vinegar, and smaller quantities of ethyl alcohol (=> metabolic acidosis). Because the acid could leach harmful quantities of lead and other toxic elements from certain types of containers -- some ceramic and painted containers and lead crystal -- such containers should not be used for storing Kombucha tea. The unconventional nature of the process used to make Kombucha tea has led to questions as to whether the product could become contaminated with potentially harmful microorganisms, such as the mold Aspergillus. Such contamination could produce serious adverse effects in immune- compromised individuals. Commercially produced sterile products have not been shown to harbor any contamination, but there is no way of knowing if the same is true about home culturing or brewing. In some countries Kombucha is used to support the healing of a wide variety of diseases. It is said that in Manchuria, the home of Kombucha, not one case of cancer has been detected where the people religiously drink the tea. Traditionally, the Kombucha culture is considered to be holy, and whoever receives the "mushroom" promises to treat it reverently; if they were unable to continue caring for the culture, then they must pass it on to a caretaker so it may continue to flourish. Anecdotally it is reported to affect a plethora of conditions, resulting in anything from a feeling of well-being to curing a variety of diseases. Controlled studies, such as would be required to have it recognized as a drug, seem to be lacking.
• euasterids I
• Gentianales
• Apocynaceae
• Apocynoideae
• Apocyneae
• Forsteronia
• Forsteronia refracta : a nondescript member of the dogbane family found in the Amazonian rain forest

=> SL0101 inhibits RSK in breast cancer cells
• Rauvolfioideae
• Alstonieae
• Alstonia
• Alstonia scholaris (dita bark, devil tree, pale mara) : in India the day of the new moon (Amavasya) in the month of July is considered to be highly auspicious. Various ancient rituals are practised on that day, one of which is drinking a herbal concoction prepared from the bark of the tree early in the morning on an empty stomach. The bark of this tree is collected fresh, well before the sunrise, and is ground up to make a herbal preparation called kashaya. This preparation is believed to cure and prevent bowel related disorders. Clinical uses of this tree have been well described in homoeopathic and ayurvedic literature. In 2004 as they usually did, 6 members of a family prepared kashaya, but this year making it from the bark of a relatively young tree. Within a few minutes, all of them had severe muscle spasms and started having convulsive movements. They were rushed to hospital, but the 2 children, aged between 6 and 8 years, were dead on arrival. The 4 adult members of the family were conscious but had muscle stiffness with periodic convulsive movements of the limbs and opisthotonos. The clinical picture was consistent with strychnine poisoning, and it was later confirmed that, in the dark, the family had taken the bark from Strychnos nux-vomica (strychnine tree) instead of Alstonia. Ancient traditions and rituals tend to abound with precepts and injunctions. To modern eyes, these can seem meaningless superstition, but much ancient wisdom can be hidden amidst such rituals. This family had blindly followed the ritual of taking kashaya but had neglected to follow the golden rule, to "Select only those trees with old scars on their trunk." This practice of selecting trees with scars on the trunk is the only sure and safe way to identify the correct tree in darkness; old scars on the trunk affirm the tree's use in the previous year. Had our patients followed this tip, identification of the right tree would not have been difficult, and the tragedy could have been averted^ref
• Tabermontantaneae
• Tabernaemontana
• Tabernaemontana citrifolia
• Tabernanthe
• Tabernanthe iboga (West African shrub)
=> iboganes, indole alkaloids :
• ibogaine (12-methoxyibogamine)
• ibogamine
• tabernanthine
• voacangine (carbomethoxy-ibogaine)
• synthetic iboga alkaloid congener 18-MC
• Vinceae
• Catharanthus
• Catharanthus roseus (a.k.a. Vinca rosea, Madagascar periwinkle)
=> vinblastine
=> vincristine
=> vinorelbine
=> vinleurosine
=> vinrosidine
• Rauvolfia
• Rauvolfia biauriculata (a.k.a. Rauwolfia biauriculata)

=> lochnerin, an indole alkaloid
• Rauvolfia serpentina (a.k.a. Rauwolfia serpentina or devilpepper or serpentwood)

=> reserpine (Adelphan^®, Barecal^®, Eubamat^®, Modenol^®, Ondasil^®, Pacyl-R^®, Sedaraupin^®, Serpasil^®, Serpatonil^®) : it impairs ACh vesicles accumulation in presynaptic terminal
• Vinca
• Vinca difformis
• Vinca minor (a.k.a. running-myrtle)
=> vinblastine
=> vincristine
• Loganiaceae
• Spigelia
• Spigelia anthelmia (a.k.a. pink root of Demerara)

=>
• Strychnos
• Strychnois ignatii
• Strychnos nux-vomica (dog or quaker button / nux vomica) : East Indies
• Strychnos toxifera

=> toxiferines : they are N antagonists.
=> brucine [from Brucea, a genus of shrubs named for J. Bruce, Scottish explorer, 1730–1794] : a poisonous alkaloid, from Strychnos ignatii and S. nux-vomica, which resembles strychnine in its action, but is less poisonous. One of the principal constituents of nux vomica and ignatia, it was formerly used in the same manner as strychnine
=> strychnine  is an alkaloid extract obtained from the dried ripe seeds : it inhibits Gly receptor ; in the past strychnine has been used as an antiseptic, stomach tonic, circulatory stimulant, CNS stimulant, and as a medication for the relief of constipation; The minimal oral LD₅₀ ranges from 30 to 120 mg, but this can be somewhat lower when given i.v. or s.c.. However, enzymes of hepatic microsomes readily metabolize strychnine, so 2 LD₅₀ can be given over 24 hours and not have cumulative effects. Of course, LD₅₀ for children may be much lower
Symptoms & signs : strychnism (strychninism is chronic strychnine poisoning) : within 15-30' (occasionally there is a delay of 1 hour if it is taken by mouth, as the time of action depends on whether the stomach is empty or full, and on the type of food that is eaten) uneasiness, restlessness, anxiety, hyperreflexia, muscle twitching, midriasis, and stiffness of the neck => increased acuity of hearing, vision, touch, taste, and smell, followed by tetanus-like tonic convulsions of all striated muscles every 10-15', severe cyanosis (which disappears after the attack subsides), and nausea and vomiting. The attacks (each lasting about 3-4') appear to be spontaneous, while at other times they are the result of external stimuli, i.e., noises, slight movements, or flashes of light. The patient never loses consciousness. When the poisoning is left untreated, each attack lasts longer than the previous one and the interval between them grows shorter. Up to 10 attacks occur before death or recovery. This could happen from 10' to 3 hrs and is a result of asphyxiation or inner tissue paralysis.
Laboratory examinations : identifying strychnine in the stomach contents and viscera by chemical tests and microscopic identification of typical strychnine crystals.
Therapy : i.v. diazepam => gastric lavage
Strychnine produces a painful death. A dog ingesting strychnine presents with no vomiting or diarrhea. The initial clinical signs are a restless, anxious dog, that is described as *walking on egg shells* with increased respirations, not quite panting. This progress to constant panting, muscle tremors. Finally tetanic seizures or convulsions that occur spontaneously or with touch, light, or noise stimuli. The limbs extend, the head is
curved upwards and backwards and the lips are pulled back in what has been termed a sardonic grin. The severity and duration of convulsions are not prognostic. Death is generally from asphyxia due to prolonged paralysis of the respiratory muscles. When the dog is in seizures, the muscles of the diaphragm are paralyzed and the dog cannot breath. Death may be as sudden as 5 to 10 minutes or as long as 2 hours. Animals poisoned with strychnine can be successfully treated. If the animal was seen ingesting a known bait, and is not showing signs the veterinarian should induce emesis (vomiting). Animals showing clinical signs should have the convulsions controlled and respiratory support initiated. Pentobarbital sodium is the drug of choice, administered to effect. (Phenobarbital is not as effective due to the long period of time before it takes effect.) It may be necessary to perform gastric lavage to decrease adsorption of any
strychnine remaining in the stomach. The veterinarian should thenadminister activated charcoal. The charcoal should be removed from the stomach by sedating the animal and flushing the stomach or by administration of a saline cathartic. Forced diuresis with acidification of the urine is appropriate. An anesthetic machine may utilized to support respiration for an extended period of time, however, this removes it from use in surgeries. A respirator is better, if available. Use of central acting skeletal muscle relaxants such as glyceryl guaiacolate and/or methocarbamol are recommended, but require frequent redosing. The animal will need to have its temperature maintained by use of blankets and placed in a dark quite room. Turn the animal periodically to prevent hypostatic congestion. The continued administration of activated charcoal may prevent the convulsions which re-occur 1-3 days after apparent recovery. Strychnine is an ugly way for an animal to die, but these animals can be saved by proper and timely assistance.
• Rubiaceae
• Cinchonoideae
• Cinchoneae
• Cinchona [named from a countess of Chinchon] : a genus of South American trees, the source of the medicinal dried bark called calisaya bark, cinchona bark, Jesuit's bark, Peruvian, or Cardinal's  bark, and quinquina. It was once widely used as an antimalarial but has been largely replaced by its alkaloids. Called also .
• Cinchona pitayensis
• Cinchona pubescens
• Cinchona succirubra Pavon et Klotzsch and its hybrids (red cinchona)
• Cinchona calisaya Weddell
• Cinchona ledgeriana (Howard) Moens et Trimen and its hybrids (yellow cinchona)
=> quinoline alkaloids
quinine and its optical isomer
quinidine
cinchonidine : an alkaloid of cinchona, used as an antimalarial, chiefly in the form of the sulfate salt; administered orally.
cinchonine : an alkaloid of cinchona used as an antimalarial, chiefly in the form of the sulfate salt; administered orally.

Laboratory examinations
Side effects :
cinchonism : poisoning by the injudicious use of cinchona bark or its alkaloids, characterized by nausea, vomiting, headache, tinnitus, deafness, symptoms of cerebral congestion, vertigo, and visual disturbances.
Tommaselli's disease : pyrexia and hematuria due to excessive use of quinine.

=> cinchoninic acid : quinoline 4-carboxylic acid, an oxidation product of cinchona alkaloids.
• Isertieae
• Isertia
• Isertia pittieri
• Guettardeae
• Guettarda
• Naucleeae
• Adina
• Adina rubella
• Mitragyna
• Mitragyna inermis
• Mytragina stipulosa
• Neonauclea
• Neonauclea sessifolia
• Pausinystalia
• Pausinystalia johimbe

=> yohimbine (Aphrodyne^®, Dayto Himbin^®, Plain Prowess^®, Yocon^®, Yohimes^®, Procomil^®, Procamil^®) is an a₂-AR antagonist
• Sarcocephalus
• Sarcocephalus latifolius
• Uncaria
• Uncaria guaianensis
• Uncaria tomentosa (a.k.a. una de gato)
 => inner part of bark and trunk base cortex is used as immunostimulant
• pentacyclic > tetracyclic alkaloids induce NK and T_h lymphocytosis
• 7 different glycosides of quinovic acid
• quinovic acid glycoside 7
• quinovic acid 3 b-O-b-D-quinovopyranoside
• quinovic acid 3 b-O-b-D-fucopyranosyl-(27----1)-b-D-glucopyranosylester
• quinovic acid 3 b-O-[b-D-glucopyranosyl-(1----3)-b-D-fucopyranosyl]-(27----1)- b-D-glucopyranosylester
• quinovic acid 3 b-O-b-D-fucopyranoside
• Ixoroideae
• Coffeeae
• Coffea spp. (a.k.a. coffee)
• Coffea arabica (coffee) : low content of ...
• Coffea canephora (a.k.a. Coffea robusta) : high content of ...
=> caffeine / teine / 1,3,7-trimethylxanthine / 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione / methyltheobromine / guaranine (Vivarin^®, Cafcit^®, No Doz^®, BL Stay Awake^®; Cafergot^® in combination with ergotamine) : it acts as both a competitive inhibitor of  phosphodiesterases, SERCA, and an antagonist on GABA_A, A₁, A_2a, A_2b, and A₃ receptors, leading to membrane hyperpolarization => decrease of vascular resistances, positive inotropic effect on cardiomyocytes, and increase of thiazide-induced diuresis. It easily crosses the placental barrier.

Caffeine has significant hemodynamic and humoral effects in habitual coffee drinkers that persist for many hours during the activities of everyday life. Furthermore, caffeine may exaggerate sympathetic adrenal-medullary responses to the stressful events of normal daily life. Repeated daily blood pressure elevations and increases in stress reactivity caused by caffeine consumption could contribute to an increased risk of coronary heart disease in the adult population^ref. There is extensive evidence that caffeine at dietary doses increases BP. However, concern that the drug may contribute to cardiovascular disease appears to have been dampened by (1) the belief that habitual use leads to the development of tolerance, and (2) confusion regarding relevant epidemiologic findings. When considered comprehensively, findings from experimental and epidemiologic studies converge to show that BP remains reactive to the pressor effects of caffeine in the diet in persons who are regular consumers, even when daily intake is at moderately high levels^ref. Overall, the impact of dietary caffeine on population BP levels is likely to be modest, probably in the region of 4/2 mm Hg. At these levels, however, population studies of BP indicate that caffeine use could account for premature deaths in the region of 14% for coronary heart disease and 20% for stroke^ref. No effect of coffee consumption on the risk of acute myocardial infarction (AMI). Self-reported coffee consumption has no overall association with post-infarction mortality^ref. For adolescents, especially African American adolescents, caffeine intake may increase blood pressure and thereby increase the risk of secondary systemic arterial hypertension. Alternatively, caffeinated drink consumption may be a marker for dietary and lifestyle practices that together influence blood pressure^ref. A significant association was found between caffeine-related increase in systolic blood pressure and caffeine-related increase in pain tolerance^ref. Intake of caffeinated beverage (>/=180 mg caffeine) may not be recommended for patients with normotensive glaucoma or ocular hypertension^ref. Caffeine intake is associated with a significantly lower risk for Alzheimer's disease, independently of other possible confounding variables^ref.
Brazilian researchers bred 3,000 Ethiopian coffee plants as part of a programme to produce low-caffeine strains. They found 3 bushes, all derived from the same plant, that were virtually caffeine free, containing 15 times less stimulant than commercial strains^ref. Caffeine-free coffee plants have been found before, growing wild in Madagascar. But they yield inferior beans unsuited for coffee production. The Brazilian shrubs belong to the species Coffea arabica, the most cultivated and consumed coffee in the world. Over 10% of coffee consumed worldwide is decaffeinated, so demand for a tasty, low-caffeine blend is high. Currently caffeine is stripped from coffee using costly industrial processes. Organic solvents and carbon dioxide are used to purge the caffeine from the beans, but they strip away key flavour compounds at the same time. An alternative that does not destroy so much of the taste is to sift out the caffeine with a carbon filter, but this is even more expensive. They have not been able to taste any coffee made from the plants as these will take several years to mature. Their bushes also grow around 30% more slowly than standard arabica plants, so the team hopes to crossbreed them with their caffeine-rich relatives to produce a fast-growing, caffeine-free variety. But selective breeding like this can take ten years or more, giving competitors a chance to edge in on the market. For example, a genetically modified low-caffeine coffee plant is just a few years from maturity.Naturally bred species can still contain trace amounts of the chemical. But those opposed to genetically modified foods may find the Brazilian approach worth the wait.
People who receive caffeine have significantly greater activation in parts of the prefrontal lobe, known as the anterior cingulate and the anterior cingulate gyrus. These areas are involved in 'executive memory', attention, concentration, planning and monitoring [Koppelstätter, 2005 meeting of the Radiological Society of North America].
Caffeine-dependent women with a family history of alcoholism were not able to follow their physician’s advice to reduce or eliminate caffeine consumption during pregnancy, despite their wanting to do so. This subgroup may require more intensive intervention to ensure caffeine abstinence and may be at greater risk for abuse of or dependence on other drugs^ref.
Web resources :
• Coffee Research
• National Coffee Association
Paullinia cupana (Guarana)
• Rubioideae
• Psychotrieae
• Psychotria
• Psychotria ipecacuanha (a.k.a. Cephaelis ipecacuanha, ipecac, "Brazil root")

=> ipecac alkaloids :
• cephaeline
• isocephaeline
• neocephaeline
• 7'-O-demethylcephaeline
• 10-O-demethylcephaeline
• 2'-N-(1"-deoxy-1"-b-D-fructopyranosyl)cephaeline
• 2'-N-(1"-deoxy-1"-b-D-fructopyranosyl)neocephaeline
• protoemetine
• emetine
• 9-demethylprotoemetinol
• psychotrine
• Psychotria viridis (Chacruna)

=> N,N-dimethyltryptamine (DMT)
• Spermacoceae
• Bouvardia
• Bouvardia ternifolia

=> bouvardin
• Lamiales
• Lamiaceae
• Coleus
• Coleus barbatus (a.k.a. Coleus forskohlii)

=> forskolin / coleonol / colforsin, labiate terpenoid
• Nepetoideae
• Lavanduleae
• Lavandula
• Lavandula angustifolia (a.k.a. lavender)
• Lavandula angustifolia subsp. angustifolia

=> lavender oil / lavender flowers oil : a volatile oil distilled with steam from the fresh flowering tops or prepared synthetically; used as a perfume in pharmaceutical preparations
• Lavandula latifolia

=> oil of spike : a volatile oil used in perfumery, and formerly in home remedies as an emmenagogue and abortive
• Mentheae
• Mentha
• Mentha x piperita (a.k.a. Mentha piperita, Mentha aquatica x Mentha spicata, peppermint)

=> peppermint oil : the volatile oil distilled from the fresh above-ground parts of the flowering plant, used as a flavor in pharmaceutical preparations, and as a gastric stimulant and carminative
• Mentha spicata (a.k.a spearmint)
• Mentha cardiaca

=> spearmint oil : the volatile oil distilled with steam from the fresh overground parts, yielding at least 55% by volume of carvone; used as a flavor for pharmaceutical preparations
• Nepeta
• Nepeta cataria (a.k.a. catnip, catmint)

=> nepetalactone

• Origanum
• Origanum vulgare (a.k.a. oregano)

=> used against Listeria monocytogenes
• Rosmarinus
• Rosmarinus officinalis (a.k.a. rosemary)

=> rosemary oil : the volatile oil distilled with steam from the fresh flowering tops, used as a flavoring or perfuming agent
=> rosmarinic acid (RosA) induces p56^lck-dependent apoptosis in Jurkat and peripheral T cells via mitochondrial pathway independent from Fas/Fas ligand interaction
•  Salvia
• Salvia divinorum (diviner's sage)

=> salvinorin A : ?

=> salvinorin B
• Salvia miltiorrhiza (a.k.a. danshen)

=> anticoagulants
• Salvia officinalis
• Salvia splendens (a.k.a. bonfire salvia, scarlet sage)

=> salviarin
=> splendidin
• Thymus
• Thymus vulgaris (a.k.a. thyme)

=> thyme oil : the volatile oil distilled from the flowering plant; used as a flavoring agent for drugs, and has been used as a rubefacient, expectorant, counterirritant, antiseptic, and carminative
• Ocimeae; Ocimum;
• Ocimum basilicum (a.k.a. sweet basil)
• Ocimum sanctu (Indian holy basil)

=> orientin (Ot)
=> vicenin (Vc), 2 water-soluble flavonoids isolated from the leaves that have shown significant protection against radiation lethality and chromosomal aberrations in vivo^ref.
=> methyl-eugenol is an aroma that protects the young plants from insects and bacteria as it grows, after which it loses its methyl and becomes nonmutagenic : in a plate of spaghetti with the best type of pesto (made with young leaves) there is a concentration of  600 times the accepted safety limit. It is structurally similar to safrole, a known animal carcinogen. Methyleugenol was found to be a very potent multisite carcinogen in male and female F344/N rats and B6C3F1 mice at all doses tested in 2-year NTP bioassays using gavage dosing^ref. Anyway in a murine model a chemopreventive response was evident from the reduced tumor burden (the average number of papillomas/mouse), as well as from the reduced percentage of tumor bearing-animals. Basil leaf, as deduced from the results, augmented mainly the Phase II enzyme activity that is associated with detoxification of xenobiotics, while inhibiting the Phase I enzyme activity. There was an induction in antioxidant level that correlates with the significant reduction of lipid peroxidation and lactate dehydrogenase formation. Moreover, Basil leaf extract was highly effective in inhibiting carcinogen-induced tumor incidence in both the tumor models at peri-initiational level^ref.
• Scutellarioideae
• Scutellaria
• Scutellaria baicalensis (a.k.a. huangqin, Baikal skullcap)
=> flavonoids
• baicalein
• Scutellaria barbata (a.k.a. banzhilian)
• Teucrioideae
• Teucrium
• Teucrium chamaedrys
=> hepatotoxic
• Oleaceae
• Ligustrum (privets)
• Ligustrum lucidum (glossy privet)

=> oleanolic and ursolic acids
=> nuezhenide
=> nuezhengalaside
=> isonuezhenide
=> neonuezhenide
=> specnuezhenide
=> salidroside (p-hydroxyphenethyl-b-D-glucoside)
=> lucidumoside A
=> lucidumoside B
=> lucidumoside C
=> lucidumoside D
=> oleoside dimethyl ester
=> oleuropein
=> iridoid glucosides
• iso-8-epikingiside
• 8-demethyl-7-ketologanin
• 8-epikingiside
• kingiside
• ligustroside
• 10-hydroxyligustroside
• ligustaloside A
• ligustaloside B
Commercially sold as Erzhi Pills and Anshenbuxin Pills
• Pedaliaceae
• Sesamum
• Sesamum indicum (a.k.a. sesame, Sesamum orientale, beniseed, gingelly)

=> sesame oil : the refined fixed oil obtained from the seed; it is used as a solvent and oleaginous vehicle for drugs, and has been used internally as a laxative and externally as a skin softener
• Veronicaceae
• Digitalis (a.k.a. foxgloves)
• Digitalis lanata

=> lanatoside A - Glc => acetyldigitoxin - acetyl => digitoxin
=> lanatoside B -Glc => acetylgitoxin - acetyl => gitoxin
=> lanatoside C - Glc => acetyldigoxin - acetyl => digoxin
They all bind to a-subunit and inhibit 3 Na⁺ / 2 K⁺ ATPase
• Digitalis purpurea (a.k.a. common foxglove)

=> purpurea glycoside A - Glc => digitoxin
=> purpurea glycoside B - Glc => gitoxin
=> formyl-purpurea glycoside - Glc => formyl-gitoxin
They all bind to a-subunit and inhibit 3 Na⁺ / 2 K⁺ ATPase
• Solanales
• Convolvulaceae
• Argyreia
• Argyreia nervosa (a.k.a. Hawaiian baby woodrose)
• Ipomoea spp.
• Ipomoea violacea (morning glory)
• Turbina
• Turbina corymbosa (ololiuqui, Rivea corymbosa, Christmasvine)
=> D-lysergic acid amide (LSA) / ergine

• Solanaceae
• Atropa
• Atropa belladonna (a.k.a. belladonna)

=> atropine / d,l-hysocyamine / dimethylscopolamine (Atropisol^®, Atropine-Care^®, Isopto Atropine^®)
Laboratory examinations
=>scopolamine / l-hyoscine (Isopto Hyoscine^®, Transderm-Scop^®)
• Capsicum spp. (a.k.a. peppers)

=> hot chili peppers, whose main pungent ingredient  is capsaicin : it excites peripheral nerve endings and activates vanilloid receptor 1 (VR1). Oleoresin capsicum (OC) is used even in self-defence sprays together with o-chlorobenzylidene malononitrile and 2-chloroacetophene.
• Datura
• Datura fastuosa
• Datura metel

=> scopolamine / hyoscine
• Datura stramonium (a.k.a. jimsonweed ("Jamestown weed", in reference to the fact that in 1676 cooks mistakenly added this species to salads eaten by English soldiers at Jamestown, Virginia), common thorn apple) : the most common species of Datura

=> atropine / d,l-hysocyamine / dimethylscopolamine
=> scopolamine / hyoscine
Its seeds sometimes contaminate animal feed and cause daturism. Higher doses may be fatal
In Bangladesh, there is a tendency to use powder of Datura spp. (most probably D. fastuosa) or some species of Oleander seed in food items, drink or cigarettes by miscreants and offering them to unsuspecting people. Because of the action of Datura or Oleander seed, people become unconscious and then the criminals grab their valuable items.
• Hyoscyamus
• Hyoscyamus niger (a.k.a. henbane)

=> atropine / d,l-hysocyamine / dimethylscopolamine
=> scopolamine / l-hyoscine
• Nicotiana spp. (a.k.a. tobaccos) :
tobacco : the dried and prepared leaves of N. tabacum; it contains various alkaloids, the principal one being nicotine, has qualities of both a sedative narcotic and an emetic and diuretic, and is also a heart depressant and antispasmodic
Epidemiology : there are nearly 1.1 billion users of nicotine and tobacco products worldwide : 80% reside in low-income and middle-income countries. Though in the USA there has been a substantial decline in cigarette smoking since 1964, when the Surgeon General's report first reviewed smoking, smoking remains widespread in the USA (about 23% of the population in 2001). Tobacco use through cigarette smoking is the leading preventable cause of death in the world and kills nearly 4 million people annually. 30% of all deaths in smokers in the 35 to 69 years age range are attributed to chronic cigarette smoking; smokers dying in this age cohort lose an average of 23 years of life. In UK the percentage of people smoking fell from 45% in 1974 to 26% in 2003-4. Smoking remains most common among manual workers (35% for men and 31% for women) and is lowest among people in managerial and professional jobs (20% for men and 17% for women)^ref. Cigarettes are probably the single most significant source of toxic chemical exposure and chemically mediated illness in humans. The WHO forecasts cigarettes will kill nearly 10 million people per year globally by the year 2020. Newly emerging tobacco products, notably products that claim to heat, rather than burn, tobacco come with claims of reduced toxicant yields and reduced harmfulness as they are test marketed internationally^ref. At the same time, governments are starting to require smoke constituents to be analysed and reported^ref. It is unlikely that a "safe cigarette" could ever be developed, as combustion products in smoke are inherently potentially harmful. Nevertheless, it may be possible to reduce some of the toxic potency of cigarettes if the most significant causative agents of disease can be identified and reduced or eliminated. However, it is important that such a strategy does not give the public the false impression that cigarette smoking has become a safe practice. Such a perception could counteract any public health gains made by the reduction of the toxicity of tobacco smoke. Ideally, policies to do with prevention of smoking would concentrate on preventing people from starting to smoke or assisting them to stop smoking entirely. However, such policies have been only partially successful, with the worldwide number of smoking related deaths at around 4 million annually and climbing.
Pathogenesis : cigarette smoke is a complex mix of some 4,000 chemicals. Many of these are harmful to hum health :
• nicotine (1-methyl-2-(3-pyridyl)pyrolidine) is a Lys derivative, a very poisonous, colorless, soluble fluid alkaloid with a pyridine-like odor and a burning taste, obtained from tobacco or produced synthetically. It is used in veterinary medicine as an external parasiticide, and in pharmacological and physiological studies for its neurological effects
• nicotine polacrilex : nicotine bound to an ion exchange resin; used in nicotine chewing gum as an aid to smoking cessation.
• nicotine sulfate : the sulfate salt of nicotine, formerly a component of veterinary vermifuges; it can cause poisoning in lambs and calves

It is an agonist of N receptor and a tumor promoter (activates PKB / Akt pathway)
=> nornicotine
=> neonicotine / anabasine
They all are used as botanical insecticides
• tabacosis (a pneumoconiosis)
• stomatitis nicotina / smoker's palate or patches
• respiratory bronchiolitis
• respiratory bronchiolitis–associated interstitial lung disease
• centriacinar or postbronchitic emphysema
• tobacco poisoning / tabagism / tobaccoism : poisoning by tobacco, usually taking the form of ...
• nicotine poisoning / nicotinism : poisoning by ingestion of excessive amounts of nicotine, usually seen in children who eat cigarettes or in workers who handle wet tobacco leaves; symptoms include stimulation followed by depression of the CNS and ANS and occasionally death due to respiratory paralysis
• green tobacco sickness (GTS) : a transient, recurrent form of nicotine poisoning seen in tobacco harvesters, caused by absorption of dissolved nicotine from wet tobacco leaves through unprotected skin; symptoms include headache, dizziness, vomiting, and prostration.
Inadvertent tobacco ingestion usually is related to a child eating all or part of a cigarette. One report of ingestions of this kind found that symptoms were reported in 1/3 of the children and included spontaneous vomiting (up to 4 episodes) (86% of those symptomatic), nausea (7%), pale or flushed appearance (7%), lethargy (3%), and gagging (3%). All 30 symptomatic children recovered fully within 12 hours^ref. Nicotine is one of the most lethal poisons known. At present, virtually all toxicities involving nicotine are being reported from cigarettes. > 90% of toxic exposures from cigarettes in the USA are reported in children less than 5 years of age. A report from Germany reported that most of the cases are in small children within the 7 month to 2 year old age range. In Nigeria, an herbal drug containing nicotine increases morbidity and mortality in this pediatric group. Ingestion of one cigarette (or 3 butts) or drinking saliva expectorated by tobacco chewer (which is often collected in a can) should be considered potentially toxic for children. In adults, suicidal ingestion of nicotine-containing pesticides, and occasionally after cutaneous exposure to nicotine, such as tobacco harvesters can cause poisoning. Green tobacco sickness (GTS) is an illness resulting from dermal exposure to dissolved nicotine from wet tobacco leaves. GTS is characterized by nausea, vomiting, weakness, dizziness, and sometimes fluctuations in blood pressure or heart rate. > 95% of the reported cigarette toxicity is either asymptomatic (70%) or mild (25%). Respiratory stimulation and gastrointestinal hyperactivity are 2 main symptoms of nicotine poisoning. Acute poisoning can even result from skin contamination or inhalation of tobacco smoke, depending on the doses
• mall doses: respiratory stimulation, nausea and vomiting, dizziness, headache, diarrhea, tachycardia, elevation of blood pressure, sweating and salivation. The patient will gradually recover, after a period of weakness
• large doses: burning sensation of the mouth, throat, stomach, followed immediately by the above symptoms. Patient may progress to prostration, convulsions, bradycardia, arrhythmia and finally coma. Death may occur within 5 minutes to 4 hours^ref.
• reduces fertility, compromises the length of gestation and infant birthweight.
• tobacco smoke contains > 60 carcinogens, including the following classes of compounds^{ref1, ref2} :
• 1,3-butadiene (BDE) appears to present the greatest cancer risk. However, BDE is not a group 1 IARC carcinogen, and it is possible that the potency factor calculated for BDE by the Cal/EPA, which is based on lung tumours in mice, assumes a relation to human cancer risk that is inappropriate. For example, recent studies indicate that the metabolic pathway of BDE leading to genotoxic products is considerably less prominent in humans than in rats^ref. However, the CPF for BDE has recently been reviewed by Cal/EPA^ref with the result a lowering of the potency factor from 3.4 (mg/kg/day)^-1 to 0.6 (mg/kg/day)^-1. Therefore the CPF for BDE is based on the best current scientific assessment. On the other hand, even if it were determined that the CPF for BDE is overly conservative and should be reduced by, for example, an order of magnitude, BDE would still be a major carcinogen in cigarette smoke. The contributions of volatile organic compounds to overall cancer risk index are dominant even in the absence of BDE. Clearly, if a harm reduction effort for cigarette smoke were to be initiated, a focus should be on the reduction of volatile organic compounds. As these compounds are not normally included in the estimate of "tar", which is total particulate matter minus nicotine, the use of tar as a surrogate for carcinogenicity of cigarette smoke may be inappropriate. This would be particularly true if some modification to cigarettes increased the BDE concentration while leaving other constituents unchanged. Some important chemicals in the gaseous phase of tobacco smoke, such as benzene, are correlated with the amount of tar^ref.
• N-nitrosamines : the estimated contribution to cancer risk from nitrosamines is smaller than that for aldehydes and small organics, but is not negligible. There are 4 tobacco specific nitrosamines (TSNAs) that are reported in the literature^ref:
• N-nitrosoanabasine (NAB)
• N-nitrosoanatabine (NAT)
• 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NKK) is formed during the curing and processing of tobacco by nitrosation of nicotine. Nicotine and NNK have structural similarities, and they are both metabolized extensively by lung tissue via several steps known to require oxidative enzyme systems, such as cytochrome P450. Nicotine can potentially interfere with the carcinogenicity of NNK by competition for enzyme systems essential for the metabolic activation of the nitrosamine and by competition as ligand for nicotinic cholinergic receptors^ref
• N-nitrosonornicotine (NNN)
• N-nitrosodiethylamine (NDEA)
• N-nitrosodimethylamine (NDMA)
• N-nitrosopyrrolidine (NP)
• N-nitroso-N-dibutylamine
• N-nitrosoethyl-methylamine
• N-nitrosodiethanolamine
• N-nitrosopiperidine
Of these, NNK and NNN appear to have the greatest mutagenic potential. NNK and NNN have been shown to cause DNA adducts associated with tumours in rodents and are classified as probable human carcinogens by IARC^{ref1, ref2}. Insufficient data currently exist to classify NAB and NAT with respect to human carcinogenicity and these 2 compounds are therefore not quantitatively factored into the hazard ranking approach. However, regulatory agencies, including the USFDA and USEPA, consider nitrosamines of any kind to be potential mutagens and cancer hazards just by virtue of their chemical structure^ref. Nitrosamine formation is promoted by high levels of nitrate and nitrite. Tobacco nitrate levels have been reported to be correlated with the formation of several volatile nitrosamines, in addition to NAB and NAT, whereas the concentrations of NNK and NNN do not seem to be affected^ref. This shows that the level of nitrosamines in cigarette smoke is a function of both existing levels of some types of TSNAs in tobacco (that is, NNK and NNN), and those nitrosamines that are products of chemical reactions during combustion in the presence of nitrate (NAB and NAT).
• volatile products of combustion also figure prominently in the potential risk to the cardiovascular system
• carbon monoxide
• hydrogen cyanide
• formaldehyde
• ammonia
• polynuclear aromatic hydrocarbons (PAH) : although benzo(a)pyrene and other carcinogenic PAHs are widely cited as important carcinogens in cigarette smoke, this analysis surprisingly showed that the potential risks from these compounds were low in comparison to many other compounds in smoke. Even if the CRIs from all the PAHs suspected to be human carcinogens were combined in mainstream smoke, the risk index would give a ranking that is still lower than the 16th highest ranked compound, NDEA. Therefore it appears that PAH’s may be receiving a greater level of attention than they actually deserve in relation to the other chemical constituents in tobacco smoke.
• benzo(a)pyrene
• dibenzo(a,i)pyrene
• benzo(j)fluoranthene
• benz(a)anthracene
• dibenz(a,h)anthracene
• 2-aminonaphthalene
• benzo(b)fluoranthene
• indeno(1,2,3-c,d)pyrene
• N-nitroso-N-propylamine
• benz(k)fluoranthene
• 7H-dibenzo(c,g)-carbazole
• 5-methylchrysene
• chrysene
• dibenz(a,j)acridine
• dibenz(a,h)acridine
• aromatic amines
• acrylonitrile
• acetaldehyde
• acetamide
• hydrazine
• DDT
• urethane
• vinyl chloride
• 4-aminobiphenyl
• metals
• arsenic
• beryllium
• cadmium
• chromium (hexavalent)
• lead
• nickel
• benzene
• 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)
In all, 158 chemical constituents of smoke were identified where this information was found. Fifty two of these compounds are known or suspected carcinogens according to IARC. One hundred and nineteen of the compounds had quantified concentrations (yields) for mainstream smoke reported in the open literature or by the British Columbia Ministry of Health^ref. Of these, 45 are known or suspected carcinogens under the IARC classification scheme^ref: group 1 (known human carcinogens) or 2A (probable human carcinogens) or group 2B (possible human carcinogens). Group 3 chemicals (not classifiable) are shown in table 1, but did not factor into the CRI calculations. CPFs expressed as (µg/m³)-1 were available for 40 of the 45 chemicals. Of those known or suspected carcinogens not having an available CPF, NNK appeared to be the most prominent in terms of exposure and suspected potency. Since a CPF did not exist for NNK, the published CPF for NNN was used as a surrogate for NNK. An additional 17 chemicals had non-cancer reference exposure levels for threshold type effects^ref.
Most of them are believed to cause smoking-associated cancers : tobacco smoke causes 63% of cancer deaths among African-American men in the USA The smoke-related cancer death burden for African-American men is highest in the South at 67%, with the lowest burden, 43%, in the Northeast. The percentage is 60 in the West and 63 in the Midwest^ref.
• lung cancer : Sir Richard Doll, the British epidemiologist whose research first established the link between smoking and lung cancer, died aged 92 in 2005. Doll warned in a 1950 study, co-written with Sir Austin Bradford Hill, that smoking was a major cause of lung cancer. Their early results showed that smokers were much more likely to die of lung cancer than non-smokers, while longer-term results linked cigarettes to heart disease and other illnesses. In 1954, 80% of British adults smoked, compared to about 25% now.
• oral cavity cancers
• highest risks for follicular lymphoma in blond (OR = 2.1, 95% CI 1.4-3.2) and mixed (OR = 1.8, 95% CI 1.1-3.0) tobacco smokers and for large cell lymphoma within the other WF group (OR = 1.6, 95% CI 1.1-2.4) only for blond tobacco^ref
People who smoke and have short telomeres have a substantially greater risk for tobacco-related cancers than people who never smoked and have short telomeres or people who smoked but had longer telomeres. Both nicotine and NKK induce AKT phosphorylation through N AChR on bronchial epithelial and endothelial cells.
The results of a 50 year analysis on 34,439 male British doctors who first reported their smoking habits at the end of 1951 show that lung cancer was the malignancy responsible for the largest number of deaths related to smoking. The number of deaths per year per 100,000 men who were heavy smokers (25 or more cigarettes a day) was 25 times that among their colleagues who never smoked (415.2 versus 16.9). For lung cancer, like a number of other cancers, there was a progressive increase in risk with the number of cigarettes smoked. Mortality from lung cancer was 3 times higher among heavy smokers than among light smokers (< 15 cigarettes a day) (130.6 deaths per year per 100,000 men). Similar differences in mortality between heavy smokers and men who never smoked were shown for esophageal cancers (50.0 versus 5.7 deaths per year per 100,000 men), bladder cancers (51.4 versus 13.7), the laryngeal cancers (17.3 versus 0), and the pancreatic cancers (52.9 versus 20.6). 2 types of cancer—rhinopharyngeal cancers and nasal cancers- contributed only small numbers of cases, but the evidence, say the authors, indicates a positive relation with smoking. No firm link was found for prostate cancers: data, now based on nearly 900 deaths, show some increasing risk with increasing numbers of cigarettes smoked per day, but only among smokers; there is no appreciable difference between non-smokers and continuing smokers and the lowest risk is recorded in ex-smokers. They tend, therefore, to support the idea that smoking is unrelated to the disease. Some evidence is shown that rectal cancers, but not colon cancers, is related to smoking^ref.
Compared with those who had never smoked, those who smoked 1-5 cigarettes a day were almost 3 times as likely to die of coronary artery disease. While there was little difference in the risk of dying from any type of cancer, this was not the case for lung cancer. Men who were light smokers were almost 3 times as likely to be killed by lung cancer. And women were almost 5 times as likely to die of the disease as their non-smoking peers. Light smokers also had significantly higher death rates from all causes - 1.5 times - than those who had never smoked, with the death rates corresponding to the number of cigarettes smoked every day. As the light smokers had smoked for fewer years than the heavy smokers, the researchers analysed the projected impact of smoking at this level for 5 years. This indicated that the risk of death from coronary artery disease would have been 7% higher, and the risk of lung cancer would have been 47% higher in women. (Tobacco Control, Sep 2005)
Major target organ systems in which non-cancer effects of smoking occur include the respiratory system, cardiovascular system, reproductive system, the eyes, and the nervous system. The current analysis shows that even a single cigarette per day provides exposures to a smoker that would be expected to exceed hazard indices for respiratory and cardiovascular effects. Fetal development, including birth weight, can also be affected but was not specifically examined in this analysis.
• the respiratory irritation NCRI of cigarette smoke appears to be driven by acrolein, acetaldehyde, and formaldehyde. A substantial amount of human exposure data have been factored into the RELs for these compounds, and so the degree of uncertainty about the RELs is minimal. It is implicit, but not firmly established, that exposure to atmospheres that exceed the RELs for chronic respiratory irritation and inflammation has a direct relation to chronic respiratory disease (asthma, or other chronic lung diseases, including emphysema).
• the NCRI estimates for cardiovascular toxicity rely more heavily upon extrapolations from primate and other lab animal data, and the compounds involved have a variety of toxicological mechanisms that may not be additive. Therefore these calculations involve a greater degree of uncertainty. However, regardless of the issue of additivity of mechanisms, hydrogen cyanide and arsenic exposures alone after only a single cigarette over a chronic period are expected to result in potential cardiovascular toxicity. The NCRI approach unfortunately does not allow for an estimation to be made of the number of individuals likely to develop heart disease. It should be emphasised that considerably greater amount of information exists on dose-response relations of carcinogens and respiratory toxicants than with cardiovascular toxicants, and this is related to the degree of confidence one has in the three types of hazard ranking.
That cigarette smoking causes respiratory and cardiovascular disease requires no further proof, and while this analysis may initially seem as though it is proving the obvious, it is instructive to observe the relative breakdown of contributions to these known adverse health effects on a chemical by chemical basis. Estimates of yield for intense or compensatory smoking are often 2-3 fold higher than the values for normal smoking^ref. This fact could contribute to the underestimate of observed cancer rates using the current analysis. While factoring this increased exposure into the risk estimates would increase the estimated risks and arguably be more representative of the real exposures and risks, the relative contribution to risk from each chemical constituent is unlikely to be changed.
Since 1950, the makeup of cigarettes and the composition of cigarette smoke have gradually changed^ref. In the USA, the sales-weighted average "tar" and nicotine yields have declined from a high of 38 mg "tar" and 2.7 mg nicotine in 1954 to 12 mg and 0.95 mg in 1992, respectively. In the United Kingdom, the decline was from about 32 mg "tar" and 2.2 mg nicotine to less than 12 mg "tar" and 1.0 mg nicotine per cigarette. During the same time, other smoke constituents changed correspondingly. These reductions of smoke yields were primarily achieved by the introduction of filter tips, with and without perforation, selection of tobacco types and varieties, utilization of highly porous cigarette paper, and incorporation into the tobacco blend of reconstituted tobacco, opened and cut ribs, and "expanded tobacco". In most countries where tobacco blends with air-cured (burley) tobacco are used, the nitrate content of the cigarette tobacco increased. In the USA nitrate levels in cigarette tobacco rose from 0.3-0.5% to 0.6-1.35%, thereby enhancing the combustion of the tobacco. The tobacco industry added certain substances to cigarettes to make them more palatable to children and young people. Menthol, for example, was added to most cigarettes (not just to those described as mentholated) because inhaling menthol has an anaesthetic effect, allowing first time smokers, who were often children, to take deep puffs. Sugar and aromatics were also added to make cigarettes taste better. The addictive potential was also increased by manipulation of filters and cigarette sheaths, which meant that smokers took deeper breaths and therefore had greater exposure to carcinogenic and other toxic substances. Additives such as ammonia, urea, menthol, sugar, and cocoa had been blended with raw tobacco over the last 5 decades. The formula for tobacco addiction was to take nicotine, decrease acidity, and add aromatic substances which enable smokers to take deep breaths. According to legal regulations cigarettes are allowed to contain up to 600 different substances and chemically undefined mixtures which make up 10% of the total weight of one cigarette : criticised additives had been legally permitted since 1964^{ref1, ref2}. Scientists at its GenApps Inc. laboratories of U.S. Smokeless Tobacco Company (USSTC) discovered nicotine demethylase, the enzyme that facilitates the conversion of nicotine into nornicotine. Nornicotine is known to be the precursor to NNN : the discovery holds the promise for commercial production of low-nitrosamine tobacco with significantly reduced NNN levels within the next decade.
beedis : tobacco rolled in Diospyus melanoxylon leaf
In recent times the tobacco industry has been active in developing and marketing new products that might be perceived as less harmful to health than typical cigarettes. At the same time, there has been an increasingly vigorous debate within the public health community over the most appropriate response to the new products being developed by the industry^{ref1, ref2}. In this debate, public health advocates have been mindful of the historical precedents set by previous tobacco industry attempts to introduce new product lines that have been perceived as less harmful. It is now clear that so called "light" cigarettes were widely believed to be less harmful (and continue to be by the majority of consumers) but in fact are no less deadly than standard cigarettes. The introduction and marketing of these products may well have had a serious adverse effect on public health by duping hundreds of millions of smokers into the belief that they could continue to smoke at reduced risk. In the current debate over tobacco harm reduction, some have cited the "Swedish experience" as an example of tobacco product switching that may have had a positive effect on smoking and public health^ref. "Snus" is the name given to the form of smokeless snuff tobacco commonly used in Sweden. It is a moist, ground oral tobacco product that is typically placed behind the upper lip, either as loose ground tobacco or contained in sachets appearing like small teabags. The snus is typically held in the mouth (without chewing) for approximately 30 minutes before it is discarded. Snus both contains and delivers a number of harmful substances, including cancer-causing tobacco specific nitrosamines (TSNAs). It has become clear that different selection and curing methods can affect the levels of nitrites and hence TSNAs present in the raw tobacco before processing. Over recent decades snus manufacturers have selected tobacco blends that have been air and sun cured (dried), while US moist snuff products tend to include blends high in fire cured tobacco. After curing, raw cured tobacco is cut into small strips, dried, ground, and sifted before processing. In Sweden, by tradition, snus production has included a process in which the tobacco is heat treated with steam for 24–36 hours (reaching temperatures of approximately 100°C). Ingredients added are: 45–60% water, 1.5–3.5% sodium chloride, 1.5–3.5% humectants, 1.2–3.5% sodium bicarbonate, and less than 1% flavouring. It is claimed that the heating process kills bacteria, producing a relatively sterile product. The product is then packaged in cans and refrigerated during storage. In Sweden the product is also kept in refrigerators by the retailers. One study examined levels of carcinogenic TSNAs in snus kept at temperatures ranging from -20°C to +23°C for 20 weeks^ref. This exposure to a variety of temperatures over time did not produce a significant increase in concentrations of TSNAs, suggesting that the exposure to heat during manufacturing may itself have prevented microbial activation of nitrites^ref. This manufacturing process contrasts with that traditionally used in the USA, in which the product is fermented (rather than being subject to high temperatures), allowing the continued formation of TSNAs. In addition, North American smokeless tobacco is not typically stored in refrigerators. One study found that nitrite and TSNA levels increased significantly in US snuff stored at 37°C for 4 weeks. Although different products vary in their pH levels, snus typically has a pH in the range 7.8–8.5^{ref1, ref2}. This is important because only nicotine in the free-base form is rapidly absorbed through the mucosal membrane, and the proportion of free-base nicotine available from tobacco is determined by the pH level. For example Brunnemann and Hoffmann compared two brands and found that one brand with a pH of 5.84 had only 1% of the nicotine in the free-base form and another brand with a pH of 7.99 had 59% of the nicotine available in free-base form for absorption^ref. Another study found that a leading Swedish snus brand had a higher pH (and therefore probably more efficient nicotine delivery) than 5 comparison brands of US smokeless tobacco^ref.13 Possibly as a result of the differences in manufacturing and storing procedures, snus has been claimed to contain lower levels of some harmful substances than many of the brands available in North America and notably lower levels than exist in the smokeless tobacco used in the Sudan and India.10Table 1 below summarises data from 5 studies^{ref1, ref2, ref3, ref4} of TSNA levels in various samples of different brands marketed in different countries. The total TSNA concentration varied greatly among the US brands from 4.1 to 128 (µg/g dry tobacco). There is little evidence to support claims that TSNA levels have consistently dropped over the past decade in North American snuff (for example, Copenhagen brand in 1994 had a measured TSNA level of 17.2 and in 2000 it was 41.1). Snus brands selected in Sweden from 1990, 1991, and 2000 have generally been lower and have varied from 9.2 to 11.2 µg/g in the 3 samples in 1990–91 and 2.8 µg/g in 2000. Brunnemann and Hoffmann13 also examined the effects of storage for 6 months at room temperature and found that in two leading US brands, the TSNA levels increased by between 30–130% whereas in the snus brand there was no increase. More recently the manufacturer of snus has created and publicised a quality standard, the Gothiatek standard, for its snus products that includes maximum permissible limits for "undesirable substances". It is unclear if all Swedish Match smokeless tobacco products produced in Sweden and abroad adhere to the Gothiatek standard. Many of the smokeless tobacco users participating in the older epidemiological studies discussed below may have been exposed to products delivering higher quantities of harmful substances than current versions of these products
• nicotine dependence : given the pattern of nicotine absorption described above there can be no doubt that snus is dependence forming in much the same way as other forms of tobacco consumption. There is some evidence that the dependence potential of nicotine and other psychoactive drugs is related to their speed of delivery to the brain23,25 and so one would expect snus and other non-inhaled forms of nicotine delivery to be proportionately less addictive than inhaled tobacco smoke. However, there is clear evidence that users of products with snus-like nicotine delivery profiles develop cravings and nicotine withdrawal symptoms when attempting to abstain, and find it difficult to quit^{ref1, ref2}. While snus probably does not produce stronger nicotine dependence than smoking, it has just minimal, if any, advantages over cigarettes or other smokeless nicotine delivery products in terms of its lower potential to induce dependence. In fact, its high nicotine delivery and hence dependence potential (relative to most other non-smoked delivery modalities) may be a critical factor enabling it to compete with the more rapidly absorbed nicotine from smoked tobacco. One of the biggest concerns about the use of smokeless tobacco stems from the relatively large body of evidence from a number of countries showing that oral tobacco use can cause cancer of the mouth, head, and neck. With regards to its use in India, the 2001 US Institute of Medicine (IOM) report stated that, "A large number of studies in India, including cohort, case-control, and intervention studies, support an association between oral cancer and smokeless tobacco, and these studies are consistent, strong, coherent and temporally plausible". The IOM report stated that toombak users in Sudan also have a much higher relative risk (RR) of oral cancer than non-users and that "In spite of conflicting US data, it can be concluded that snuff use in the United States also increases the risk of oropharyngeal cancers". In contrast, there is consistent evidence from two case–control studies in Sweden showing no increased risk of cancer of the head, neck, or mouth among snus users. Schildt and colleagues^ref investigated whether snus leads to increased risk of oral cancer by comparing various risk factors in 410 cases of oral cancer and 410 matched controls identified during the period 1980–89. 96% of the identified cases and 91% of identified controls participated in the study (leaving full data from 354 matched pairs) and 20% of the overall sample were current or ex snus users. Univariate analyses found significant increased risk of oral cancer as a result of smoking (odds ratio (OR) 1.8 for active smokers), and alcohol (OR 1.9 for beer drinkers) but no increased risk for active snus use (OR 0.7, 95% confidence interval (CI) 0.4 to 1.1). The authors concluded:"Our results do not support any association between use of oral snuff and oral cancer." Lewin and colleagues^ref conducted a similarly designed study, identifying cases of head and neck cancer in 2 regions of Sweden between 1988 and 1991 and matched controls. Interviews were conducted with high proportions of identified cases (90%) and controls (85%). This study found significantly increased risks of head and neck cancers associated with alcohol use and smoking, but no increased risk associated with former or current snus use. The RR for head and neck cancer among snus users as compared with non-snus users, after adjusting for age, region, alcohol, and smoking was 1.0 (95% CI 0.6 to 1.6). Similarly there were no significant relations between duration of snus use or lifetime consumption and head/neck cancer. A recent systematic review of the health effects of smokeless tobacco concluded:"Chewing betel quid and tobacco is associated with a substantial risk of oral cancers in India. Most recent studies from the US and Scandinavia are not statistically significant, but moderate positive associations cannot be ruled out due to lack of statistical power."^ref Snus causes a number of non-malignant oral diseases, including oral lesions and dental caries^ref. However, it appears as though the lesions produced by snus are reversible and disappear if snus use ceases
• other cancers : Ye and colleagues32 conducted a case control study (504 cases and 1164 controls) examining the effects of smoking, alcohol, and snus use on gastric cancer in Sweden. They found a significant dose and duration related increase in gastric cancer risk with smoking, but no effect of snus or alcohol. They concluded that "smoking, but not the oral use of tobacco in the form of moist snuff, is positively associated with risk of gastric cancer". Lagergen et al^ref conducted a case–control study designed to test the association between smoking, snus, and alcohol use, and cancer of the oesophagus and gastric cardia in Sweden. Combined smoking and alcohol use was strongly associated with oesophageal squamous cell carcinoma (OSCC)(OR 23.1 for heavy users compared with never users), but snus use was not significantly associated with any of the cancer sites under study in multivariate analyses. There was some indication of a possible link between snus use and OSCC in that the odds ratio was 2.0 for use for over 25 years versus never snus use, although because of the relatively small size of this sub-sample (n = 14 cases) this was not significant (95% CI 0.9 to 4.1). The authors concluded:"we found no statistically significant association between snuff dipping and risk of any of the studied tumors." It remains possible, but unlikely, that a carcinogenic effect of snus only emerges after very long term use. Bolinder and colleagues^ref found a non-significant RR of death from cancer of 1.1 for snus users compared with never tobacco users (95% CI 0.9 to 1.4) in a prospective study of Swedish construction workers that included a relatively large sample, many of whom had used snus for over 40 years. The RR for cancer death was 1.0 (compared with non-tobacco users) for the 1734 snus users aged 55–65 years, most of whom would presumably have used snus for over 35 years. However, this study found significantly increased all cause mortality in snus users compared with never tobacco users, largely from elevated cardiovascular mortality. The RR for lung cancer among snus users compared with never tobacco users was 0.8 among men aged 55–65, whereas the RR was 30.6 (95% CI 14.6 to 64.1) for smokers of > 15 cigarettes per day (again compared with never tobacco users). Overall, the results of the five large studies examining snus in relation to cancer are consistent in finding no increased cancer risk among snus users. All of the Swedish studies of the relation between snus and cancer were robust enough to detect significant effects for tobacco smoking (often involving very large effect sizes), and the studies of oral cancer were also able to detect significant relations with alcohol use. The lack of relation with snus is therefore unlikely to be caused by methodological problems such as low statistical power.
• cardiovascular disease : Bolinder and colleagues conducted a series of epidemiological and clinical studies^{ref1, ref2, ref3, ref4, ref5} examining the effects of long term snus use on health, focusing on cardiovascular risk factors and myocardial infarction. Their first report^ref focused on a cross sectional study of almost 98 000 Swedish construction workers undergoing health examinations in 1971–4, including over 5000 exclusive snus users. This study found an increased prevalence of circulatory and respiratory symptoms among snus users and heavy smokers as compared to non-tobacco users, and an increased prevalence of hypertension in snus users compared to non-tobacco users. Surprisingly this study found the lowest prevalence of hypertension among smokers of at least 15 cigarettes per day. The results were based on univariate analyses, and did not control for potential confounders other than age^ref.  Bolinder’s second study^ref examined the relation between tobacco use and cardiovascular mortality in a larger sample (n = 135 036) of Swedish male construction workers recruited at a health examination in 1971–4 and followed up 12 years later. This study found that snus users had a significantly higher risk of dying from a cardiovascular event than never tobacco users (RR 1.4, 95% CI 1.2 to 1.6). This excess risk was comparable to that of ex-smokers who had quit in the past five years, but smaller than heavy smokers (RR 1.9 compared with never tobacco users). The analyses in this study adjusted for age and region of origin, and (for at least some analyses, although it was not always stated) also adjusted for body mass index, blood pressure, diabetes, and heart problems at the time of entering the study. Alcohol consumption and cholesterol were not measured and so could not be controlled for. Subsequent studies focused on a smaller sample of Swedish firemen (around 140, split approximately equally between snus users, smokers, and non-tobacco users). These studies found that snus use did not influence exercise capacity^ref, or play a major role in the atherosclerotic process^ref (both of which were adversely affected by smoking). However, they replicated the previous finding of higher daytime (but not night time) heart rate and blood pressure among both snus users and smokers as compared to non-tobacco users^ref. Overall, these studies by Bolinder and colleagues are suggestive of an increased cardiovascular risk from snus use, that is probably mediated by nicotine’s sympathetic stimulant effects, and is of a smaller magnitude than the excess cardiovascular risks caused by smoking. It was suggested that snus’ effects on blood pressure may be related to its sodium content (1.3–3.5% sodium chloride and 1.5–3.5% sodium bicarbonate). However, two subsequent case–control studies by Huhtasaari and colleagues^ref did not find a significantly increased risk of myocardial infarction among snus users as compared to non-tobacco users. Both of these studies were based on data collected in northern Sweden as part of the World Health Organization MONICA (multinational monitoring of trends and determinants in cardiovascular diseases) project. In both reports, the cases and controls were identified in the 1990s. Huhtasaari and colleagues40 found an age adjusted OR for myocardial infarction (MI) of 0.89 (95% CI 0.62 to 1.29) for snus use versus no tobacco use, whereas smoking significantly increased risk of an MI (OR 1.87, 95% CI 1.40 to 2.48). In multivariate analyses smoking remained significantly associated with MI, whereas snus use was not. Huhtasarri subsequently conducted a larger study than the one reported in 1992, and included more detailed tobacco use histories and closer matching of cases and controls (matched for sex, date of birth, and area of residence)^ref. This study found (after adjustment for multiple cardiovascular risk factors) that cigarette smoking significantly increased risk of an MI (OR 3.53, 95% CI 2.48 to 5.03), whereas snus use significantly reduced the risk (OR 0.58, 95% CI 0.35 to 0.94) compared with men who never became regular tobacco users. When the analysis focused only on fatal cases, there was a tendency towards increased risk in snus users, but this was not significant (OR 1.5, 95% CI 0.45 to 5.03). There is no clear explanation for the difference in results between the Bolinder^ref and Huhtasaari^ref studies, although the different study populations, time periods covered, and outcomes measured (sudden death versus non-fatal MI) may have contributed. The similar magnitude of effect for fatal cardiovascular events found in these studies is suggestive of a slightly increased risk overall. On the other hand it remains possible that the effect of snus in the Bolinder study was caused by some unmeasured (and therefore uncontrolled) confounding factor, with dietary habits and alcohol consumption being examples of baseline variables not measured in that study. This possibility is supported by a recent report of the effects of smokeless tobacco in the USA, based on analyses of the First National Health and Nutrition Examination Survey epidemiologic followup study (NHANES-1) data^ref. This study had 96% follow up of the original 14 407 participants and 98% identification of death certificates for the 4604 decedents by 1992. Male smokeless tobacco users were found to have moderately increased risks of some disorders, but all of these excess risks disappeared when variables such as race and poverty were controlled for. For example, the crude hazard ratios for male smokeless users versus non-tobacco users were 1.5 and 2.1 for circulatory and respiratory diseases before adjustment, but after adjustment for confounders these hazard ratios became 1.0 and 0.9. One potentially serious flaw with this study42 is that pipe and cigar users were included in the "non-tobacco user" comparison group, seriously undermining confidence in their conclusion that US smokeless tobacco users have similar mortality outcomes to non-tobacco users. We cite this paper as an example of the changes in outcomes that can result from controlling for baseline variables, rather than as evidence of the safety of US smokeless tobacco. Bolinder et al’s first study^ref found snus users to be at excess risk of a number of respiratory symptoms. For example, the OR for "cough in the morning" for snus users versus never tobacco users was 2.1 (95% CI 1.8 to 2.4), as compared with an OR of 7.9 for smokers versus never tobacco users. It is not easy to think of a plausible mechanism whereby exclusive snus use might cause respiratory symptoms. This study excluded all those who reported mixed use of snus and cigarettes or reported being an ex-smoker (n = 59, 864 excluded). However, the increased respiratory symptoms suggest the possibility that some of those reporting exclusive snus use were actually occasional or ex-smokers. Passive smoke exposure is another possible confounding factor that could potentially contribute to these findings. This study was initially funded by a health insurance group with the purpose of examining factors affecting sick leave and disability pensions. Some participants may have under-reported their recent or ex-smoking due to their belief that it either was not worth mentioning, or out of a concern that it may somehow affect their future benefits. In reviewing the evidence from a range of clinical and experimental studies, Benowitz^ref concluded:"Overall, the epidemiologic and experimental data suggest that nicotine absorbed from smokeless tobacco, nicotine gum or transdermal nicotine is not a significant risk factor for accelerating coronary artery disease or causing acute cardiovascular events." This conclusion is supported by a recent case–control study that examined risk factors for stroke among Swedish men^ref. In multivariate analyses, controlling for other risk factors, smoking was related to increased risk of stroke (OR 1.74) whereas snus use was not (OR 0.87, 95% CI 0.41 to 1.83). Given the inconsistencies in the results of these studies, it remains possible that snus users have a slightly increased cardiovascular risk as compared to never tobacco users, even after controlling for other confounding factors. However, all of the large studies of the effects of tobacco use on cardiovascular disease in Sweden are in agreement that "the use of smokeless tobacco (with snuff being the most studied variant) involves a much lower risk for adverse cardiovascular effects than smoking does"^ref.
• respiratory diseases : a Pubmed search did not identify any studies that specifically examined the effect of snus on respiratory diseases; similarly the IOM report did not address the effects of smokeless tobacco on respiratory illnesses.3 The reason for this is presumably that there is no plausible causal mechanism whereby smokeless tobacco could cause respiratory disease. A recent study of mortality in US smokeless users reported no increased risk of respiratory diseases in smokeless users^ref. This contrasts heavily with the effect of continued smoking on chronic obstructive pulmonary disease, with 50% of elderly Swedish smokers developing the condition as compared with less than 20% of never smokers^ref.
• diabetes : Bolinder found that smokers had significantly higher fasting blood glucose values than never tobacco users whereas snus users were not significantly different from never users. Eliasson and colleagues47 found that neither smoking nor snus use was associated with changed glucose tolerance or insulin concentrations. However, a more recent study by Persson^ref found an increased risk of (asymptomatic) type 2 diabetes among both heavy smokers (25+ cigarettes per day) and heavy snus users (3+ cans per week), with significant odds ratios of 2.7 and 2.6, respectively, for these two groups as compared with non-tobacco users. It should be noted that this study specifically recruited men over 35 years old, 50% of whom had a family history of diabetes. The effects of snus on risks for diabetes are unclear and it may be that any effects are restricted to heavy users and/or those with a family history of diabetes.
• pregnancy : a Pubmed search did not identify any studies that had specifically examined the effects of snus use during pregnancy. However, given that animal studies have implicated nicotine as a cause of some of the widely known adverse effects of tobacco exposure during pregnancy (on both the health of the mother and healthy development of the fetus), it follows that snus use during pregnancy is likely to incur some of the risks associated with smoking during pregnancy^ref. The preliminary results of one study (as yet unpublished) have been presented at a conference earlier this year. The study examined data from the Swedish Birth Register for women who delivered babies during 1999–2000. The study compared 789 snus users to 11 242 cigarette smokers and 11 500 women not using any tobacco. Smokers gave birth to babies weighing an average of 206 g (7.3 ounces) less than non-tobacco users. Snus users gave birth to babies weighing an average of 40 g (1.4 ounces) less than non-tobacco users. Snus users were also about twice as likely as non-tobacco users to deliver prematurely (perhaps partially explaining the slightly lower birth weight), and were more likely than both smokers and non-tobacco users to suffer pre-eclampsia. Clearly, the full results of this study and additional studies on this topic are required before coming to conclusions, particularly given the possibilities for confounding variables to cause small sized effects. However, given the known risks of nicotine in pregnancy, and the preliminary results of this unpublished study, it seems likely that snus use can cause adverse health effects in pregnancy and should not be promoted as safe for use in pregnancy. It would be a particular cause for concern were there to be evidence of increased snus use among women of reproductive age, without an equal or greater reduction in smoking in that group. Given that smoking during early pregnancy in Sweden has already declined from 31% in 1983 to 12% in 2000, it could be argued that the potential for snus to have a "positive" impact on smoking in pregnancy has similarly shrunk. It would seem as though Swedish women are on a positive trend towards tobacco-free pregnancies without snus, and that it would be best kept that way.
Total consumption of snus and cigarettes in Sweden have changed dramatically over the past century, with the most pronounced changes occurring over the past 20 years when cigarette consumption has reduced significantly and at the same time snus consumption has risen significantly. A crude snapshot of overall sales hides sex-specific changes and changes in the size of the population. Adult (over 14) cigarette consumption went from approximately 0.2 kg/person in the 1920s to 1.1 kg/person in 1970 and then down to 0.6 kg/person at the end of the 20th century. Across the same time points Snus consumption fell from 1.4 kg/person to 0.4 kg/person and then has increased again to 0.9 kg/person by 2000. The large drop in cigarette sales in 1997 was probably related to an 18% price increase in January of that year, and the rebound in 1999 was probably caused by a 24% price decrease in August of 1998. Chewing tobacco is also available in Sweden, but the total amount sold is less than 1% of the quantity of snus sold. Similarly, in addition to cigarettes, cigars, cigarillos, pipe tobacco and "roll-your-own"(RYO) tobacco are available in Sweden. These represent a relatively small and diminishing segment of the smoking market. For example, 125 million cigars/cigarillos were sold in 1983, as compared with 58 million in 1999 (< 1% of the number of cigarettes sold); 1510 metric tons of pipe/RYO tobacco were sold in 1983, compared with 906 tons in 1999 (and 4479 tons of cigarettes sold in 1999). A more detailed picture of recent trends can be seen by examining prevalence of daily smoking and daily snus use by sex. This shows a much larger drop in male smoking (from 40% in 1976 to 15% in 2002) compared with the fall in female daily smoking (34% in 1976 to 20% in 2002) coinciding with an increase in male daily snus use from around 10% in 1976 to 23% in 2002. Other surveys of tobacco use in Sweden such as those carried out by the Swedish government, or as part of the WHO MONICA project (discussed below), similarly show a greater reduction in male smoking prevalence than female smoking prevalence in Sweden from the 1980s (when more men than women smoked) to the late 1990s (when more women than men smoked)^{ref1, ref2}. One recent study has specifically examined whether snus use appears to have directly influenced smoking rates in northern Sweden^ref. This study used the dataset developed for the northern Sweden component of the WHO MONICA study. This involved collection of data from four representative population based surveys conducted in 1986, 1990, 1994, and 1999, including detailed questions on tobacco use among approximately 1500 adults at each time point. This study found stable prevalence of "all tobacco use" among men (at around 40%) over the 13 year period, but with male smoking decreasing from 23% to 14% and snus use increasing from 22% to 30%, as the proportion of snus using ex-smokers increased from 9% to 14%. In women, smoking prevalence remained stable from 1986 to 1994 at 27% then dropped to 22% in 1999 when snus use rose from 2% to 6%. A more detailed picture of the likely role of snus in smoking cessation in Sweden can be gained by examining the prevalence of ex-smoking among ever smokers by history of snus use and by sex in the Rodu study^ref. A higher proportion of male than female ever smokers had quit, and most of these had also used snus. The data from this study provide strong support for the role of snus in promoting smoking cessation among Swedish men. The same research group has recently published a prospective follow up study of over 70% of the participants in 1986, 1990, and 1994 who were successfully followed up in 1999 (n = 1651).56 This study found a continuing trend away from smoking among men in northern Sweden, moving to a smoking prevalence around 10% in those followed up in 1999. Of those men who were smokers (no snus use) in the 1986–94 surveys, 39% had quit smoking by 1999, one third of whom had switched to snus use. Among women who were smokers at the baseline surveys, 30% had quit by 1999, only 10% of whom had switched to snus. This study concluded:"use of snus played a major role in the decline of smoking rates amongst men in northern Sweden. The evolution from smoking to snus use occurred in the absence of a specific public health policy encouraging such a transition." While cigarette smoking has fallen dramatically among Swedish men, overall tobacco use has not. Some may view this as a failure of tobacco control (compared with some other countries). We view changes in tobacco caused disease as the decisive factor when evaluating the effects of tobacco control, and as discussed below, these changes have been very positive for Swedish men. It could also be argued that this reduction in male smoking may have occurred without snus. Here we regard the comparison with Swedish women (little snus use, smaller smoking reduction, smaller health improvement) and the characteristics of male ex-smokers (large proportion switching to snus when quitting smoking) as strongly suggestive of snus having a direct effect on the changes in male smoking and health. The reductions in male smoking prevalence that have occurred in Sweden over the past 25 years have been the largest of any developed nation in the world. At the same time, Swedish men have also experienced a notable reduction in the incidence of the major smoking caused diseases. To exemplify this, fig 6 shows the pattern of changes in lung cancer incidence in Sweden and its near neighbour, Norway, from 1960 to 1999. Since the mid 1970s there has been a pronounced reduction in the incidence of lung cancer in Swedish men, as compared with Swedish women, and both men and women in Norway. Interestingly Swedish men have also had a significant improvement in cardiovascular health over the same period. For example, Rosen and colleagues studied trends in heart attacks in Sweden over the years 1987 to 1995 (amounting to 360 000 separate heart attacks in total)^ref. They found a 22% drop in heart attacks in men aged 30–64 years during that period, roughly double the decline among same aged women over the same period. It is noteworthy that these improvements in tobacco caused illnesses have occurred primarily in men, despite a stable consumption of tobacco among men during that time period. The main factor that has changed is that many Swedish men have switched from smoked tobacco to snus. Of course one cannot state with absolute certainty that if snus had not been available in Sweden that just as many men would have quit smoking either without assistance or perhaps by switching to nicotine replacement therapy. However, the pattern of sex differences in smoking cessation and snus use within Sweden, together with the between-country differences in smoking prevalence changes and health changes (comparing Sweden with other similar countries that have lower snus use, such as Norway), strongly suggests that a significant portion of the health improvement among Swedish men over the past 20 years has been due to a large proportion quitting smoking or never starting to smoke, but using snus instead. It has been argued that smokeless tobacco could become a "gateway" product, hooking young people on nicotine from a cheaper and more easily concealed product, before they more easily move on to yet more addictive and harmful products such as cigarettes. For many reasons, the evidence from Sweden is not supportive of such a view. Firstly, if snus was acting to attract young people towards smoking one might expect the only country in Europe with a sizable snus market to have had the worst record for reducing smoking prevalence rather than the best. Secondly, when one examines the sex differences in tobacco use patterns, if snus was attracting young men towards smoking, one would expect the change in smoking prevalence to have been worse for men than for women, whereas it has been significantly better (that is, smoking prevalence has fallen more for men than for women in Sweden). Looking only at daily smoking prevalence among 16 year olds in Sweden, this has remained remarkably stable at around 11% for boys and 16% for girls for the past 20 years. Again this is not consistent with the idea that snus is acting as a gateway to smoking among boys. Thirdly, when one looks at the pattern of changes in tobacco use among Swedish men, the proportion of current smokers who are ex snus users is consistently smaller than the proportion of current snus users who are ex smokers (4%v 14% of the adult male population in 1999, with only 3% current users of both snus and smoked tobacco, in the Rodu et al 2002 study^ref). A study recently presented by Ramstrom60 examined smoking status in Sweden by snus use, using data from a representative sample (n = 6700) of the Swedish population aged 16–79 years collected in 2001–2. In the sample of men, 15% were daily smokers and 20% were daily snus users (19%v 2% among women). Among 2879 men, 468 (16%) were primary daily snus users (that is, they started daily snus without having previously started smoking). 20% of this group subsequently became daily smokers, compared with 45% of men who were not primary snus users. This suggests that snus use is protective against smoking rather than a gateway towards it. It is possible that this pattern of results could be caused by a combination of age and cohort effects. However, when we examined this issue we found lower rates of smoking onset among primary snus users in both older (born 1922–56) and younger (born 1957–1985) cohorts. Among those men who ever became daily smokers, 71% with a history of snus use quit smoking completely, compared with 54% of those with no snus history. Of those men who have quit smoking completely after having used snus as a cessation aid, 75% are currently daily snus users and 25% have quit snus use as well. Of all those men who quit smoking and mentioned the use of a single smoking cessation aid, 62% stated that they used snus as a cessation aid, compared with 38% who mentioned using nicotine replacement therapy. Again this is more consistent with snus being a pathway from smoking. A study recently reported by Gilljam and Galanti also suggests that snus has primarily been a pathway from smoking among Swedish men. Their study consisted of a survey of approximately 1000 current smokers and 1000 ex-smokers (all men aged 25–55 years). Twenty nine per cent of the ex-smokers had used snus to quit, and smoking cessation was significantly more likely among men who had used snus as compared with men who had not. Among those who used snus, 28% gave "health concerns" as their primary reason for snus use (for example, to help quit smoking or because it was less dangerous than smoking). A recent study of tobacco use among young people in Sweden reported a larger prevalence of combined snus and cigarette use^ref than reported in adult studies. This study was based on a 1998 survey targeting all 15–16 year old children in Stockholm (the capital city). Only 1.3% of girls reported snus use so this paper focused on boys (n = 6287): 14.3% were cigarette users, 5.7% were snus users, and 13.8% used both. Thus the majority (71%) of male snus users at that age were also smoking tobacco, although it should be noted that these percentages include people using these tobacco products less than daily. This study also highlighted the fact that at this age the young people had not yet established a stable profile of tobacco use, and that tobacco use, and particularly combined smoking and snus use, was linked with a number of other problem behaviours. Thus the likelihood of being a current snus user was several times higher among boys who reported having been drunk (OR 9.6), or used illicit drugs (OR 2.4) compared with those who did not. The authors of this study concluded:"smokeless tobacco use in adolescence does not substitute cigarette smoking and can be an indicator of a drug- and risk-seeking lifestyle." It therefore seems unlikely that either form of tobacco use is a "gateway" to the other, but rather that both are markers of risk taking behaviour in adolescent males in Sweden. Unless there is a more recent cohort effect, or a sustained difference in use patterns between Stockholm and northern Sweden, the data on tobacco use among Swedish men suggest that many of these combined non-daily users at age 15 will subsequently quit smoking and will transfer to exclusive snus use. However, given the high frequency of combined snus and cigarette use in this study, it is clear that the pattern of transitional and combined use of different tobacco products among young people should continue to be closely monitored. One study in Finland examined the effect on youth snuff use of legislation banning the sale of snuff in 1995^ref. It reported very little effect on snuff use (1% reduction in prevalence) and some negative consequences, including 12% of existing snuff users switching to smoking. A recent report on smokeless tobacco use in the USA and Sweden concluded that at least 77% of US smokeless users and 83% of Swedish snus users appear to be "non-gateway" users in that their snuff use did not lead to smoking or their smoking preceded their snuff use^ref. Overall, the patterns of tobacco use in Sweden suggest that those who start using snus are less likely to become smokers, and that among people who become smokers, their chances of quitting smoking are higher if they use snus. None of the studies reviewed in this paper were randomised controlled trials and so no specific causal relations can be inferred from any individual study. Both within and outside Sweden, smoking is primarily influenced by factors other than availability of smokeless tobacco (for example, real price of cigarettes, health education, smoke-free air policies, industry marketing, etc). That having been said, we feel that the analysis of the change in patterns of tobacco use and health outcomes over time described here, including the comparison between countries and between sexes within Sweden, is suggestive of a positive rather than a negative net effect of snus use on tobacco smoking and hence on public health in Sweden. A key component of the evidence on this is the differential smoking quit rate between men and women. Most of the other important background factors affecting cigarette consumption (for example, price) would be expected to have similar effects on men and women and so they are unlikely to account for the sex differences in quitting. One important reason for male smoking cessation rates being higher is that many more Swedish men than women use snus. We do not assume that these same benefits would automatically transfer to other countries, or even that they will remain constant in Sweden. Most countries of the world have very limited (or no) regulation of tobacco ingredients, or marketing. There may be little to stop a company from introducing a product that delivers significantly higher quantities of toxins than snus, and directing the marketing at young people, or even young non-smoking women of childbearing age. In such a scenario it is perfectly possible that snus or other smokeless products would have a negative effect on public health. However, in Sweden we have a concrete example in which availability of a less harmful tobacco product has probably worked to produce a net improvement in health in that country.
The main conclusions that can be drawn from the Swedish Experience are as follows:
• implementation of stronger, evidence based regulation of tobacco products is necessary to avoid unintended public health consequences from both tobacco availability and tobacco bans in Sweden and worldwide^ref.
• significant proportions of smokers are capable of transferring their nicotine dependence from an ultra-fast nicotine delivery product (a cigarette) to a medium rate nicotine delivery product (snus) so long as it delivers comparable amounts of nicotine, and so long as it is competitive on price, accessibility, and long term availability. This suggests that were a comparable non-tobacco pharmaceutical product (for example, a high dose nicotine gum) to become available and be able to compete on an even (or advantageous) basis, it may also have similar effects in helping a significant proportion of the smoking population transfer to a safer product. Unfortunately pharmaceutical nicotine replacement therapy (NRT) is currently regulated as part of a different regulatory system (along with medicines) that puts it at a competitive disadvantage as compared with tobacco products.66 The total elimination of most of the toxins in the nicotine delivery product (as in NRT) is clearly preferable to the marginal or unverified reductions in toxin delivery that are typically achieved by tobacco products.
• it appears to be extremely unlikely that nicotine is capable of stimulating cancer under normal use conditions. The media regularly issues scare stories about nicotine replacement products potentially causing cancer, usually stemming from media coverage of laboratory studies in animals or test tubes that interpret their findings as implying that nicotine may cause cancer in humans. In Sweden large numbers of snus users are consuming large quantities of nicotine, absorbed at a single part of the body (the mouth), along with significant concentrations of other carcinogens, for most of their adult life without evidence of increased cancer risk. The epidemiology of snus and cancer in Sweden does not support the view that nicotine itself is a risk factor for cancer^{ref1, ref2, ref3, ref4, ref5, ref6}.
• snus is certainly not harmless. It can cause reversible lesions in the mouth, it most likely causes harmful effects to the unborn fetus when used by a pregnant woman, and long term use may contribute to cardiovascular disease (although most of the available evidence suggests that cardiovascular risks are not increased by snus).
• snus is clearly less harmful to the individual user than smoked tobacco, and also less harmful than the types of smokeless tobacco used in some other parts of the world, notably Sudan and India^ref. The manufacturers of snus have voluntarily set fairly sensible toxicity standards for their product in order to reduce health risks as much as technologically possible. These or more thorough standards should now be applied across the industry and across countries. It could be argued that these same standards should also be applied to the other tobacco products (chewing tobacco, cigars, and pipe tobacco) that Swedish Match also produces and sells, and that a similar set of standards should apply to all nicotine delivery products.
In accepting that we now have smokeless tobacco products available that are less harmful than the dominant products (cigarettes), public health professionals and policymakers need to decide whether to focus effort on restricting access to the most harmful products (smoked tobacco products), or focus much time, energy, and legislation on restricting access to the least harmful products, that under some circumstances can produce a net public health benefit.
The tobacco industry maintained, for many years, that it was unaware of research about the toxic effects of smoking. By the 1970s, however, the industry decided that it needed this information but they were unwilling to seek it in a way that was open to public scrutiny. By means of material from internal industry documents it can be revealed that one company, Philip Morris, acquired a research facility, INBIFO, in Germany and created a complex mechanism seeking to ensure that the work done in the facility could not be linked to Philip Morris. In particular it involved the appointment of a Swedish professor as a 'co-ordinator', who would synthesise reports for onward transmission to the USA. Various arrangements were made to conceal this process, not only from the wider public, but also from many within Philip Morris, although it was known to some senior executives. INBIFO appears to have published only a small amount of its research and what was published appears to differ considerably from what was not. In particular, the unpublished reports provided evidence of the greater toxicity of sidestream than mainstream smoke, a finding of particular relevance given the industry's continuing denial of the harmful effects of passive smoking. By contrast, much of its published work comprises papers that convey a message that could be considered useful to the industry, in particular casting doubt on methods used to assess the effects of passive smoking^ref. Mutations in the p53 tumour suppressor gene lead to uncontrolled cell division and are found in over 50% of all human tumours, including 60% of lung cancers. Research published in 1996 by Denissenko and colleagues demonstrated patterned in-vitro mutagenic effects on p53 of benzo[a]pyrene, a carcinogen present in tobacco smoke^ref. We investigated the tobacco industry's response to p53 research linking smoking to cancer. We searched online tobacco document archives, including the Legacy Tobacco Documents Library and Tobacco Documents Online, and archives maintained by tobacco companies such as Philip Morris and R J Reynolds. Documents were also obtained from the British American Tobacco (BAT) Company depository in Guildford, UK. Informal correspondence was carried out with scientists, lawyers, and tobacco control experts in the USA and Europe. Executives and scientists at the highest levels of the tobacco industry anticipated and carefully monitored p53 research. The tobacco industry's own scientists conducted research which appeared to cast doubt on the link between smoking and p53 mutations. Researchers and a journal editor with tobacco industry ties participated in the publication of this research in a peer-reviewed journal without clear disclosure of their tobacco industry links. Tobacco industry responses to research linking smoking to carcinogenic p53 mutations mirror prior industry efforts to challenge the science linking smoking and lung cancer. The extent of tobacco industry involvement in p53 research and the potential conflict of interest discussed here demonstrate the need for consistent standards for the disclosure and evaluation of such potential conflicts in biomedical research^ref. More complete combustion decreases the carcinogenic PAH, yet the increased generation of nitrogen oxides enhances the formation of the carcinogenic N-nitrosamines, especially the TSNA in the smoke. However, all analytical measures of the smoke components have been established on the basis of standardized machine smoking conditions, such as those introduced by the Federal Trade Commission, that call for 1 puff to be taken once a minute over a 2-s period with a volume of 35 ml. These smoking parameters may have simulated the way in which people used to smoke the high-yield cigarettes; however, they no longer reflect the parameters applicable to contemporary smokers, and especially not those applicable to the smoking of low- and ultra-low-yield filter cigarettes. Recent smoking assays have demonstrated that most smokers of cigarettes with low nicotine yield take between 2 and 4 puffs per minute with volumes up to 55 ml to satisfy their demands for nicotine. Cigarette manufacturers currently use a suction machine to assess tar and nicotine levels : the device takes one small puff of a lit cigarette every minute and catches nicotine and tar in a fibre filter. But human smokers take bigger, more frequent puffs and the machine test is fundamentally misleading and it may underestimate carcinogen intake. The naturally occurring tobacco ingredient solanesol lodges in the cigarette filter as smoke is breathed in — in quantities proportional to the amount of tar and nicotine that are sucked into the mouth. The chemical hangs around for weeks, so butts can be collected and stored for bulk analysis, which takes just a few hours : solanesol could be used to gauge daily differences in smoking behaviour (smokers may drag harder on their first cigarette of the day. They may also puff differently when they are at work, snatching short but intense cigarette breaks). But this test has drawbacks too : some people puff but don't inhale, so solanesol counts may overestimate their smoke intake. Although invasive, blood or saliva assays give a more realistic estimate of nicotine in the body : cotinine — a chemical that is formed as the body breaks down nicotine — can be easily measured in both.
Craving is related to a decreased activity variant of the CYP2B6 gene. The earlier someone starts smoking, the more likely they are to be life-long smokers and the more trouble they have in kicking their addiction : in the US, 88% of smokers had started before they were 18, despite it being illegal to sell cigarettes to anyone under that age. The amount of carcinogens sucked up by smokers remains high even when they cut down on the numbers of cigarettes they smoke : the decrease in levels of metabolites of NNK in the urine (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides (NNAL-Gluc)) is, on average, < 50% of the drop in smoking. The results are consistent with previous studies which showed that smoking a large or small number of cigarettes exposes a smoker to similar amounts of thiocyanate - a chemical marker of cigarette smoke that is not a carcinogen. This was also thought to be because smokers inhale more deeply when smoking fewer cigarettes. Surprisingly, nicotine patches didn't make much difference to how long and hard the smokers puffed : even when allowed to use as many patches as they wanted, the smokers still inhaled a disproportionate amount of carcinogens. The results indicate that nicotine patches aren't helping as much as they could : that's either because the patches don't deliver nicotine in the same way (don't create the same 'high') as cigarettes, or because there are other addictive substances in cigarettes that nicotine patches don't yet replace^ref.
An art survey on 1,000 pictures from the National Portrait Gallery in London has shown that smoking is on the decline in portraits. Between 1950 and 1960, about 10% of the subjects drawn were enjoying a cigarette, cigar or pipe. By the 1990s, smoking had disappeared from the portraits. Of the 50 total pictured smokers, 33% were writers; no scientists, engineers or doctors were pictured having a drag.
Externalities are the costs or effects of a consumer behaviour that may not be borne by the consumer and hence may not be included in the price of the consumed good. For example, a commonly analysed externality of cigarette smoking is the economic cost of smoking-attributable medical care for smokers, which is borne by non-smokers and by governments as well as by the smoker^ref. Another externality is the health effects of environmental tobacco smoke on non-smokers and on families of smokers. Finally, other environmental externalities include deforestation as a result of tobacco production, pesticide use in tobacco agriculture, and fires caused by cigarette smoking. All these externalities affect the social costs of smoking, which may need to be addressed by policy actions of government or the private sector. Here we describe additional externalities of tobacco use involving waste production due to individual consumption as well as to the tobacco manufacturing process. The waste products of cigarette consumption are clearly visible whenever one walks on a city sidewalk or uses a public beach. Cigarette butts, packages, cellophane wrappers, and cartons are ubiquitous forms of trash. Although the paper and tobacco components are biodegradable, the filters and plastic wrappers are retained in the environment for long periods of time. Cigarette filters most commonly contain cellulose acetate, and some research has been undertaken by the tobacco industry to improve biodegradation of this material. Cellulose acetate filters may persist under normal environmental conditions for > 18 months. Moreover, the butts themselves may be an acute health hazard to animals and to small children, who may eat them^ref. Historically, the ocean has been a common dumping ground for human-made debris. Although cities can successfully treat sewage before environmental discharge, much of the marine debris from developed countries originates inland, even on city streets, where cigarette butts are dropped casually by the smoker, washed into storm sewers or drainage ditches, and out into larger waterways to the ocean. These items and the cigarette debris tossed directly onto beaches and other waterways have been subject to the Center for Marine Conservation (CMC) International Cleanup Project since 1990. In addition, tobacco manufacturing produces chemical wastes, including nicotine, in the manufacture of cigarettes, cigars, smokeless tobacco, and other products. Many of these waste products are potential environmental hazards, and they are subject to careful regulation regarding disposal in most developed countries. The most hazardous chemicals released to the environment by all manufacturers, including the tobacco industry, in the United States are reported through the Toxics Release Inventory (TRI) each year. Worldwide, an estimated 5.535 trillion commercially manufactured cigarettes were consumed in 1995. Specific estimates on filtered cigarette consumption for that year are available for 49 countries.14 These estimates were calculated as the number of units manufactured in the country, plus imports and minus exports; smuggling totals were excluded (globally, up to a third of annual exports are contraband, or smuggled^ref). Based on a weighted average of filtered cigarette consumption reported from the 49 countries, it was estimated that 83% of cigarettes consumed were filter-tipped. The number of packages (assumed average 20 cigarettes per package) produced globally was estimated at 276 753 million, and the number of cartons (assumed average 10 packets per carton) was estimated at 27 675 million. This does not include estimates for other packing materials, such as the corrugated paper boxes used to package cartons and the plastic wrappers used on some cigarette packages.The tobacco manufacturing process produces liquid, solid, and airborne wastes.11 Liquid wastes include tobacco slurries, solvents, oils, and greases that originate in the manufacturing processes, building services, and facilities that may need special treatment or disposal. Solid wastes include paper, wood, plastics, unusable tobacco, packaging materials, and dirt that originate in the manufacturing process. These waste products are resold, recirculated, compacted, or put in landfills. Airborne wastes include non-toxic odours of manufacturing, in-plant dust, tobacco volatiles and particles, and other emissions. Abatement programmes for airborne waste include use of filters, dust collectors and scrubbers, low-sulphur fuels, and other controls. Of greatest environmental concern among the manufacturing wastes are those chemicals (n = 643) specified as reportable to the TRI, developed by the United States Environmental Protection Agency (EPA) under the Emergency Planning and Community Right-to-Know Act of 1986. A waste is considered hazardous if it exhibits one or more of the following characteristics: ignitability (flammability), corrosivity (against metal), reactivity (capability of causing explosions, toxic fumes, gases, or vapours), or toxicity (harmful or fatal when ingested or absorbed). In the United States in 1992, the TRI reported in the Statistical record of the environment that tobacco manufacturing generated more than 27 million kilograms of production-related chemical waste, of which 2.2 million kilograms were TRI-treated or released into the environment. Overall, the tobacco industry ranked 18th among all industries in total chemical waste production. A 1970 study on solid waste management in the United States tobacco manufacturing industry estimated that in 1963, 2700 kg of general solid waste were generated per manufacturing employee (total 225 million kilograms).The estimated total chemical waste production for 1992 and the estimated solid waste production for 1963 was applied to the number of cigarettes manufactured in those years to develop ratios of each waste to cigarettes produced. Adjusting these data for 1995 (the last year for which cigarette manufacturing data are available), it was estimated that in the USA, 293 million kilograms of solid waste and 27 million kilograms of total chemical waste were produced. Releases to the environment of Toxics Release Inventory chemicals by tobacco manufacturing industry, United States, 1996 (includes air, water, land, underground injection, and offsite transfers)
• ammonia 946 155 kg
• ethylene glycol 8 936 kg
• hydrochloric acid 407 371 kg
• hydrogen fluoride 27 937 kg
• methyl ethyl ketone 340 821 kg
• nicotine and nicotine salts 900 377 kg
• nitric acid 58 970 kg
• phosphoric acid 6 804 kg
• sulphuric acid 67 228 kg
• toluene 349 622 kg
Globally, these totals are 2262 million kilograms for total solid wastes and 209 million kilograms for chemicals. Nicotine is an interesting tobacco production waste product. The tobacco manufacturing process and all activities that use tobacco produce solid or liquid wastes with high concentrations of nicotine. Partly in response to information about the addictive nature of nicotine, the market for low-nicotine cigarettes has been growing. Thus, an ironic outcome of this market growth is the increased need to detoxify nicotine in tobacco production waste. A non-recyclable, powdery, nicotine-containing waste is formed during tobacco production, which has average nicotine content of 18 g per kg of dry weight. This waste is classified as "toxic and hazardous" by European Union Regulations when the nicotine content exceeds 500 mg per kg dry weight. According to a 1997 study from Italy, an average 3 million kilograms of this waste are reported in 1995 by the tobacco industry to be produced from 55 300 million cigarettes manufactured in that country. If manufacturing processes and waste outputs per million cigarettes produced in the United States and globally are similar to those reported in Italy, it is estimated that 38 870 000 kg of nicotine waste was produced in the United States in 1995, and 300 274 000 kg was produced globally in the same year. Denicotinisation of waste requires chemical-physical treatments or biological methods with microorganisms to reduce the nicotine content of released wastes below the threshold of 500 mg per kg. In the United States, nicotine has been included on the TRI list since November 1994. Nicotine itself is an anti-parasitic plant pesticide. The health consequences of cigarette smoking to smokers and exposed non-smokers are well known. Cigarette products and production may also affect environments in other ways that require attention from environmental groups, industry, and government. Cellulose acetate filters from cigarette butts do not rapidly biodegrade; thus, they are a relatively long-lasting environmental problem, especially in waterways and run-offs from urban environments. At least 4.5 trillion filter-tipped cigarettes are deposited annually somewhere in the world. Many will find their way into appropriate disposal facilities, but the CMC clean-up data suggest that a large number end up on beaches and in other aquatic environments. Smokers may not consider that a cigarette butt is litter, but these waste products seem to be ubiquitous. Perhaps because of the proliferation of restrictions on smoking in worksites and public places, it is common for building entrances to have a collection of cigarette butts nearby. These collections come in large part from smokers discarding cigarettes before they enter the building and from workers smoking on breaks. Some worksites have made special attempts to provide appropriate disposal facilities. Nevertheless, cigarette butts are frequently a source of urban blight and environmental pollution. In addition to the environmental contamination by cigarette butts, consumption waste left in ashtrays in the homes of smokers may be a source of poisoning for young children. In 1994-1996, the Rhode Island Department of Health identified 40 cases of cigarette butt ingestion among children aged 6 to 24 months as reported by the poison-control system in that state^ref. The cases of ingestion produced symptoms such as vomiting, gagging, and lethargy. The cigarette butt problem may be mitigated through several channels other than general tobacco control efforts. First, laws against littering could be better enforced relative to cigarette butts. Second, additional taxes could be levied on cigarette products that could be directed to environmental clean-up efforts for consumption and production waste. Third, the tobacco industry should improve the biodegradability of filters, reduce packaging waste, educate its customers about their responsibility to the environment, and strive to responsibly manage production waste in developing countries as well as developed countries. Fourth, administrators of worksites and public buildings should be encouraged or required to supply appropriate disposal mechanisms at all building entrances (this might even be cost-effective in terms of public image, janitorial costs, and fire prevention). Fifth, increased public awareness campaigns about the magnitude and prevention of tobacco consumption and production waste could be developed through partnerships between environmental groups, health organisations, and environmental protection agencies. Tobacco manufacturers, like other manufacturers in the United States and in other developed countries, generate several toxic chemicals as production waste. The EPA and other similar organisations in developed countries help assure that industry reports and manages such waste. However, it is not known what abatement procedures are being used in developing countries, where cigarette production capacity has rapidly increased in recent years. To meet the demands of emerging markets, it is likely that cigarette manufacturers will gravitate towards manufacturing venues where regulation is less stringent. In the absence of public awareness and governmental regulations, tobacco manufacturers may not address the problem of significant solid, liquid, airborne, and chemically toxic waste produced in cigarette manufacturing. Thus, it may be prudent for multinational health, trade, and economic agencies to raise environmental considerations related to tobacco production as a global health issue. Additional research is needed to quantify the environmental impact of both tobacco consumption and production waste. Tobacco is a hazardous product when used as directed, but there is also a hazard due to production and consumption waste deposited into the environment. Perhaps the tobacco industry should be held partly accountable for the environmental clean-up costs related to cigarette butts and totally responsible for abatement of hazardous wastes resulting from the manufacturing process. It has been increasingly held accountable for the medical care costs associated with treating tobacco-attributable illnesses. This accountability should extend beyond the provision of cigarette butt disposal devices to smokers, which is primarily a public relations gimmick. It should also extend beyond the borders of developed countries, where regulatory controls on manufacturing waste may actually be enforced, to developing countries, which are increasingly at risk for environmental contamination as cigarette production capacity in those countries expands^ref
Successful cancer treatment can be significantly compromised by continued tobacco use. Despite the importance of stopping smoking for all cancer patients, the diagnosis of cancer is underused as a teachable moment for smoking cessation. More research is needed to empirically test cessation interventions for cancer patients, and attention must be given to complex and unique issues when tailoring cessation treatment to these individuals^ref.
Smokers tend to have boozier nights out than non-smokers. A work, done in rats, shows that a heavy dose of nicotine can cut blood-alcohol levels in half. If cigarettes similarly lower intoxication in people, it could mean that smokers need to drink more than non-smokers to get the same buzz. Many studies have shown that smokers tend to drink more alcohol than non-smokers, and a number of reasons are proposed for this. People who indulge in one habit may be simply more inclined to indulge in another, and socially both habits tend to go hand-in-hand at pubs and parties. Researchers also know that both nicotine and alcohol trigger a release of the feel-good brain chemical dopamine, but that indulging too much in either habit can breed tolerance to the drugs and reduce this pleasurable reward. So heavy users of one may boost use of the other to help bring their dopamine response back up. The research suggests that nicotine also directly alters the potency of alcohol in the body. Wei-Jung Chen of Texas A&M University, College Station, first saw hints of this in 1998, in a study of newborn rats given alcohol and nicotine^ref. To mimic more closely the effect in human drinkers, Chen and his colleagues studied the effects of binge drinking in adult rats. They injected rats' stomachs with a dose of alcohol roughly equivalent to around 4-5 drinks in quick succession; enough to make their blood alcohol hit double the USA legal driving limit of 0.08%. The team also gave the animals a range of nicotine doses similar to those in the bodies of light, moderate or heavy smokers. In 'heavy smoking' animals, the nicotine slashed the rats' peak blood-alcohol level, which came about an hour after injection, in half. Blood alcohol of 'moderate smoking' animals dropped by around 30%, and animals mimicking light smokers were not affected^ref (Parnell S.E., West J.R.& Chen W-J.A. . Alcoholism: Clinical & Experimental Research, 30. 1 - 6 (2006)). A lower blood-alcohol level means less intoxication: the nicotine-dosed rats were less drunk than their colleagues. But smoking would not ameliorate the other effects of alcohol or prevent a hangover, because the toxic by-products of alcohol breakdown still remain in the body. Nicotine slows the emptying of the stomach, so more alcohol is broken down and less finds its way into the intestine where it mainly enters the bloodstream. In support of this idea, his group found that nicotine does not affect blood alcohol if the alcohol is injected directly into the abdomen, bypassing the stomach and going straight into the bloodstream. The researchers have not yet shown that the same thing happens in people, but it might be a factor in smokers' tendency to drink more. People should be aware that smoking could reduce the intoxicating effects of a drink and make some reach for an ill-advised second, third or fourth. The study may have other, worrying implications. If nicotine does slow stomach emptying, then it may also affect the rate at which other prescription or over-the-counter drugs are absorbed, and the overall impact of the drug. A lot of scientists focus on one drug, but in reality people are using both drugs together so we have to study them together
See also environmental tobacco smoke (ETS) / second-hand smoke / involuntary smoking
Laboratory examinations : NicCheck I: a dipstick method for analyzing nicotine and its metabolites^ref
Therapy : smoking cessation interventions :
• behavioral (counseling) : more intensive behavioral therapy is more effective and should be delivered when possible. Physicians should discuss with their smoking patients "relevance, risk, rewards, roadblocks, and repetition," and with patients who are willing to attempt to quit, physicians should use the 5-step system of "ask, advise, assess, assist, and arrange."


• pharmacologic :
• nicotine replacement therapy (NRT)^ref
• nicotine patches have been studied extensively in patients with stable CVD and have been shown to be safe
• non-nicotine medications
• sustained release bupropion (bupropion SR), an atypical antidepressant, has relatively few cardiovascular adverse effects and may be especially useful for patients with CVD; its safety is currently being studied
• D₃ receptor antagonists
• noradrenaline reuptake inhibitors (NRI)
• GABA_B receptor agonists
• mGluR5 antagonists
• CB₁ antagonists
• CRF1 receptor antagonists
• immunopharmacotherapy
• anti-nicotine vaccine
• anti-nicotine monoclonal antibody
• N receptors partial agonists
• interference with the liver enzymes metabolising nicotine is another approach who has just reached the testing phase
Special consideration is needed for hospitalized patients with acute coronary syndromes. The safety of pharmacotherapy in the acute setting is not yet established
Smoking reduction promotes smoking cessation. Smokers report an increase in upper respiratory infections in the early phase of stopping smoking. For the pre-smoking cessation measure a longer time since the last cigarette is significantly related to lower S-IgA levels. There is a significant decline in S-IgA, relative to pre-smoking abstinence levels, following abstinence of one day, but levels return to pre-abstinence values after 1 week. There is no evidence of any significant changes in saliva volume following smoking cessation, relative to pre-cessation levels. Users of 15 mg patches are likely to experience a decline in S-IgA levels on the first day of smoking cessation, independent of saliva volumes, and this decline in S-IgA is likely to occur acutely, within the first few hours of smoking abstinence. This acute drop in S-IgA appears to stem from a factor other than depletion of nicotine from the body. The observed decrease in S-IgA may help to explain the increased susceptibility of smokers to upper respiratory tract infections in the immediate post-cessation period^ref.
Prevention : changes in the lungs due to smoking include inflammation, epithelial damage, and remodeling of the airways. Airway inflammation is likely to play a critical role in the genesis and progression of tobacco smoke-induced airway disease. Soluble epoxide hydrolase (sEH) is involved in the metabolism of endogenous chemical mediators that play an important role in inflammation. Epoxyeicosatrienoic acids (EETs) have demonstrated antiinflammatory properties, and hydrolysis of these epoxides by sEH is known to diminish this activity. To examine whether acute tobacco smoke-induced inflammation could be reduced by a sEH inhibitor, 12-(3-adamantane-1-yl-ureido)-dodecanoic acid n-butyl ester was given by daily s.c. injection to spontaneously hypertensive rats exposed to filtered air or tobacco smoke for a period of 3 days (6 h/day). Acute exposure to tobacco smoke significantly increased by 3.2-fold (P < 0.05) the number of cells recovered by bronchoalveolar lavage. The sEH inhibitor significantly decreased total bronchoalveolar lavage cell number by 37% in tobacco smoke-exposed rats with significant reductions noted in neutrophils, alveolar macrophages, and lymphocytes. A combination of sEH inhibitor and EETs was more significant in its ability to further reduce tobacco smoke-induced inflammation compared with the sEH inhibitor alone. The sEH inhibitor led to a shift in some plasma epoxides and diols that are consistent with the hypothetical action of these compounds. An sEH inhibitor, in the presence or absence of EETs, can attenuate, in part, inflammation associated with acute exposure to tobacco smoke^ref.
The hospital discharge records of Piedmont region (northern Italy) were used to evaluate whether a national law banning smoking in public resulted in a short-term reduction in hospital admissions for acute myocardial infarction (AMI). Rates of admission for AMI before the ban (October–December 2004) and during the ban (February–June 2005) were analysed. Each period was compared with the corresponding period 12 months before. Among persons aged under 60, the number of admissions for AMI decreased significantly after the introduction of the ban: from 922 cases in February–June 2004 to 832 cases in February–June 2005 (sex- and age-adjusted rate ratio, 0.89; 95% confidence interval, 0.81–0.98). No decrease was seen before the ban. No effect was found among persons aged > 60. The observed reduction in active smoking after the introduction of the ban could account for a 0.7% decrease in admissions for AMI during the study period, suggesting that most of the observed effect (11%) might be due to the reduction of passive smoking. The study, based on a population of about 4 million inhabitants, suggests that smoke-free policies may result in a short-term reduction in admissions for AMI^ref.
A historic agreement to curb the millions of deaths caused each year by tobacco comes into force at the end of Feb 2005. The pact is the first international and legally binding treaty targeted at the use of tobacco. Tobacco kills nearly 5 million people every year, around 1 in 10 adults. It is the leading preventable cause of death. Whereas some countries have already successfully introduced measures to check smoking, the habit is rampant in others, such as China and India. The World Health Organization (WHO) Framework Convention on Tobacco Control aims to rein in tobacco's use and the harm it causes. Countries that ratify the treaty have to introduce regulations and restrictions such as health warnings on cigarette packets, limits on tobacco advertising and protections against secondhand smoke. The convention is the first legally binding treaty to be negotiated by the WHO; it normally relies on non-binding resolutions. The WHO Tobacco Free Initiative began work on the tobacco convention in 1999. It was adopted by member states in 2003, but required > 40 countries to ratify the agreement before it became law. When Armenia and Ghana did so in late November 2004, this triggered a 90-day countdown to the convention coming into force, on Sunday 27 February 2005. The treaty has now been ratified by 57 out of 192 member countries in the WHO, together representing about one-third of the world's population. Many more are expcted to join within the next few months, and the treaty is one of the fastest to be embraced in the United Nations. Even before it came into force, the treaty prompted many countries to implement measures to discourage smoking. Within 2004, for example, Ireland, Norway and Italy have introduced smoking bans in workplaces or public spaces. But public-health experts believe the agreement will strengthen and coordinate efforts made by individual countries, so they are better able to combat multinational tobacco companies and deal with problems that span country borders. For example, the treaty requires countries to stem the widespread practice of cigarette smuggling by clamping down on counterfeiting and improving tracking and accounting for products. Many countries now need money and support to help them enforce the new rules. For example, some nations lack a central office for tobacco control. The impact of the treaty on deaths from smoking may not be seen for 30 to 40 years. The new restrictions are expected to cut smoking-related deaths by around 1% per year, but it will take far longer for this decline to outweigh the growth in the world's population and the accompanying growth in the number of smokers.
Web resources :
• Action on Smoking and Health
• Tobacco at London School of Hygiene and Tropical Medicine
• Solanum
• Solanum tuberosum (a.k.a. potato)

=> 4-ipomeanol can cause extensive lung Clara cell necrosis and can increase the severity of pneumonia in mice
=> a-chaconine and a-solanine, AChE inhibitors. Most potatoes contain levels of about 2-13 mg solanine/100 g fresh weight of potato, but when the potato starts to "green" these levels increase to as high as 80-100 mg/100 g fresh weight. Most experts suggest that 20 mg/100 g should be the upper limit to assure safety of the potato and some data suggest that a dose of about 200 mg of solanine will cause problems. For the potatoes that most of us will encounter, it has been calculated that someone weighing 160 pounds would need to eat 3.2 pounds (about 9 normal sized potatoes) in one sitting to get a toxic dose of the chemical. Even if the potatoes contained the maximum amount of solanine considered safe (20 mg/100 g) the same 160 lb person would have to eat 4-5 whole potatoes to get sick. At maximum observed concentration of solanine (100 mg/100 g of potato) you would need to eat 200 grams or little less than 1 cup of mashed potatoes. Poisoning causes gastrointestinal (abdominal pain, diarrhea and nausea and vomiting) and neurological symptoms (apathy, drowsiness, mental confusion, dyspnea, tachycardia, systemic arterial hypotension). In very severe cases of alkaloid poisoning coma and death can result. Symptoms generally occur 8 to 12 hours after eating. Even in severe cases, recovery is usually complete in two to three days.
Cases of solanine poisoning that have been reported have occurred because someone ate a lot of really green potatoes, or made tea from tomato leaves. The greenish hue of potato skin is actually chlorophyll, but it is also an indicator that solanine, may be present under the skin of the potato. Solanine develops in potatoes when they are stored in the presence of light (which also encourages chlorophyll formation) and either at very cold or quite warm temperatures. Since solanine collects just under the skin, it is safe to peel away the skin and a thin layer of white flesh before you cook the potato. Solanine is also found in the sprouts. It is not soluble in water or destroyed by heating. Some potato varieties, no longer grown, could make excess solanine during unusual growing seasons without any external greening : because of its toxicity, the potato variety Lenape was withdrawn from the market.
• Lycopersicon
• Lycopersicon esculentum (a.k.a. tomato)

=> solanine in all parts except fruit
=> green tomatoes are quite high in tomatine, another glycoalkaloid that inhibits AChE.
• euasterids II
• Apiales
• Apiaceae
• Aegopodium
• Aegopodium podagraria (a.k.a. goutweed, bishop's weed, herb gerard)
• Ammi
• Ammi visnaga

=> visnagin
=> khellin, precursor for disodium cromoglycate (DSCG)
• Anethum
• Anethum graveolens (a.k.a. dill)

=> oil of dill : an oil distilled from the dried ripe fruits of Anethum graveolens, used as an aromatic carminative and as a source of carvone
• Angelica
• Angelica sinensis (a.k.a. tang-kuei, dong quai)

=> ?
• Apium
• Apium graveolens
• Apium graveolens var. dulce (a.k.a. celery)

=> linear furanocoumarin phytoalexins psoralen, bergapten, and xanthotoxin that can cause photosensitization and also are photomutagenic and photocarcinogenic
• Carum
• Carum carvi

=> caraway oil : a volatile oil distilled from the dried ripe fruit yielding at least 50% by volume of carvone; used as a flavoring agent for drugs and as a carminative.
• Cicuta
• Cicuta virosa

=> cicutoxin
• Conium
• Conium maculatum (a.k.a. hemlock, Socrates's major cicuta)

=> coniine is a Lys derivative
• Coriandrum
• Coriandrum sativum (a.k.a. coriander)

=> coriander oil : a volatile oil distilled with steam from the dried ripe fruit, used as a flavoring agent.
• Foeniculum
• Foeniculum vulgare (a.k.a. fennel)

=> fennel oil : a volatile oil distilled from the seeds, used as a flavoring agent for pharmaceuticals and formerly as a carminative
• Pastinaca
• Pastinaca sativa (a.k.a. parsnip)

=> linear furanocoumarin phytoalexins psoralen, bergapten, and xanthotoxin that can cause photosensitization and also are photomutagenic and photocarcinogenic
• Petroselinum
• Petroselinum crispum (a.k.a. parsley)

=> linear furanocoumarin phytoalexins psoralen, bergapten, and xanthotoxin that can cause photosensitization and also are photomutagenic and photocarcinogenic
• Thapsia
• Thapsia garganica

=> thapsigargin : a SERCA inhibitor
• Araliaceae
• Hedera spp.

=> nausea and vomiting
• Panax
• Panax ginseng (a.k.a. Korean ginseng)
• Panax notoginseng (a.k.a. tienchi, san-qi)
• Panax pseudoginseng
=> saponin glycosides (ginsenosides)
=> ginsenoids
=> polyacetylenes
=> sesquiterpenes
• Aquifoliales
• Aquifoliaceae
• Ilex
• Ilex guayusa
• Ilex paraguariensis (a.k.a. Yerba maté)
=> teine / caffeine / 1,3,7-trimethylxanthine / 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione / methyltheobromine / guaranine
• Asterales
• Asteraceae
• Asteroideae
• Anthemideae
• Artemisia
• Artemisia annua (a.k.a. qing hao or sweet wormwood or annual wormwood)

=> artemisin / qinghaosu
• Artemisia absinthium (a.k.a. wormwood)

=> thujone, a bicyclic terpene
• Artemisia vulgaris

=> moxa
•  Chamaemelum
• Chamaemelum nobile (a.k.a. Anthemis nobilis) is used to treat insomnia
• Chrysanthemum
• Chrysanthemum indicum (a.k.a. yejuhua, wild chrysanthemum)
• Chrysanthemum x morifolium (a.k.a. juhua)
=> sesquiterpenes
=> flavonoids
• Tanacetum
• Tanacetum cinerariifolium (a.k.a. Pyrethrum cinerariifolium, Chrysanthemum cinerariaefolium)

=> pyrethrum is an allergenic, crude extract containing the 6 naturally occurring pyrethrins (I-VI) :
• cinerins
• cinerin I
• cinerin II
• jasmolin I
• jasmolin II
• pyrethrin I
• pyrethrin II
They are voltage-gated Na⁺ channel activators used as insecticides themselves, precursors for the semisynthetic pyrethroids insecticides and precursors for the semisynthetic antiectoparasitary permethrin
• Astereae
• Gutierrezia : the broomweeds or snakeweeds, a genus of herbs that have yellow flowers
• Gutierrezia diversifolia and Gutierrezia sarothrae may cause selenium poisoning in livestock when growing in selenium-rich soil
• Gutierrezia microcephala causes abortion in pregnant female animals.
• Heliantheae
• Echinacea
• Echinacea angustifolia
• Echinacea pallida
• Echinacea purpurea (a.k.a. black sampson, cone-flower, red echinacea, rudbeckie, red grape)
root in the blooming stage of mid July is used as immunostimulant ranging from external application for wounds, burns and insect bites to the chewing of roots for toothache and upper respiratory tract infections, and internal application for pain, coughs, stomach cramps and snake bites, with over $200 million in sales in 2000. Although in vitro studies have shown that Echinacea constituents stimulate humoral and cellular immune responses, systematic reviews of the clinical trials have not concluded that they are beneficial. Extracts of Echinacea angustifolia root, either alone or in combination, do not have clinically significant effects on prophylaxis of infection with rhinovirus type 39 (beginning 7 days before the virus challenge)  or on the treatment of the clinical illness that results from it (beginning at the time of the challenge) : there were no significant effects of treatment on the volume of nasal secretions, on neutrophil or IL-8 concentrations in nasal-lavage specimens, or on quantitative-virus titer^ref. The dose equivalent of 900 mg of dried root derives from the German Commission E monograph for Echinacea pallida root, a different species from E. angustifolia. E. angustifolia root is not officially approved and thus has no recommended dosage in Germany, owing to a lack of sufficient supporting data. The 1999 World Health Organization monograph on E. angustifolia root cites a 3-g daily dose^ref
=> caffeic acid and its derivatives :
• cichoric acid / 2R,3R-O-dicaffeoyltartaric acid (1.35%) induces neutrophilia and monocytosis
• caftaric acid
•  2-O-feruloyl-tartaric acid
=> alkylamides
• dodeca-2E, 4E, 8Z, 10E/Z-tetraenoic acid isobutyl amide
=> polyacetylenes
=> polyamides
=> polyines
=> glycoproteins
=> chlorogenic acid
=> cynarin
=> echinacoside
=> 6-O-caffeoylechinacoside
=> verbascoside
=> ketoalkenes
=> polysaccharides
=> increased ACTH => antiinflammatory properties
=> inhibits hyaluronidase
Side effect : very rarely recurrent erythema nodosum
• Madieae
• Arnica : a genus of composite-flowered plants (family Compositae), known also as leopard's bane, wolf's bane, and mountain tobacco. The dried flowerheads of Arnica montana are called arnica / wolf's bane or wolfsbane and leopard's bane, contain arnicin, arnisterol, anthoxanthins, tannin, and resins and are used topically in tincture form for contusions, sprains, and superficial wounds, and as a counterirritant
• Senecioneae
• Senecio spp.

=> hepatotoxic pyrrolizidinic alkaloids (senecio disease)
• Tussilago
• Tussilago farfara (a.k.a. coltsfoot, mat'-i-machekha)

=> hepatotoxic pyrrolizidinic alkaloids
• Carduoideae
• Cardueae
• Arctium
• Arctium lappa (great burdock)

=> arctigenin, naturally occurring in Bardanae fructus, Saussurea medusa, Arctium lappa L., Torreya nucifera and Ipomea cairica, is a phenylpropanoid dibenzylbutyrolactone lignan with antioxidant and anti-inflammatory activities, which inhibits MAP kinases and AP-1 activation via potent MKK inhibition^ref. An appropriate formulation containing A. dahurica, rhizoma coptidis and G. glabra could be helpful for the prevention and treatment of acne lesions^ref. Arctium lappa (a.k.a. gobo) contains anticandidal activity^ref, anti-inflammatory and radical scavenge effects^ref, inhibitory activity against HIV^ref and a desmutagenic factor^ref. Burdock may cause allergic contact dermatitis (ACD)^ref and anaphylaxis^ref
• Carthamus
• Carthamus tinctorius (a.k.a. safflower)

=> safflower oil : an oily liquid extracted from the seeds; used as a dietary supplement in the management of hypercholesterolemia.
• Centaurea
• Centaurea cyanus (a.k.a. feverfew, daisy-plant or bachelor's button)

=> parthenolide, an antileukemic agent
• Campanulaceae
• Lobelia
• Lobelia inflata

=> lobeline : It is an agonist of N receptor.
• Dipsacales
• Adoxaceae
• Sambucus
• Sambucus ebulus

=> ebulin, a class I RIP
• lamiids
• lamiids incertae sedis
• Boraginaceae
• Borago
• Borago officinalis
• Cynoglossum spp.
• Heliotropium spp.
• Symphytum spp.
=> hepatotoxic pirrolizidinic alkaloids
• rosids
• malvids
• Sapindales
• Sapindaceae
• Litchi
• Litchi chinensis (a.k.a. lychee)
  => methylenecyclopropylglycine (MCPG), a compound that causes hypoglycemia in animal studies^{ref1, ref2, ref3} and hypoglycemic encephalopathy in humans in India^{ref1, ref2, ref3}, similar to hypoglycin A.
  

• rosids incertae sedis
• Vitales
• Vitaceae (grape family)
• Vitis
• Vitis sp. (a.k.a. grape)
Chronic ethanol ingestion is known to cause oxidative damage to a number of organs including the brain. This is partly due to the ability of ethanol to enhance oxygen free radical production and lipid peroxidation. Increase in oxidative stress has been regarded as an important underlying factor for a number of human health problems including cardiovascular diseases, aging, as well as many age-related neurodegenerative diseases. The strikingly lower incidences of coronary heart diseases (CHD) in people in France than in Britain or USA, despite eating a similar amount of saturated fat (a phenomenon known as the "French paradox"), have been attributed to the consumption of red wine containing high levels of ...
=> polyphenols / red wine polyphenolic compounds (RWPCs) (in the skin of red grapes; absent in white and rosée wines) are beneficial to circulatory disorders such as capillary fragility, peripheral chronic venous insufficiency, and microangiopathy of the retina. They inhibit formation of endothelin-1
• procyanidins : regular, moderate consumption of red wine is linked to a reduced risk of coronary heart disease and to lower overall mortality1, but the relative contribution of wine's alcohol and polyphenol components to these effects is unclear. Procyanidins are the principal vasoactive polyphenols in red wine and are present at higher concentrations in wines from areas of southwestern France and Sardinia, where traditional production methods ensure that these compounds are efficiently extracted during vinification. These regions also happen to be associated with increased longevity in the population^ref
• proanthocyanidins
• prodelphinidins
• tannins
• ellagitannins
• acutissimin A (discovered 16 years ago in the bark of the sawtooth oak) and closely related compounds form in red wine as it ages in oak barrels (in the lab it is made by reacting vescalagin, extracted from oak wood, with the flavanoid catechin from grapes). The precise mixture of these compounds in red wine changes as it ages : this not only affects its taste, but also alters the potential pharmacopeia that it harbours. It inhibits DNA topoisomerase II 250 times more potent than etoposide, preventing the growth of cancerous cells
• resveratrol (red wine) : in diverse organisms, calorie restriction slows the pace of ageing and increases maximum lifespan. In Saccharomyces cerevisiae, calorie restriction extends lifespan by increasing the activity of Sir2, a member of the conserved sirtuin family of NAD⁺-dependent protein deacetylases. Included in this family are sir-2.1, a Caenorhabditis elegans enzyme that regulates lifespan, and SIRT1, a human deacetylase that promotes cell survival by negatively regulating the p53 tumour suppressor. Resveratrol lowers the K_M of SIRT1 for both the acetylated substrate and NAD⁺, and increases cell survival by stimulating SIRT1-dependent deacetylation of p53. In yeast, resveratrol mimics calorie restriction by stimulating Sir2, increasing DNA stability and extending lifespan by 70% (normally, the organism divides around 25 times and then dies. Resveratrol-treated yeast underwent an extra 15 replications). To match the yeast doses humans would need to drink a glass of their favourite vintage morning, noon and night. ^ref.
Polyphenols also react with components of saliva to produce the astringency that gives red wine its distinctive taste
• Caryophyllidae
• Caryophyllales
• Cactaceae
• Cactoideae
• Browningieae
• Stetsonia
• Stetsonia coryne (Toothpick cactus)
• Cacteae
• Lophophora
• Lophophora williamsii (a.k.a. Mexican dumpling cactus, mescal, peyotl, pellote, peyote)

=> mescal buttons : transverse slices of the flowering heads, whose major active principle is mescaline; used in divinatory and religious ceremonies in some North American Indian cultures.
• Pelecyphora
• Pelecyphora aselliformis
• Pachycereeae
• Stenocereus spp.
• Stenocereus beneckei
• Stenocereus eruca
• Stenocereus stellatus
• Stenocereus treleasei
• Trichocereeae
• Gymnocalycium spp.
• Gymnocalycium gibbosum
• Trichocereus
• Trichocereus bridgesii
• Trichocereus candicans
• Trichocereus chiloensis
• Trichocereus cuzcoensis
• Trichocereus fulvilanus
• Trichocereus macrogonus
• Trichocereus pachanoi (San Pedro)
• Trichocereus peruvianus (Peruvian torch cactus)
• Trichocereus spachianus
• Trichocereus strigosus
• Trichocereus taquimbalensis
• Trichocereus terscheckii
• Trichocereus validus
• Trichocereus werdermannianus
• Opunctioideae
• Opuntia spp.
• Opuntia acanthocarpa
• Opuntia basilaris (Beavertail cactus, beavertail pricklypear)
• Opuntia echinocarpa (Silver cholla, staghorn cholla)
• Opuntia ficus-indica
• Opuntia imbricata
• Opuntia spinosior
• Pereskiopsis spp.
• Pereskiopsis scandens
• Pereskiodeae
• Pereskia spp.
• Pereskia corrugata
• Pereskia tampicana
=> mescaline (3,4,5-trimethoxyphenethylamine)

=> N-acetylmescaline
=> N-methylmescaline (benzenethanamine,3,4,5-trimethoxy-N-methyl-)
=> pellotine
=> hordenine
=> anhalonine
Islaya minor
Polaskia chende
Pterocereus gaumeri
• Caryophyllaceae
• Dianthus
• Dianthus barbatus

=> dianthin 29, a class I RIP
• Dianthus caryophyllus (clove pink)

=> dianthin 30, a ribosome-inactivating protein (RIP)
=> dianthin 32, a ribosome-inactivating protein (RIP)
• Saponaria
• Saponaria officinalis (a.k.a. common soapwort)

=> saporin S6, a class I RIP
=> saporin L1, a class I RIP
• Chenopodiaceae
• Spinacia
• Spinacia oleracea (a.k.a. spinach)

=> cyanhydric acid (HCN)
• Phytolaccaceae
• Phytolacca
• Phytolacca americana (a.k.a. Virginian or common pokeweed)

=> pokeweed antiviral protein (PAP) a, a class I RIP. In seeds as PAP-S.
=> pokeweed lectin B (PL-B) / pokeweek mitogen (PWM)
=> nausea and vomiting
• Polygonaceae
• Polygonum
• Polygonum capitatum

=> relinqing granules are powder of extract
• Rheum
• Rheum x cultorum (a.k.a. rhubarb)

=>barbaloin
• Rheum undulatum

=> rhaponticin is an immunosuppressant stilbene from the rhizome
• Rosidae
• eurosids I
• Celastraceae
• Catha
• Catha edulis (a.k.a. qat, khat, Somali tea)

=> cathinone,  an akaloid similar to amphetamine widely chewed in East Africa and Yemen
• Maytenus spp.

=> maytansine, an ansamacrolid
• Salacia
• Salacia oblonga which is native to regions of India and Sri Lanka, binds to and inhibits intestinal a-glucosidase. The largest dose of the herb extract - 1,000 mg - decreased insulin and blood glucose levels by 29% and 23%, respectively. While the test beverages caused an increase in breath hydrogen excretion, reports of gastrointestinal discomfort were minimal^ref. It is still relatively difficult to find in the United States, Hertzler said, although there are manufacturers that sell the herb through the Internet.
• Cucurbitales
• Coriariaceae
• Coriaria
• Coriaria sarmentosa, a plant of New Zealand

=> toot poison : a poison
• Cucurbitaceae
• Bryonia
• Bryonia dioica (a.k.a. red bryony)

=> bryodin, a class I RIP
• Momordica
• Momordica charantia (a.k.a. balsam pear)

=> momordin I / a-momorcharin, a class I RIP
=> b-momorcharin, a class I RIP almost identical with the anti-tumor and anti-HIV-1 protein MAP30
• Trichosanthes
• Trichosanthes kirilowii (a.k.a. Mongolian snake-gourd)

=> a-trichosanthin, a class I RIP
• Fabales
• Fabaceae
• Caesalpinioideae
• Caesalpinieae
• Caesalpinia
• Caesalpinia coriaria (Jacq.) Willd., plants of South America

divi-divi : the leguminous pods; the seeds contain tannin and gallic acid and have been used as an astringent and in tanning.
• Cassieae
• Cassia
• Cassia angustifolia (a.k.a. Tinnevelly senna, India senna)
• Cassia senna (a.k.a. Cassia acutifolia, Alexandrian senna)
=> senna consists of dried leaflets or fruits containing rhein dianthrone glycosides :
• sennoside A
• sennoside B
• Mimosoideae
• Acacieae
• Acacia
• Acacia berlandieri

=> N-methly-b-phenyl ethyl amines and tyramine are the toxic agents in , which also causes a similar clinical picture and has been the cause of human intoxication in Mexico and other South American countries
• Acacia longifolia (Sydney golden wattle, golden wattle, long-leaved wattle, long-leaved acacia, sallow wattle, coast wattle, golden rods)
• Acacia phlebophylla (Buffalo sallow wattle)
• Mimoseae
• Anadenanthera
• Anadenanthera colubrina (a.k.a. yopo, cohoba, vilca)

=> 5-MeO-DMT
=> bufotenine
• Anadenanthera peregrina
• Mimosa spp.
• Mimosa hostilis (a.k.a.  jurema, Mimosa tenuiflora; "tepescohuite")
=> N,N-dimethyltryptamine (DMT)

Virola calophylla
• Papilionoideae
• Abreae
• Abrus
• Abrus precatorius (a.k.a. Indian licorice)

=> abrin, a class II RIP
• Arachis
• Arachis hypogaea (peanut)

=> peanut oil / arachis oil / groundnut oil : the refined fixed oil used as a solvent and oleaginous vehicle for drugs, and as a laxative in veterinary medicine
• Crotalarieae
• Crotalaria

=> hepatotoxic pyrrolizidinic alkaloids
• Dalbergieae
• Andira
• Andira araroba (a.k.a. Voucapoua araroba)

=> Goa powder / Araroba powder / Bahia powder / Brazil powder / Ringworm powder, whose active ingredient is chrysarobin Galegeae
• Astragalus
• Astragalus membranaceus

=> calycosin
=> 10-hydroxy-3, 9-dimethoxypeterocarpan
=> (3R) 8,2'-dihydroxy-7,4'-dimethoxyisoflavan
=> formonenetin (7-hydroxy-4'-methoxyisoflavone)
=> 8,3'-dihydroxy-7,4'-dimethoxy-isoflavone
=> 2'-hydroxy-3', 4'-dimethoxyisoflavan-7-O-glucopyranoside and
=> alycosin (7,3'-dihydroxy-4'-methoxyisoflavone)
=> astragaloside IV
• Glycyrrhiza spp. (a.k.a. licorice)
• Glycyrrhiza glabra (a.k.a. gancao)
• Glycyrrhiza uralensis
=> estrogen receptor binders (isoflavone formononetin)
=> flavonoids and isoflavonoids, coumestans, coumarins
=> carbenoxolone, which is traditionally used to soothe ulcers, improves by 10% mental functioning in healthy elderly men and cognitively impaired patients with type 2 diabetes mellitus by lowering levels of cortisol in the brain^ref.
=> triterpene glycosides
• sitosterol
• stigmasterol
• glycyrrhizic acid / glycyrrhizinic acid / glycyrrhizin / glycyrrhetinic acid glycoside(inhibitor of 11b-hydroxysteroid dehydrogenase 2 (HSD11B2) =hydrolysis by bacterial enzymes in intestinal flora=> diglucuronic acid + aglicone glycyrrhetic acid (GA) (a 200-1000 times more potent inhibitor of HSD11B2 compared to glycyrrhizic acid) => glycyrrhetic acid monoglucuronide (GAMG). They are used as antivirals but can cause secondary systemic arterial hypertension and hypokalemia by inhibiting aldosterone catabolism
• Genisteae
• Cytisus
• Cytisus laburnum (a.k.a. maggiociondolo, citiso alpino)

=> ?
• Lupinus spp.

=> lupinosis : acute atrophy of the liver, often fatal, in ruminants such as cattle, sheep, goats, and horses, due to the ingestion of seeds that are contaminated with the fungus Phomopsis leptostromiformis
• mycotoxic lupinosis :  poisoning of livestock due to ingestion of Lupinus plants contaminated with the fungi Phomopsis leptostromiformis or Phomopsis rossiana; symptoms include liver damage with jaundice and photosensitization. Lupinosis is caused by a mycotoxin produced by a fungus that grows on the stubble animals graze upon. The fungus grows when the conditions are correct -- generally warm moist conditions following summer rains. Lupines are often raised as a cash crop in Australia, and it is customary for the animals to graze the stubble. Sheep are most often affected, but cattle, horses, and donkeys have also been affected. Although goats may be affected and can be experimentally infected, it is not the usual field condition to see affected goats. Affected sheep have a depressed appetite, lag behind during gathering, and are ataxic. Generally the mucous membranes in the mouth and eyes may be a bit yellow, as the animals are often jaundiced. Death follows quickly from this stage. Cattle may be affected by the same mycotoxin, but the mycotoxin must be consumed by the animal; it is not transmitted between animals. Treatment for affected animals is immediate withdrawal from fields containing lupines. Good-quality hay (without lupines), access to shade, rest, and clean water are important. Some veterinarians recommend other measures depending upon severity. The livers of these animals are affected; though the liver may regenerate, it is a slow process.
• Millettiaeae
• Derris spp. : a genus of woody vines, native to Australia and other islands of the southern Pacific
• Derris elliptica yields the toxic insecticide rotenone.
• Lonchocarpus spp.
• Tephrosia spp.
=> rotenone : it is used as a botanical piscicide
• Phaseoleae
• Erythrina spp.

=>erythroidines : they are antagonist of N receptors.
• Glycine
• Glycine max (a.k.a. sooybean)

=> cyanhydric acid
• Mucuna
• Mucuna pruriens

=> N,N-dimethyltryptamine (DMT)
• Physostigma venenosum (a.k.a. Calabar bean, ordeal bean, esere nut)

=> eserine / physostigmine inhibits AChE and served as model compound for the development of the carbamate insecticides.
• Trifolieae
• Medicago
• Medicago sativa
• Medicago sativa subsp. sativa (a.k.a. alfalfa)

=>L-canavanine (LCN) is a prominent non-protein cationic amino acid constituent of alfalfa sprout seeds and may cause SLE-like disease by affecting B-cell function.
• Melilotus
• Melilotus officinalis

=> dicoumarin
• Trifolium
• Trifolium pratense (a.k.a. red cloves, purple cloves, rotklee)

=> isoflavones
• biochanin
• genistein
• formononetin
• daidzein
• Vicieae
• Lathyrus spp.
• Lathyrus cicera (a.k.a. flat-pod pea)
• Lathyrus clymenum (a.k.a. Lathyrus articulatus, Spanish vetch)
• Lathyrus savita (a.k.a. vetch, the Indian sweet pea, or green vetch)
=> b-aminopropionitrile, or other aminonitriles
• lathyrism
• osteolathyrism
• Vicia
• Vicia faba (fava bean)

=> divicine : a toxic pyrimidine aglycone produced by endogenous degradation of vicine by b-glucosidase in fava beans; it is believed to be important in the pathogenesis of favism [Italian fava bean], an acute hemolytic anemia caused by ingestion of fava beans or inhalation of the pollen of the plant, occurring in susceptible individuals usually as a result of a hereditary deficiency of glucose-6-phosphate dehydrogenase in erythrocytes
• Fagales
• Fagaceae
• Quercus
• Quercus coccifera
• Quercus suber (a.k.a. cork oak)
• Quercus petraea (a.k.a. sessile oak, durmast oak)
=> ellagitannins
• 2,3-(S)-hexahydroxydiphenoyl-glucose
• pedunculagin
• vescalagin
• castalagin
=> flavanoellagitannins
• acutissimin A
• acutissimin B
• eugenigrandin A
• guajavin B
• stenophyllanin C
• phillyraeoidin A
=> procyanidinoellagitannin
• mongolicanin
• Malpighiales
• Clusiaceae
• Hypericum spp. (a.k.a. Saint John's weed or St.John's wart)
• Hypericum perforatum
=> hypericin
=> hyperforin (antidepressant) depletes synaptic vesicles content and induces compartmental redistribution of nerve ending monoamines
Extracts :
• extract LI 160
• extract WS 5570
Several Studies have shown that St. John's Wort is at least as effective as TCAs and SSRIs in the treatment of depression. It is thought to alleviate mild to moderate depression and is used widely among cancer patients. In the treatment of moderate to severe major depression, 900 mg/day hypericum extract WS 5570 3 times a day  is at least as effective as 20 mg paroxetine once a day for 6 weeks and is better tolerated. In initial non-responders doses were increased to 1800 mg/day hypericum or 40 mg/day paroxetine after two weeks^ref. Among the most popular herbal product worldwide, numerous small studies and systematic reviews suggested it to benefit patients with a wide range of depressive syndromes. High-quality, randomized, placebo-controlled trials, found St.-John's-wort to not be superior to placebo for treatment of major depression of moderate severity, a spectrum of illness that clearly warrants professional evaluation and treatment. Of all the SSRIs, Seroxat has the worst reputation, with survivors groups around the world, accusations of a link with suicide, law suits, and enough adverse event reports to cause regulators around the world to alter their safety advice. Anyway it upregulates expression of the pregnane X receptor, a promiscuous nuclear regulatory factor that promotes the expression of many hepatic oxidative, conjugative, and efflux enzymes (e.g. P-glycoprotein) engaged in drug and food metabolism, lowerig the plasma concentration of indinavir, irinotecan, cyclosporine, etoposide, tamoxifen, paclitaxel, .. The fact remains that St. John's Wort can have unpleasant side effects, and can be fatal if combined with some blood pressure drugs.
• Erythroxylaceae
• Erythroxylum
• Erythroxylum coca

=> chewed coca leaves : the alkaloidal cocaine is slowly absorbed through the buccal mucosa => lower plasma levels => little, if any, abuse or dependence despite use over thousands of years by natives of the Andes mountains
=> cocaine / methylbenzoylecgonine

• oral route
• nasal route (sniffed)
• cocaine hydrochloride powder
• nasal route (sniffed)
• intravenous route
• alkaloidal cocaine / free base (a.k.a. "crack", from the noise produced by crystal sublimation;  lower fusion point => smoked vapors => large surface area for absorption into the pulmonary circulation, bypassed hepatic first-pass effect => higher plasma levels)
• "speedball" in combination with heroin
It inhibits DAT, NET, SERT and MAO (indirect orthosympathetic agonist) and blocks voltage-gated Na⁺ channels. It also acts as a mutagen.
Catabolism :

When cocaine and ethanol are taken concurrently, some cocaine is transesterified to cocaethylene, which blocks DAT and may lead to death.
Epidemiology : a study of drug chemicals in sewage water suggests that the level of cocaine use could be many times the figure suggested by questionnaires. Ettore Zuccato of the Mario Negri Institute for Pharmacological Research in Milan and his colleagues took river and sewage samples from 4 medium-sized Italian cities. They analysed these samples for cocaine and its main metabolite, benzoylecgonine, which is found in urine. They then scaled this up to estimate the total amount of drugs travelling through the water system in a day, using figures of overall water flow. This approach revealed that the 5 million people living around the Po, Italy's largest river, consume 4 kg of cocaine each day. This translates into at least 40,000 daily doses of this drug, or about 200,000 lines of cocaine^ref. In contrast, a 2001 survey by the Italian Welfare Ministry indicated that the roughly 1.5 million young adults living near the river take cocaine > 15,000 times a month. In the survey, 1.1% of those aged 15-34 admitted to having used cocaine at least once in the preceding month. It is the first time that a community's drug abuse has been measured in this way, though the same technique has been used in 2000 to measure the amounts of medications such as antibiotics in river and sewage waters^ref. The levels were as expected or lower. The researchers now plan to search for other illegal drugs in waste water, although some drugs might be difficult to distinguish from legitimate pain relief medication. It will be difficult to distinguish between heroine and morphine because there are similar metabolites. Other drugs, such as marijuana, produce too few stable metabolites to be easily detected in sewage and river water.
Symptoms & signs :
• acute toxicity : anxiety, loquacity, excitation, tachycardia, dyspnea, nausea and vomiting, abdominal pain, convulsions, cardiac arrhythmias, myocardial ischemia, toxic myocarditis, secondary pulmonary and systemic arterial hypertension => aortic dissection, cerebral vasoconstriction, and seizures, premature labor and abruptio placentae.
• chronic toxicity : severe psychic but no physical dependance
Cocaine-addicted rats that had been denied the drug for 3 weeks produce increased levels of AGS3 in the prefrontal cortex, which is linked to the brain's motivational circuitry. AGS3 interfers with G-proteins, which communicate with other brain areas involved in motivation : this fits with the idea that recovering addicts have skewed interests, for example becoming more excited by their drug than by the prospect of sex
Levamisole is a veterinary antihelminthic previously used as an immunomodulator in rheumatoid arthritis and as adjuvant therapy in the treatment of colorectal cancer. It is no longer available in North America for human use but is available in the United States and South America for veterinary administration. Since 2004, pharmaceutical agents have been found in cocaine supplies in North America and Europe^ref. Levamisole contaminated 30% of cocaine seized by the U.S. Drug Enforcement Agency from July to September 2008 (U.S. Department of Justice, Drug Enforcement Administration. Cocaine Signature Program Report. January–October 2008. Internal document.) and 11% of cocaine samples tested in Alberta, Canada, from April to December 2008 (Office of Research and Surveillance, Health Canada. Personal communication.). Levamisole causes reversible agranulocytosis in up to 20% of cases, and this has been reported in 5 patients using cocaine adulterated with levamisole^ref. Cocaine achieves its psychoactive effects by increasing dopamine concentrations in the euphoric centers of the brain, and animal studies have found that levamisole also increases dopamine levels in these regions^ref. Levamisole may potentiate the euphoric effects of cocaine by further increasing brain dopamine levels. Prompt urine toxicology testing is essential because levamisole has a short-elimination half-life of 5.6 hours^ref and little of the parent drug (2% to 5%) is detected in urine^ref. In addition, cocaine metabolites are detected up to 3.4 days on average after last use^ref. Because levamisole is not detected by routine immunoassay toxicology screening tests, other techniques, such as GC/MS, are required.
Web resources :
• Cocaine anonymous
• Cocaine at NIH
• Euphorbiaceae
• Crotonoideae
• Crotoneae; Croton
• Croton sublyratus

=> diterpene esters (among which are phorbol esters) are potent irritants and cocarcinogens :
• 4-a-phorbol 12,13-didecanoate (4-a-PDD)
• 12-O-hexadecanoyl-16-hydroxyphorbol-13-acetate (HHPA)
• phorbol-12,13-dibutyrate (PDBu)
• phorbol myristoyl acetate (PMA) / 12-O-tetradecanoyl phorbol-13-acetate (TPA) : it mimics cellular 1,2-diacylglycerol (DAG).
• Croton tiglium

=> croton oil : the thick, fixed oil of the seeds used as a drastic purgative and counterirritant, unsafe for human use, and is used as a standard irritant in pharmacological research.
=> crotonism : poisoning of humans or other animals by croton oil, characterized by burning of the mouth and sometimes emesis with severe diarrhea and colic; it may be accompanied by headache, somnolence, vertigo, prostration, and collapse, with death from circulatory or respiratory failure
• Gelonieae; Gelonium ; Gelonium multiflorum (a.k.a. Euphorbiaceae himalaya)

=> gelonin, a class I RIP
• Manihoteae; Manihot ; Manihot esculenta (a.k.a. cassava, ubi kayu, manioc, tapioca, yuca) is the most important food crop in the humid and semi-humid tropics and subtropical countries. Cassava is a root crop widely consumed in the Philippines as well as in Africa and South America. Although it originated in Brazil (where it is called manioc), it was brought to Africa by Portuguese colonists, and it is now an important crop there and in Indonesia and Southeast Asia. It is the principal source of nutrition for about 500 million people. Its leaves are edible, but the prize is its starchy root, rich in protein, minerals, and vitamins A, B and C. Cassava is used in a vast variety of cakes, snacks, and desserts and grows wild in many places, being tough and drought-resistant. In a country where hunger is now a reality for many poor households, cassava is among those food crops that can make the crucial difference between starvation and survival. Cassava roots are excellent sources of energy, while the leaves, which are also cooked and eaten, contain vitamins A and C, calcium, protein, and iron.  The cassava plant is the world's 3rd most important crop. Cassava enters the North American diet also -- as it is made into tapioca. 'Kokonte' (also known as lapiwa or face-the-wall) is a food made from cassava : for unknown reasons, it is said that people who eat it outside hide from passerbys by facing the wall.

=> cyanogenic glucosides / cyanoglucosides are hydrolized by the enzyme linamarase, with liberation of cyanohydrins that can break down to highly toxic hydrogen cyanide.
• linamarin / a-hydroxyisobutyronitrile-b-D-glucopyranoside => regular long-term exposure to sublethal quantities, ingested or inhaled during cooking, can cause epidemic spastic paraparesis / konzo / tropical ataxic neuropathy (TAN) : unmetabolized linamarin is transferred to the brain and transported into neural cells via a glucose transporter; alternatively it can be enzymatically converted to cyanide by bacteria in the intestine, and this is absorbed into the blood and then damages neural cells); worsening of iodine deficiency; disorders such as goiter and cretinism; and increased risk of diabetes.
• =deglycosylation=> acetone cyanohydrin=spontaneously at pH > 5. 0 or catalyzed by hydroxynitrile lyase (HNL, present in all cassava tissues except roots and stems)=> cyanide + acetone
• lotaustralin
When ingested, hydrogen cyanide can lead to acute intoxication and death. Normally, the more bitter cultivars of cassava are processed, and traditional processing (including combinations of several methods -- peeling, slicing, soaking, retting, fermenting, boiling, drying, and roasting among others) lowers cyanide contents to safe levels. Loss of cyanoglucosides in gari (the most popular cassava food in West Africa eaten by soaking its granules in cold water or by adding boiling water to make a food called eba) during short-term storage and when gari is made to eba will reduce dietary cyanide load in consumers. Because of changing socioeconomic situations (such as famine and war), people are often unable to follow traditional preparation methods because they tend to be very time-consuming. This change in preparation procedures leads to an increase in related diseases. Also, since bitter cultivars usually have higher yields, they account for a growing share of cassava cultivation. Reviewing cassava toxicity reports produces the observation that almost all are from the African continent, but reports do occur from Asia^ref. Surprising for an important edible plant, cassava is quite poisonous  without proper preparation. The toxin in cassava is called linamarin. When eaten raw or inadequately prepared, the human digestive system will convert this to cyanide. Even 2 cassava roots contain a fatal dose of poison. While the bitter variety (white cassava) of the plant has larger concentrations of cyanide than the sweet variety (yellow cassava), the sweet cassava is not without risk. To prepare cassava, it is peeled and grated and soaked in warm water for several days. This allows the cassava's own natural enzyme (linamarase) to convert the cyanogen linamarin to sugar and cyanide gas, and the volatile gas disperses usually harmlessly. However, women -- who are usually charged with processing the plant -- can be sickened by inhaling cyanide gas. What remains after processing can be boiled and eaten, or more usually, dried and ground. The shelf life of a cassava root is quite short once it is removed from the stem, so there's an urgency to get the food to market. Roots can turn to mush in less than a week.  The rush to get cassava to the market may keep some batches of cassava from being processed properly.
Symptoms & signs resulting from exposure to nonlethal concentrations of cyanide include breathing difficulties, nervousness, vertigo, headache, nausea, vomiting, precordial pain, and electrocardiogram (EKG) abnormalities.
• chronic, low-level cyanide exposure is associated with the development of goiter and with tropical ataxic neuropathy, a nerve-damaging disorder that renders a person unsteady and uncoordinated
• severe cyanide poisoning, particularly during famines, when there is obviously pressure to process the cassava more rapidly, is associated with outbreaks of a debilitating, irreversible paralytic disorder called konzo and, in some cases, death.
The incidence of konzo and tropical ataxic neuropathy can be as high as 3% in some areas of Africa.
Prevention : in an effort to avoid this toxicity, it has been reported by Siritunga and Sayre^ref that transgenic cassava free of cyanogens can be produced.  The investigators generated transgenic plants in which cytochrome oxidase enzymes that catalyze the 1st step in linamarin synthesis are inhibited. The plants showed a 94% reduction in leaf linamarin content and a 99% decrease in root linamarin levels. Additionally, the same group (Siritunga D, Arias-Garzon D, White W, Sayre RT: Over-expression of hydroxynitrile lyase in transgenic cassava roots accelerates cyanogenesis and food detoxification.  Plant Biotechnol 2004; 2:37-43) has reported that transgenic cassava plants can be produced that overexpress the gene for hydroxynitrile lyase, facilitating cyanogenesis during processing and producing a final product with less risk. The tubers of cassava do not have this enzyme, and processing relies on spontaneous conversion. Combining these methods could further decrease the risk of cyanide poisoning from cassava. The mechanism of rapid deterioration relates to the inevitable traumatic consequences of harvest. The trauma initiates a chain of events leading to spoiling, which often precedes invasion by any microorganism. The phenylpropanoid pathway seems integrally involved in this. Genetic manipulation of the system may be useful in slowing deterioration.
• Euphorbioideae
• Euphorbieae; Euphorbia spp. (spurges)
• Euphorbia lagascae

=>trans-3,4,3',5'-tetrahydroxystilbene / piceatannol in seeds
=> nausea and vomiting
• Euphorbia tirucalli

=> Burkitt's lymphoma
• Hippomaneae; Homalanthus ; Homalanthus nutans (a.k.a. Samoan native mamala tree) :

=> prostratin from the bark is a unique phorbol ester that stimulates membrane translocation of classical, atypical, and expecially novel protein kinase C (PKC) isoforms but is nontumor promoting and has long been used by native healers in the 2-island Pacific nation, which is inhabited by fewer than 200,000 people, to treat hepatitis. It is also active against HIV
• Ricinus (the name is derived from a word for tick and the seeds actually can appear to look like an engorged tick); Ricinus communis (a.k.a. castor bean) is native to Africa but is now grown in many areas of the world and can be used as a house or backyard plant. The plants and the seeds (attractively mottled and used to make necklaces) are available on the Internet


=> triglyceride of ricinoleic acid / castor oil, hydrolized in small bowel to glycerol and ricinoleic acid (used as irritant laxatives).
=> ricin is a disulfide-bound class II RIP which shows similar affinity for both Gal and GalNAc, but it has little affinity for terminal sialic acid sequences for which MLI also has some affinity. It is considered by CDC as a category B biological weapon. There have been >750 cases of documented ricin intoxication in humans^ref. It is likely that ricin was used in the Iran-Iraq war during the 1980s and that quantities of ricin were found in Al Qaeda caves in Afghanistan. Ricin is a phytotoxin that is easily derived from the waste mash from castor oil production, produced from castor beans (actually they are seeds) which come from soft-spined fruits : it can contain as much as 5% ricin. > 750 cases of intoxication in humans have been described. Although ricin's lethal toxicity is approximately 1000-fold less than that of botulinum toxin, ricin may have significance as a biological weapon because of its heat stability and worldwide availability, in massive quantities. There is a 100-fold variation in the lethal toxicity of ricin for various domestic and laboratory animals, per kilogram of body weight
• chicken and frog are least sensitive
• the horse is the most
Toxicity of ricin also varies with route of challenge. In laboratory mice, the approximate LD₅₀ and time to death are, respectively :
• 3-5 mg/kg and 60 hours by inhalation
• 5 mg/kg and 90 hours by intravenous injection
• 22 µg/kg and 100 hours by intraperitoneal injection
• 24 µg/kg and 100 hours by subcutaneous injection
• 20 mg/kg and 85 hours by intragastric administration
The clinical signs, symptoms, and pathological manifestations of ricin toxicity vary with the dose and the route of exposure :
• cutaneous contact with ricin is inocuous but if injected systemically, it can be lethal. Castor seed constituents are highly antigenic. Contact dermatitis and even anaphylaxis has been reported after contact with castor seed necklaces. Hypersensitivity symptoms have occurred in workers in castor oil factories, merchant seamen and dock workers who may be directly or indirectly exposed to sacks of the seeds, felt industry workers (derivatives of the seed may be used in felt manufacture) and even in those with latex allergy (the plants are in the same Euphobiaceae family)
• ingestion causes gastrointestinal signs and gastrointestinal hemorrhage with necrosis of liver, spleen, and kidneys. Exposures due to ingestion of ricin have not been reported. Due to poor absorption, lethality is less than with inhalation. The clinical presentation is most likely similar to that observed with castor bean ingestion : the oil itself does not contain the toxin but the bean itself if chewed and ingested can produce a significant hemorrhagic enteritis which can be, but is not usually, fatal^ref.
• intramuscular intoxication causes severe localized pain, muscle and regional lymph node necrosis, and moderate involvement of visceral organs
• inhalation results in respiratory distress and airway and pulmonary lesions; although data on aerosol toxicity exposure are not available for humans, lesions induced by oral and parenteral exposure are consistent with those seen in experimental animal studies, suggesting that the same would hold true for aerosol exposures. The only information on inhalation of ricin in humans is an allergic syndrome reported in workers accidentally exposed to sublethal castor bean dust in or around castor oil processing plants in the 1940s : 4-8 hours after exposure with fever, cough, shortness of breath and nausea. Studies in rodents suggest an inhaled ricin aerosol could lead to necrosis of the upper and lower airway, respiratory distress syndrome and respiratory failure. Chest x-ray would be expected to show bilateral infiltrates. In animal studies death occurred in 36 to 72 hours and was dose dependent. In a recent study of nonhuman primates^ref, inhalational toxicity was characterized by a dose-dependent preclinical period of 8 to 24 hours, followed by anorexia and progressive decrease in physical activity. Death occurred 36 to 48 hours after the challenge, time to death also being dose dependent. All monkeys had acute marked-to-severe fibrinopurulent pneumonia, with variable degrees of diffuse necrosis and acute inflammation of airways. There were also diffuse, severe alveolar flooding and peribronchovascular edema, acute tracheitis, and marked-to-severe purulent mediastinal lymphadenitis. 2 monkeys had acute adrenalitis

Symptoms & signs : sudden onset of congestion of the nose and throat, itchiness of the eyes, urticaria, and tightness of the chest. In more severe cases, wheezing, leading to bronchial asthma, may also occur, and may last for several hours. Affected individuals respond to symptomatic therapy and removal from the source of exposure
Differential diagnoses of aerosol exposure to ricin would include staphylococcal enterotoxin B, exposure to pyrolysis by-products of organofluorine polymers (e.g., Teflon [polytetrafluoroethylene, manufactured by Du Pont Polymers, Wilmington, Delaware], Kevlar [poly-p-phenyleneterephthalamide, manufactured by Du Pont Advanced Fiber Systems, Wilmington, Delaware]) or other organohalides, oxides of nitrogen, and phosgene. Insecticides such as paraquat and anaphthylthiourea (ANTU), can be spread aerially over large geographical areas and are also potent edemagenic agents. Acute pulmonary edema may develop 1-3 days after ricin exposure, in contrast to staphyloccocal enterotoxin B (SEB) from Staphylococcus aureus or phosgene where time to development of pulmonary edema is 12 and 6 hours respectively.
Laboratory examinations : confirmation of ricin inhalational intoxication would most likely be through
• immunoassays (including polyclonal and monoclonal ELISAs^{ref1, ref2}) analysis of a swab sample from the nasal mucosa; ricin can be identified by this method for at least 24 hours after the challenge
• fluoroimmunoassay using the fluorescent dye Alexa Fluor 647 in RAPTOR, a fiber optic biosensor^ref
Signs and symptoms usually occur within 8 hours of inhalation exposure but within 6 hours of ingestion. Because ricin is extremely immunogenic, individuals surviving a ricin attack would likely have circulating antibody within 2 weeks after the exposure; serum samples should be obtained from survivors. Following inhalational intoxication in laboratory animals, laboratory findings are generally nonspecific. The most likely scenarios in which ricin intoxication might be seen are :
• small-scale battlefield or terrorist delivery of an aerosol. If used as a biowarfare agent, the ricin is likely to be aerosolized although massive quantities of ricin are though to be necessary as compared to kg quantities of anthrax spores in order to cause 50% lethality over a 100 kg² area
• parenteral administration of the toxin to an individual as an assassin's tool
Because ricin acts rapidly and irreversibly (directly on lung parenchyma after inhalation, or is distributed quickly to vital organs after parenteral exposure), postexposure therapy is more difficult than with slowly processed, peripherally acting agents (such as the botulinum toxins or bacterial agents) that can be treated with antibiotics. Therefore, immunization of personnel at risk for ricin exposure is even more important than it is for some of the other potential biological warfare agents. As is the case in toxicity and pathogenesis of intoxication, the route of exposure is important in relation to possible modes and their likelihood of success of prophylaxis and therapy
• for oral intoxication, supportive therapy includes activated charcoal administration and intravenous fluid and electrolyte replacement
• for inhalational intoxication, supportive therapy to counteract acute pulmonary edema and respiratory distress is indicated. Symptomatic care is the only intervention presently available to clinicians for the treatment of incapacitating or lethal doses of inhaled ricin. Positive end-expiratory ventilatory therapy, fluid and electrolyte replacement, antiinflammatory agents, and analgesics would likely be of benefit in treating aerosol-intoxicated humans
As we learn  more about the pathogenesis of intoxication by this route, specific mediator blocking agents may prove valuable, as well
Prevention : subunit vaccine
Bibliography : David R. Franz, D.V.M.,
PH.D.; and Nancy K. Jaax, D.V.M., Ricin Toxicity
• Linaceae
• Linum
• Linum usitatissimum (a.k.a. flax)

=> raw linseed oil / flaxseed oil : the fixed oil obtained from the dried ripe seed; used as an emollient in liniments, pastes, and medicinal soaps, and in veterinary medicine as a laxative
• Malpighiaceae
• Banisteriopsis
• Banisteriopsis caapi (part of ayahuasca plant mixture)

=> harmine (7-methoxy-1-methyl-b-carboline)
=> N,N-dimethyltryptamine (DMT)
• Diplopterys
• Diplopterys cabrerana (Chaliponga)

=> N,N-dimethyltryptamine (DMT)
• Passifloraceae
• Passiflora
• Passiflora incarnata is used to treat insomnia
• Salicaceae
• Salix spp. (a.k.a. willows)

=> salicylic acid, a precursor of acetylsalicylic acid (aspirin)
• Rosales
• Cannabaceae
• Cannabis (there are countless street terms for marijuana including dagga, ganja, grass, hash, hemp, herb, pot, weed, widow and zol, as well as terms derived from trademarked varieties of cannabis, such as, Northern Lights^®, Fruity Juice^®, Afghani #1^®, and a number of Skunk varieties)
• Cannabis indica
• Cannabis sativa
• Cannabis sativa subsp. sativa (cannabinoid-free cannabis)

Epidemiology : grows in temperate climate areas as India, Pakistan, Morocco, Iran, Nepal, Syria, Saudi Arabia, ... The first written evidence of medical use of Cannabis sativa comes from China some 5,000 years ago. The drug was then introduced in Europe by Napoleon Bonaparte’s troops when returning from Egypt
=> 61 different cannabinoids :
• cannabinol (CBN)
• cannabidiol (CBD) can inhibit and delay destructive insulitis and inflammatory T_h1-associated cytokine production in NOD mice resulting in a decreased incidence of diabetes possibly through an immunomodulatory mechanism shifting the immune response from T_h1 to T_h2 dominance^ref. CBD, a non-psychoactive cannabidinoid has been previously shown by us to suppress cell-mediated autoimmune joint destruction in an animal model of rheumatoid arthritis. CBD treatment significantly reduces the incidence of diabetes in NOD mice from an incidence of 86% in non-treated control mice to an incidence of 30% in CBD-treated mice. CBD treatment also resulted in the significant reduction of plasma levels of the pro-inflammatory cytokines, IFN-g and TNF-a. T_h1-associated cytokine production of in vitro activated T-cells and peritoneal macrophages was also significantly reduced in CBD-treated mice, whereas production of the Th2-associated cytokines, IL-4 and IL-10, was increased when compared to untreated control mice. Histological examination of the pancreatic islets of CBD-treated mice revealed significantly reduced insulitis. CBD can inhibit and delay destructive insulitis and inflammatory T_h1-associated cytokine production in NOD mice resulting in a decreased incidence of diabetes possibly through an immunomodulatory mechanism shifting the immune response from T_h1 to T_h2 dominance^ref.
• cannabidiolic acid (CBDA)
• cannabichromene
• tetrahydrocannabinolic acid (THCA)
• D⁸-tetrahydrocannabinol (THC)
• D⁶-3,4-trans-tetrahydrocannabinol (THC)
• D⁹- / D¹-3,4-trans-tetrahydrocannabinol (THC) (Marinol^®; source : Bayer : a synthetic version of THC, dronabinol, supplied in capsules, is approved in the USA for chemotherapy-associated nausea and for anorexia and wasting among patients with AIDS) exists in 4 isomeric forms, but, in common parlance, the term is very often used for the natural component of cannabis, the trans, L-isomer, which acts as an agonist for CB₁ and CB₂ receptors. It can accumulate in fatty tissues, including the brain and testes. THC stimulates brain cells to release more dopamine, a process that initially stimulates pleasure but can later also lead to paranoia or hallucinations.


• Sativex^® (source : GW Pharmaceuticals plc) is a whole plant medicinal liquid cannabis (whose principal active ingredients are dronabinol and cannabidiol) that is sprayed under the tongue : in a phase II trial, it produced statistically significant improvements in morning pain at rest (p<0.05), quality of sleep (p<0.05), disease activity score (p<0.01) and Short Form McGill Pain Questionnaire – pain at present (p<0.05) in patients with rheumatoid arthritis; it was approved in Canada in June 2005 for the treatment of neuropathic pain in multiple sclerosis
On the basis of the THC content and Federman's ratio (FR) = (%THC + %CBN) / %CBD, cannabis plants are divided into :
• fibre-type (FR < 1; THC < 0.4%, used in industry for the production of oil and rope)
• drug-type (FR > 1; 0.4 < THC plants < 10%). Drug-type cannabis leaf contains on average 1% THC and the female flowering heads on average 3.5% THC
=> poor stupefacting power :
• marijuana / cannabis resin ([D⁹-THC] = 1-4%) : a crude preparation of the leaves and flowering tops of C. sativa, dried and triturated, usually employed in cigarettes and inhaled as smoke for its euphoric properties
• bhang : a decoction of leaves used in India
=> intermediate stupefacting power : ganja : an homogenate of resin and leaves 3-fold more active than marijuana, smoked by particular pipe
=> high stupefaction power :
• hashish / hash ([D⁹-THC] = 2-15%, on average 5%) : a preparation of the unadulterated resin scraped from the flowering tops of cultivated female hemp plants, Cannabis sativa L., which is smoked, drinked as thea, or chewed (together with tobacco or sweeties) for its intoxicating effects. It is far more potent than marijuana
• hashish oil / hash oil / cannabis oil ([D⁹-THC] = 13-34% = 3-1500 mg/g) : a concentrated extract of the resin painted over the cigarette. Black-market cannabis can contain wildly differing levels of THC. In the Netherlands concentrations are getting very high, up to 20% in some places. Youngsters think this is normal, but many of the old hippies in Amsterdam refuse to take it; they are used to 2 or 3%
Intestinal absorption is just 33% of pulmonary one as many substances are degraded by intestinal microflora. Once in bloodstream, D⁹-THC binds to plasma lipoproteins and catabolytes are found in urine. Cannabis spp. contain 50% more carcinogens than Nicotiana spp.. LD₅₀ = 30 mg/kg^ref
Symptoms & signs :
• acute toxicity : tachycardia, orthostatic systemic arterial hypotension, peripheral vasodilataion with conjunctival hyperemia, palpebral ptosis and edema, photophobia, nystagmus, muscular fasciculations and hypotonia, vertigo, hypoacusis and blurred vision, anguish and fear 10-30' after smoking, followed by relaxation and pleasure.
• 15-20 mg smoked or 40 mg chewed cause loss of memory, fear, loss of control, sleepiness and fatigue in newsmokers and euphoria and hallucinations in abitual users.
• 250 mg smoked or 400 mg chewed cause visual and acoustic hallucinations.
Reverse tolerance causes more pleasant feelings at low doses in abitual consumers. Deaths following third-grade coma and decerebration rigidity or muscular hypertony have been reported. It produces a high that lasts about 2 hours, impairing cognitive functions, perception, reaction time, learning, memory, coordination and tracking behavior, giddiness and increased hunger, panic or hallucinations and even acute psychosis, anxiety (50-60%) with oral rather than smoked marijuana. Youngsters are very aware of their acute reactions to cannabis : for example, 1 in 7 get paranoid ideas that they find distressing
• chronic toxicity :
• immunodepression
• traditionally tobacco-related head and neck cancers and lung cancer. When associated with marijuana use, such tumors occur in a much younger patient population than do similar tumors in tobacco smokers. Marijuana smoking might increase the risk of transitional cell carcinoma of the bladder^ref. Regular smokers - of cannabis or tobacco alike - are more likely to develop respiratory problems such as asthma^ref. Sativex and Marinol were formulated as oral drugs to avoid this problem.
• controversial studies have shown that the drug can lower sperm counts in men and suppress ovulation in women
• amotivational syndrome :
• Cannabis smoke weekly increases 2-fold likelihood to develop depression and anxiety, while smoke each day increases 5-fold
• long-term use can affect memory and sap a user's motivation.
• taking cannabis can induce panic attacks and paranoia
• a study from the Institute of Psychiatry in London showed that cannabis increases the risk of schizophrenia by 30%, and exacerbates symptoms in people who already have mental health problems : : the earlier the teenagers start using, the greater the risk of schizophrenia increases (e.g. 10% of those who start at age 15 develop schizophrenia at age 26). Those using cannabis during adolescence or early adulthood have, on average, a 6% greater chance of suffering psychotic symptoms such as schizophrenia, delusions and paranoia, compared with those who don't take the drug. But for the 10% of people who are already vulnerable to such problems, such as those with a family history of schizophrenia, this figure leaps to 25% : these figures depend on the level of drug intake, particularly for those already in danger : if you are vulnerable, then the more cannabis you use, the greater your risk of psychosis. There is no doubt cannabis use can worsen mental illnesses such as schizophrenia, but it is more difficult to say how many people would never have become ill if they had not used cannabis. Volunteers who were predisposed to mental problems and frequently smoked cannabis had roughly a 50% chance of suffering psychotic symptoms within the four years of the study, which took place in Germany and is the first to track the subsequent effects of cannabis use, rather than examining the past behaviour of psychiatric patients^ref. Patients see the connection at first, but when they start to get better they remember the pleasurable aspects of cannabis. Infant rats exposed in to cannabis compounds in the womb (giving mother low daily dose of a synthetic cannabinoid for the last 2 weeks of their 3-week pregnancy) have lower levels of glutamate in hippocampus, causing memory difficulties and hyperactivity : similar changes may explain why some children whose mothers smoked marijuana while pregnant suffer attention problems later in life
• although there is still debate around whether marijuana is physically addictive, people can certainly become compulsive users of the drug. The UK Department of Health says that "cannabis is a weakly addictive drug but does induce dependence in a significant minority of regular users". Some users can experience withdrawal symptoms such as cramps and shaking when they stop taking the drug
• the 1999 US Institute of Medicine report found no evidence that marijuana led to use of harder drugs, or that allowing medical use would markedly increase wider recreational use.
Benefits :
• pain and tremors relief in patients with multiple sclerosis. Some small clinical trials have shown that cannabis can have these medical benefits. An influential US Institute of Medicine report^ref from 1999 concluded that no health benefits were yet proven, and called for more research in the area^ref.
• appetite stimulant in anorexics and cancer patients to combat the nauseating side-effects of chemotherapy
• only at certain doses (lower, relative to body weight, than that which would produce the mind-altering altering effects of cannabis in humans) THC reduces the progression of blood-vessel blockage formation by > 33% by toning down the immune response via CB₂ (feeding the mice a compound that interferes with binding to CB2 abolished the therapeutic effect of THC). At higher and lower doses, THC has no therapeutic effect on blood vessels, remembering the  similarly moderated effects of alcohol on heart disease. It does not mean that smoking cannabis is beneficial to the cardiovascular system, as cannabis smoke contains many toxins which may actually lead to cardiovascular diseases. The body also produces its own cannabis-like chemicals and whether they may play a role in the above beneficial effects is unclear. THC could be deployed alongside currently used cholesterol-controlling drugs called statins to fight atherosclerosis. Because THC might suppress the immune system in a general way, there is a danger that it may harm the body's ability to fight infection^ref
The Supreme Court of the USA ruled on 6 June 2005 that medical use of marijuana is illegal under federal law, even though 11 individual states allow it. The judgement is the result of an appeal by Bush's government over a case against 2 women in California who use the drug medicinally. The pair may now be arrested. Technically, the ruling means that federal authorities may prosecute the doctors, patients and suppliers involved in medicinal marijuana use, although lawyers point out that federal enforcement is likely to be lax. The ruling is seen as a victory by those who dispute the medical benefits of marijuana use. Medical use of marijuana has been allowed in Canada since 2001, and the Netherlands since 2003. Although it is strictly illegal in Britain, legal authorities have generally taken a lenient attitude towards medicinal users. In most countries, certain marijuana extracts are also available on prescription. California's Compassionate Use Act of 1996 ensures that "seriously ill Californians have the right to obtain and use marijuana for medical purposes". Similar acts allow limited marijuana use in Alaska, Arizona, Colorado, Hawaii, Maine, Montana, Nevada, Oregon, Vermont and Washington. These state laws remain in effect, so prosecution of users would have to be a federal undertaking. Marijuana is the most frequently used illegal drug in the USA : according to federal statistics, nearly 95 million Americans over the age of 12 have tried marijuana at least once. It is commonly said that thousands of people in North America use marijuana for medicinal purposes, but the numbers are difficult to assess. In Canada, where there is a federally sanctioned process for getting marijuana on prescription, a surprisingly small number of people actually have permission to use the drug: 821, to be precise, as of April 2005. The Canadian government currently receives about 40 applications a month for 'authorization to possess' the drug. This drug, often known as cannabis, is also available as a resin or oil made from the plant. The quality of the drug as bought on the street varies widely. Experts in the USA say that today's marijuana is generally much stronger that it was in the 1960s. The average strength of cannabis in Europe seems to have remained fairly steady at around 6-8% THC (King L. A., An overview of cannabis potency in Europe, Office for Official Publications of the European Communities (2004)). In Canada there is a federally sanctioned operation that grows plants in a controlled environment in an abandoned mine. Patients have to go through their doctors to get permission to use it. Before the US government prohibited the use of marijuana in 1937, many medicines containing the drug were legally available. Today, other cannabinoids are available on prescription. But many medicinal users buy their cannabis from the same sources as recreational users do. The National Institute on Drug Abuse, which is the only legal source of cannabis in the USA, supports research on the drug's effects, although researchers have sometime found it difficult to get approval for medicinal trials. Other research projects abound. The University of California's Centre for Medicinal Cannabis Research is conducting clinical trials on pain relief. And the Multidisciplinary Association for Psychedelic Studies, based in Sarasota, Florida, has spent > $2 million since 1995 on education and research into medical marijuana use. There are a number of ongoing studies into the possible benefits of MDMA, the active ingredient in ecstasy, for treatment of stress-related syndromes. The hallucinogenic peyote cactus, which is traditionally used by some Native Americans to cure drug addiction and alcoholism, contains the promising drug mescaline. Researchers are investigating its effects. And there are some trials involving psilocybin, the active ingredient in 'magic' mushrooms. These aim to see whether it can manage symptoms of obsessive-compulsive disorder or relieve anxiety in terminally ill cancer patients.
Laboratory examinations : direct extraction of D⁹-THC with petroleum ether => gas chromatography (GC)
• in overdoses : from urine
• in diagnosis : from fingers with cotton
D⁹-THC content in samples is determinated by mixing 100 mg of resin or 500 mg of extracted with petroleum ether and a-cholestan => gas chromatography (GC) (or thin-layer chromatography with silica plates) shows 4 peaks corresponding to CBD, THC, CBN, and a-cholestan.
> 50% of people will use marijuana sometime in their life. Australian rates of cannabis use are higher than the US, UK and much of Europe : 60% of young adults have used cannabis. About 10% of people who were regular users of cannabis would become dependent daily users who found it hard to control their drug use. In Britain, drugs are grouped into three categories. Class A drugs include heroin and morphine, class B drugs include amphetamines and barbiturates, and those in class C, now including cannabis, are judged to be the least damaging. An estimated 3 million people in Britain take cannabis each year, some for medicinal reasons, but most for recreational use. This includes 25% of those aged between 16 and 24
Bibliography : Recovered Not Cured by Richard McLean
Web resources :
• Marijuana-info.org by NIDA
• Usenet sci.med.cannabis
• Alliance for Cannabis Therapeutics
• Moraceae
• Artocarpus
• Artocarpus heterophyllus (a.k.a. Artocarpus integrifolia, jackfruit)

=> jacalin, a D-Gal binding lectin used for IgA isolation
• Ficus spp.

=> nausea and vomiting
• Rhamnaceae
• Rhamneae
• Karwinskia
• Karwinskia humboldtiana (also known variously as coyotillo, Humboldt coyotillo, tullidora, capulincillo, capulincillo Cimarron, capulin, palo negrito, margarita, cacachila, china, frutillo negrito, cochila, or margarita del cero^ref)

=> karwinol A, found in the seeds, causes a neurological picture similar to that for Guillain-Barre syndrome or other polyradiculoneuropathies. The toxin is frequently seen in people in Mexico.
• Rhamnus
• Rhamnus purshiana

=> cascara sagrada (sacred bark of the buckthorn tree, containing the glycosides :
• barbaloin
• chrysaloin
• Rosaceae
• Amygdaloideae
• Prunus
• Prunus spp.(a.k.a. cherry)
• Prunus armeniaca (a.k.a. apricots)

=> persic oil : an oil expressed from the kernels; used as a vehicle for drugs.
• Prunus domestica (a.k.a. plum)
• Prunus dulcis (a.k.a. Prunus amygdalus, bitter almond)

=> bitter almond oil : the volatile oil obtained from the bitter almond or from other kernels containing amygdalin; used in perfumery and liqueurs and formerly as a topical antipruritic.
• Prunus dulcis var. sativa (sweet almond)

=> almond oil / expressed or sweet almond oil : a preparation of the fixed oil obtained from the seed used as an emollient, perfume, and oleaginous vehicle and as an ingredient of rose water ointment
• Prunus persica (a.k.a. peach)

=> persic oil : an oil expressed from the kernels; used as a vehicle for drugs.
pruno - a liquor concocted from a mixture of ingredients (such as prunes and raisins and milk and sugar) that can be fermented to produce alcohol; made by prison inmates
• Maloideae
• Crataegus spp. (hawthorn)
• Crataegus oxyacantha is used to treat insomnia
=> pinnatifin I
=> quercetin
=> kaempferol
=> epicatechin
Therapeutic daily dose = 160-900 mg of a native water-ethanol extract of the leaves or flowers in 2-3 doses. It has positive inotropic and antiarrhythmic effects. Side effects : mild rash, headache, sweating, dizziness, palpitations, sleepiness, agitation, and gastrointestinal symptoms.
• Malus
• Malus x domestica (a.k.a. apple tree)
• Pyrus
• Pyrus communis (a.k.a. pear)
• Rosoideae
• Rosa
• Rosa alba
• Rosa centifolia
• Rosa damascena
• Rosa gallica (a.k.a. French rose)
=> rose oil / attar of roses : the volatile oil distilled with steam from the fresh flowers, used as a perfuming agent and flavoring agent
• Rosaceae incertae sedis
• Spiraea (bridal-wreaths)
• Spiraea ulmaria

=> acetylsalicylic acid
=> amygdalin and prunulaurosin cyanogenic glucosides in stones and pips. There are official limits for cyanide concentration in marzipan.
• Urticaceae
• Urtica
• Urtica dioica (a.k.a. great or stinging nettle) b-sitosterol
•  eurosids I incertae sedis
• Zygophyllaceae
• Larreoideae
• Larrea
• Larrea tridentata (a.k.a. creosote bush, chaparral) : antifungal
• eurosids II
• Brassicales
• Brassicaceae (a.k.a. mustard family, cruciferae, cruciferous vegetables)
• Brassica
• Brassica napus
• Brassica napus var. napobrassica (a.k.a. rutabaga)
• Brassica oleracea
• Brassica oleracea var. italica (a.k.a. asparagus broccoli)

=>sulforaphane
• Brassica oleracea var. gemmifera (a.k.a. Brussels sprouts)
• Brassica rapa
• Brassica rapa subsp. rapa (a.k.a. turnip)
• Brassica rapa chinensis (a.k.a. bok choy or Chinese  white cabbage)
=> glucosinolates are readily converted into goitrogenic isothiocyanates, nitriles, and oxazolidines, which may cause primary hypothyroidism. Studies in the 1920s were the first to note the development of hypertrophic goiters in rabbits that were mainly fed a diet of cabbage (Chesney AM, Clawson TA, Webster B. Endemic goiter in rabbits. Bull Johns Hopkins Hosp 1928;43:261-261).  Interest in the possible goitrogenic properties of foodstuffs led to the discovery of 1,5-vinyl-2-thiooxazolidone in brassica seeds and in yellow turnips. The compound was termed a goitrin because it inhibited the uptake of iodine by the thyroid gland^ref. When eaten raw, brassica vegetables release the enzyme myrosinase, which accelerates the hydrolysis of glucosinolates; the cooking process largely deactivates the myrosinase in these vegetables (Dekker M, Verkerk R, Jongen WM. Predictive modelling of health aspects in the food production chain: a case study on glucosinolates in cabbage. Trends Food Sci 2000;11:174-81). Anyway glucosinolates are are also used for cancer chemoprevention :
• goitrin / (-)5-vinyl-2-thiooxazolidone / 5-vinyloxazolidine-2-thione
• thiocyanate ion
• allyl isothiocyanate
• 
  
=> mustard : the ripe seeds of black mustard or white mustard; when they are crushed and moistened, volatile oils are liberated that are responsible for the counterirritant, stimulant, and emetic properties of mustard.
• black or brown mustard : Brassica nigra (L.) Koch, a source of oil of mustard and allyl isothiocyanate; used internally as an emetic and externally as a counterirritant. Since the plant contains sinigrin, animals consuming large quantities of it may develop fatal gastroenteritis.
• white or yellow mustard : Brassica alba (L.) Rabenh.; it is a source of oil of mustard and is used the same as black mustard. Since the plant contains sinigrin, animals consuming large quantities of it may develop fatal gastroenteritis.
• Isatis
• Isatis indigotica (a.k.a. daqingye, banlangen, qingdai)
=> indirubin, which is effective for granulocytic leukemias
• Malvales
• Bixaceae
• Bixa
• Bixa orellana (a.k.a. arnatto, lipstick tree)

=> bixin : lycopene is subject to remodeling in a sequential reaction by a dioxygenase, an aldehyde dehydrogenase, and a methyltransferase. It is one of the oldest natural pigments used by humans. It is currently employed in the manufacture of cosmetics and as a soluble color additive for food, but a consumer ban on azo dye has increased the demand for bixin.
• Malvaceae
• Bombacoideae ; Adansonia (a.k.a. baobab) contains all amino acids^ref and vitamin C^{ref1, ref2}. The baobab milk contained more protein (1.5%) and minerals (Fe, 17.8 mg; Ca 134.2 mg) than those of human milk (protein, 1.3%, Fe, 0.2 mg, Ca 30 mg) and cow milk (Fe, 0.1 mg; Ca 1.20 mg) and most leading national commercial infant formulas e.g. cerelac (Fe, 10.0 mg). The composite flours contained more nutrients than the baobab or the acha flour alone. The BF96 had greater advantage over other BF flours as a supplement to acha. The mixtures are within the reach of lower income group and can be incorporated into their diets^ref.
• Adansonia digitata : "pain de singe", fruit of baobab, is used for the prevention and treatment of acute dehydration in infantile diarrhea^ref
• Adansonia gibbosa
• Adansonia grandidieri
• Adansonia madagascariensis
• Adansonia perrieri
• Adansonia rubrostipa
• Adansonia suarezensis
• Adansonia za
• Byttnerioideae ; Theobroma ; Theobroma cacao (a.k.a. cacao, cocoa)

=> anandamide
=>theobromine inhibits phosphodiesterases, and acts as an antagonist on A₁, A_2a, A_2b, and A₃ receptors
=> (-)epicatechin : it has beneficial effect on atherosclerosis, but absorption into the bloodstream and plasma total antioxidant capacity (TAC) is significantly reduced following ingestion of dark chocolate accompanied by milk or chocolate containing milk.
The effects of chocolate on cardiovascular health are still a matter of debate. Chocolate may adversely affect cardiovascular risk because of its effects on glucose, lipids, and body weight or potentially favour cardiovascular health through antioxidative effects of chocolate ingredients, such as flavonoids (present in dark but not white chocolate). Dark chocolate improves endothelial and platelet function, cornerstones in the pathogenesis of atherothrombosis, leading to vasoconstriction, thrombus formation, and inflammation. Smoking is a major cardiovascular risk factor. The mechanisms promoting atherothrombosis in smokers primarily include increased oxidative stress that enhances proatherogenic processes such as LDL oxidation and inactivation of endothelium derived NO. Platelets contribute both to ACS and to the progression of atherothrombosis. Both active and passive cigarette smoking has consistently been shown to induce endothelial dysfunction. Therefore, smokers serve as an ideal model to study the beneficial vascular effects of antioxidant strategies^ref
• Malvoideae ; Gossypium spp.

=> cotton : a textile material derived from the hair of the seeds
=> gossypol is a male contraceptive derived from cotton seeds in China as long ago as 1929, but after large scale studies in the 1970s it was abandoned because some men remained infertile after stopping treatment. There were plans in Brazil in the 1990s to market the drug but these were shelved. In 1998 the World Health Organization said research on its use for contraception should be abandoned. It is a putative TERT inhibitor and inhibits the function of Bcl-2/x_L and makes the cancer more sensitive to radiation therapy in human prostate tumors in mice.
• Sterculioideae ; Cola
• Cola acuminata (a.k.a. guru nut)
• Cola nitida (a.k.a. Kola nut)
=> teine / caffeine / 1,3,7-trimethylxanthine / 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione / methyltheobromine / guaranine
• Thymelaeaceae
• Daphne : a genus of trees and shrubs
• Daphne gnidium
• Daphne mezereum L. (mezereon)
are medicinal species that are vesicatory and purgative in small amounts but in larger amounts are poisonous, causing severe or even fatal irritation of the alimentary tract in humans and other animals.
• daphnetin : 7,8-dihydroxycoumarin, the aglycon of daphnin.
• daphnin : 7,8-dihydroxycoumarin-7-b-D-glucoside, a glycoside found in Daphne mezereum.
=> daphnism : severe enteritis with diarrhea
• Myrtales
• Myrtaceae
• Eucalyptus spp.
• Eucalyptus globulus (blue gum)

=> eucalyptol
=> eucalyptus oil : a volatile oil distilled with steam from the fresh leaf used as a pharmaceutical flavoring agent, and as a veterinary and human expectorant and local antiseptic
=> nausea and vomiting
• Melaleuca
• Melaleuca leucadendra

=> cajeput or cajuput oil / oil of cajeput : a volatile oil from the fresh leaves and twigs used as a stimulant, expectorant, counterirritant, and external parasiticide, and in veterinary medicine as a rubefacient and parasiticide in the treatment of ringworm
• Sapindales
• Burseraceae
• Boswellia
• Boswellia serrata

=>boswellic acid (5-Loxin^®) is a 5-LOX inhibitor^ref
• Meliaceae
• Azadirachta
• Azadirachta indica

=> azadirachtin (Margosan-O^®) : it is used as botanical insecticide
• Nitrariaceae
• Peganum
• Peganum harmala (a.k.a. African rue)

=> harmaline (3,4-dihydro-7-methoxy-1-methyl-b-carboline) : an alkaloid that has hallucinogenic properties, found in the seeds and also in the South American vine Banisteria caapi => demissidine
=> harmine / banisterine : an alkaloid that has hallucinogenic properties, found in the seeds and also in the South American vine Banisteria caapi
=> 6-methoxyharmalan
=> norharmane
• Rutaceae
• Citrus
• Citrus bergamia (a.k.a. bergamot)

=> bergamot oil, a volatile oil obtained by expression from the rind of the fresh fruit of bergamot, used as a perfuming agent and insecticide. It may cause berlock dermatitis
• Citrus limon (a.k.a. lemon)

=> lemon oil : the volatile oil obtained by expression from the fresh peel used as a flavoring agent.
• Citrus sinensis (a.k.a. apfelsine, naranja, sweet orange, navel orange Valencia organge)

=> sweet orange oil : the volatile oil obtained by expression from the fresh peel of the ripe fruit; used as a flavoring agent in pharmaceuticals
• Citrus aurantium (a.k.a. Seville orange, bitter orange, sour orange

=> bitter orange oil : a volatile oil obtained from the fresh peel of the fruit used as a flavoring agent.
=> orange flower oil / neroli oil : a volatile oil distilled from the fresh flowers, used as a flavoring agent and perfume
• Pilocarpus spp.
• Pilocarpus racemosus

=>pilocarpine : it activates all kinds of M AChRs.
• Triphasia
• Triphasia trifolia

=> coumarins :
• heraclenol
• isomeranzin
• Sapindaceae
• Aesculus (horse chestnuts); most species of which contain the coumarin glycoside esculin, which makes them toxic to livestock.
• Aesculus glabra is the buckeye.
• Aesculus hippocastanum (common horse chestnut)

=> bark and seeds were formerly used to treat rheumatism and malaria and as an anticoagulant
=> horse chestnut extract (HCE), containing 70% of the saponin aescin (Essaven^® gel (EG), Veinotonyl 75^®, Venostasin retard^®) has shown satisfactory evidence for a clinically significant activity in chronic venous insufficiency (CVI) (as effective as compression therapy), haemorrhoids and post-operative oedema. Anti-oedematous, anti-inflammatory and venotonic properties are mainly related to the improved entry of ions into channels, thus raising venous tension. Other mechanisms are release of PGF_2a from veins, antagonism to 5-HT and histamine, and reduced catabolism of tissue mucopolysaccharides
• escin Ia
• escin Ib
• escin IIa
• escin IIb : escins Ib, IIa, and IIb with either the 21-angeloyl group or the 2'-O-xylopyranosyl moiety showed more potent activities than escin Ia which had both the 21-tigloyl group and the 2'-O-glucopyranosyl moiety.
• b-aescin (Reparil^®)
• desacylescins I and II are obtained by alkaline hydrolysis of escins
• Blighia
• Blighia sapida (a.k.a. ackee)
=> hypoglycin A, which is found in unripened ackee fruit (causing a condition termed Jamaican vomiting sickness), similar to MCPG. The syndrome is best known from Jamaica, where ackee is widely eaten, and occurs most frequently in 2- to 10-year-old children, who develop severe hypoglycemia and metabolic acidosis. Clinical manifestations of Jamaican vomiting sickness include headache, thirst, sweating, vomiting, lethargy, seizures, coma, and death over a span of hours to days. Patients may be mildly to moderately febrile, and emesis may not be present in all cases. Heavy ingestion of the immature fruit of ackee (Blighia sapida) or other members of the soapberry family (Sapindaceae), including lychee (Litchi sinensis), rambutan (Nephelium lappaceum), and longan (Dimocarpus longan), by an undernourished child with low glycogen/glucose stores probably has the potential to result in toxic hypoglycemic syndrome.

• Simaroubaceae
• Brucea
• Brucea antidysenterica

=> bruceantin
=> quassinoid
• Zygophyllaceae
• Larrea
• Larrea divaricata

=> hepatotoxic compounds
• Santalales
• Santalaceae
• Santalum
• Santalum album (a.k.a. white sandalwood)

=> sandalwood oil / santal oil : a viscid oily liquid with a characteristic odor and taste, distilled with steam from the dried heartwood; formerly used as a urinary antiseptic.
• Viscaceae
• Viscum
• Viscum albus (a.k.a. European mistletoe)

=> viscotoxins (VT) (mM concentrations are cytotoxic)
• viscotoxin A1 (VTA1) (85 nM)
• viscotoxin A2  (VTA2) (18 nM)
• viscotoxin A3 (VTA3) (8 nM)


=> mistletoe lectins (ML) / viscumins / Viscum album agglutinins belongs to the family of class II RIP
• MLI is the most abundant and is a Gal specific lectin showing little affinity for GalNAc
• MLII has similar affinity for both
• MLIII is GalNAc specific with little affinity for Gal
The A-chain is an a/b protein consisting of 252 amino-acid residues and one glycosylation site, and the molecular weight is about 30kDa. The B-chain is an all b protein with 2 globular domains. It has 263 residues and 3 glycosylation sites, and the molecular weight is about 35kDa. 2 chains are linked by a disulphide bond between Cys²⁴⁷ in the A-chain and Cys⁵in the B-chain. The active site is located in a prominent, centrally located cleft of the A-chain. Each domain of the B-chain consists of 3 repetitive subdomains that form a pseudo 3-fold symmetry around a hydrophobic core. The fold of one such domain has been classified as the b-trefoil fold. 2 sugar-binding sites are located in the subdomains 1a and 2g. MLI exists as a non-covalently associated dimer, (A-B)₂ whereas MLII, MLIII and ricin are monomeric toxins (a disulphide-linked heterodimer A-B is taken as the protomer here). 2 protomers are associated with the N-terminal domain of the B-chain to form a dimer
=> chitin-binding lectin
Iscador Quercus special (IQ)^® is known to be rich in mistletoe lectin (ML)-1 while Iscador Pini (IP)^® is poor in ML-1 but enriched in viscotoxins.
• Saxifragales
• Crassulaceae
• Cotyledon : a genus of herbaceous plants found in southern Africa; several species contain cotyledontoxin.

=> cotyledontoxin : a neutral, nonalkaloidal, nonglucosidal, non-nitrogenous, amorphous substance toxic to humans and other animals (krimpsiekte : a disease of cattle in South Africa : symptoms include abdominal pain and convulsions that can be fatal)
• Rhodiola
• Rhodiola rosea (a.k.a. Sedum roseum)

=> lotaustralin
=> rosavin
=> rosarin
=> rosin
=> rosiridin
=> salidroside
=> b-sitosterol
• Hamamelidaceae
• Hamamelis (witch hazels)
• Hamamelis virginiana

=> hamamelis, effective against hemorrhoid
• Ranunculales
• Berberidaceae
• Berberis (barberry)

=>
• Podophyllum
• Podophyllum peltatum (mayapple, mandrake plant)

=> podophyllotoxin, a model for the synthetic analog etoposide.
• Menispermaceae
• Chondodendrum tomentosum

=> d-tubocurarine (dTC) (Curarin^®, Curarin-Asta^®, Curarin-Haf^®, Curarine^®, d-Tubocurarine^®, d-Tubocurarine Abbott^®, Intocostrin-T^®, Intocostrine-T^®, Tubadil^®, Tubarine^®, Tubocurarina^®, Tubocurarine Bruneau^®) is a reversible antagonist of N AChR
• Cocculus spp.

=>picrotoxin is a GABA_A antagonist
• Stephania spp.

=> L-tetrahydropalmitine : hepatotoxic. It represents 36% of jin bu huan.
• Nigella
• Nigella sativa

=> melanthin : an amorphous and poisonous glycoside or saponin from the seeds
• Papaveraceae
• Argemone mexicana (a.k.a. prickly poppy, Mexican poppy) : contamination of cooking oil by mustard argemone oil (from the seeds), which contains the toxic glycoside sanguinarine (benzophenanthridine alkaloid) and dihydrosanguinarine. The prickly poppy grows as a wild weed with a yellow flower, but the seeds are black to black brown with a wrinkled seed coat or surface. Mustard seeds have a smooth round surface. Mustard seeds are usually harvested earlier than those of the poppy, which would present little chance of accidental mixing. However, most cases of contamination result from being a little late on the harvest of a crop, resulting in contamination of the mustard seeds. Sanguinarine causes an increased permeability of the blood vessels

=> epidemic dropsy : a sometimes fatal condition seen in India (the earliest recorded case may be 1872 in West Bengal), Fiji, South Africa, and elsewhere, characterized by pedal and hand edema (100%), skin erythema (75-100%); persistent tachycardia (98%), prolonged Q-T interval  (23%), cardiac insufficiency with biventricular dilatation (14-23%); bloated stomach, diarrhea (51%), acute nausea, vomiting, ataxia, hepatomegaly (34%), acute renal failure  (rare), and dilatation of vessels of uveal tract, resulting in open-angle glaucoma over a 3-month follow-up period (9%). There was an outbreak of > 3,000 cases of epidemic dropsy associated with assumed adulterated cooking oil in India in August-September 1998
Laboratory examinations : ferric chloride and nitric acid tests
Prognosis : mortality : 2%. All those who survive recover completely, but a few patients are left with sarcoid-like changes of skin telangiectasia.
Treatment seems to be primarily symptomatic
• Fumarioideae
• Corydalis spp.

=> L-tetrahydropalmitine : hepatotoxic. It represents 36% of jin bu huan.
• Papaver
• Papaver somniferum (a.k.a. opium poppy)

Opium (the milky juice from the unripe seed capsules of the poppy plant) is dried and powdered to make powdered opium, which contains a number of alkaloids termed opioids :
• phenantrenes
• morphine (Avinza^®, Duramorph^®, MS Contin^®, ...)


10% of opium, hydrophilic; precursor for heroin and apomorphine. Catabolyzed to morphine-6-glucuronide (active), morphine-3-glucuronide (inactive), and morphine 3,6-diglucuronide, or normorphine (via N-demethylation)
Although long-term use of morphine has been shown to promote tumor growth, the question whether tumorigenesis occurs as a result of an immunosuppressive effect remains to be investigated. In mice rendered tolerant to morphine, the efficacy and mechanism of a vaccination to rescue morphine-induced immunosuppression and prevent tumor growth was assessed both in vitro and in vivo. Morphine-injected mice exhibited higher tumor growth rates and lower percentages of CD8⁺ T lymphocytes. The mechanism of morphine suppression of immunity might be through the suppression of E7-specific CD8⁺ T lymphocyte proliferation and the promotion of apoptosis of these cells by the Bcl-2 and Bax pathways. The suppressive effect of E7-specific CD8⁺ T lymphocytes by morphine could be reversed by naloxone. Calreticulin linked with E7 (CRT/E7) could enhance the CD8⁺ T cell response and the anti-tumor effects^ref. CRT/E7 DNA vaccine could overcome the immunosuppressive effect of morphine and suppress tumor growth. Long-term morphine treatment dose-dependently promotes tumor growth and a DNA vaccine may serve as a useful approach to treat the profound immunosuppressive function and prevent tumorigenesis after long-term morphine treatment^ref.
• codeine / methylmorphine (Senodin^®-AN in combination with prophenpyridamine; Co-efferalgan^® in combination with  acetaminophen)


0.5% of opium; lipid-soluble; most morphine in the "legitimate" opium business is converted to codeine synthetically. Codeine has exceptionally low affinity for opioid receptors due to the presence of a methoxy group in place of the hydroxyl group, but in vivo 10% of codeine is O-demethylated in hepatocytes to form morphine.
• thebaine (0.2% of opium) has little analgesic action but is a precursor of several important 14-OH compounds, such as buprenorphine, oxycodone and naloxone.
Laboratory examinations : gas chromatography (GC) (100 mg of raw opium or 25 mg of extracted opium or 1 ml of opium tincture are mixed in 5 mL of 70% alcohol, heated by 30' at 60°C, cooled, filtered and diluted with 70% alcohol up to 10 mL)
• benzylisoquinolines
• noscapine (6.0% of opium)
• papaverine (1.0% of opium) inhibits PDE


Paregoric is a camphorated tincture of opium.
The poppy mutant known as top1 (for 'thebaine oripavine poppy 1') accumulates the morphine and codeine precursors thebaine and oripavine and does not complete their biosynthesis into morphine and codeine. The original discovery of top1 stimulated a re-engineering of the opioid industry in the island state of Tasmania, which grows over 40% of the world's licit opiates, in order to produce thebaine and oripavine efficiently from morphine-free poppy crops to provide precursors for highly effective analgesics and for treatment of opioid addiction^ref. Opium poppies usually demonstrate an alkaloid profile of morphine, codeine, oripavine, and thebaine. Codeinone reductase (COR), the penultimate enzyme in morphine biosynthesis, silenced via RNAi should lead to thebaine accumulation in opium poppy plants, the compound preceding COR in the pathway and substrate for commercial analgesics buprenorphine and oxycodone. The 18 transgenic poppies produced by the Australian group instead displayed the nonnarcotic alkaloid S-reticuline, which lies seven enzyme steps upstream of COR, and its methylated derivatives codamine, laudanine, and laudanosine. Reticuline is a precursor for potential anticancer and antimalarial pharmaceuticals. It normally makes up < 2% of total alkaloids in the opium poppy. the unexpected reticuline phenotype may have been caused by a buildup of morphine substrates codeinone and neopinione that triggered negative feedback on one or more earlier enzymes or transport steps of the morphine branch. Alternatively, the substrate feedback may have inhibited transcription of genes encoding earlier enzymes or transporters. Loss of COR enzyme from a larger interdependent enzyme complex may also have disabled the other enzyme reactions normally associated with the complex
• Sanguinaria
• Sanguinaria canadensis (a.k.a. sanguinaria, red puccoon). The seeds of the plant are pressed and processed for oil, a process which may concentrate the alkaloids present. The seeds are most likely the most toxic portion of this plant.
• sanguinarine
=> epidemic dropsy. Members of Sanguinaria spp. have been known to be used medicinally to treat gingivitis, halitosis, and cough. However, prolonged use or overdose has been demonstrated to cause stomach pain, diarrhea, visual changes, paralysis, fainting, and collapse. The plant is unsafe for use in children and should not be used by pregnant or lactating women.
• Ranunculaceae
• Aconitum spp. (a.k.a. aconite or sini tang)

=> aconitine : it binds to site 4 on voltage gated Na⁺ channel and blocks Na⁺ flux. Used therapeutically for osteoarthritis, may cause refractory ventricular tachycardia^ref
• Delphinium
• Delphinium semibarbatum
• Liliopsida
• Araceae
• Arum
• Arum maculatum (a.k.a. cuckoo-pint)

=>
• Dieffenbachia spp.

=> nausea and vomiting
• Epipremnumspp.

=> nausea and vomiting
• Philodendron spp.

=> nausea and vomiting
• Spathiphyllum spp.

=> nausea and vomiting
• Arecaceae
• Arecoideae
• Areceae
• Arecinae
• Areca
• Areca catechu (a.k.a. catechu, areca-nut, betel palm, pinang), found throughout South and South-East Asia and many Pacific Island nations. A mixture called betel nut quid, is made using the betel nut, betel leaf, and lime (calcium oxide), with or without the addition of tobacco. Much like smokeless tobacco, betel nut quid is chewed and kept inside of the mouth from 5 minutes to several hours. It is also addictive. Between 10-20% of the world's population, especially women, aged 8-20, chews betel nut quid. The habit appears to be epidemic and spreading from Asia throughout the Pacific and is accompanying immigrants to the West. Cancers related to betel nut quid use appear to be aggressive in nature. Stage I and II betel nut-induced oral carcinomas (betel or buyo cheek cancer), especially those located in the buccal region, should be treated aggressively with follow-up > the usual 5 years. The most common site for the primary tumour is the buccal mucosa (the inner lining of the cheeks and lips), appearing in 70% of cases. Other primary sites included the tongue, lower lip, alveolar ridge, tonsil, and the floor of the mouth. 66% of patients die of their disease after an average of 35.4 months; 33% patients had no remaining evidence of disease. 78% present at the most advanced stages (Stage III or IV) with a 5-year disease free survival rate < 36%. Those patients presenting at Stage I had 100% survival; at Stage II survival dropped to 50%.

=> arecoline : it is an agonist of M₁, M₂, M₃, M₄ and M₅ ACh receptors.
• Coryphoideae
• Corypheae
• Livistoninae
• Serenoa
• Serenoa repens (a.k.a. saw palmetto)
=> 5a-reductaseinhibitors and AR antagonists, effective against bening prostatic hypertrophy
• Asparagales
• Alliaceae
• Allium
• Allium cepa (a.k.a. onion)

=> propanthial-S-oxide, synthetized by lachrymatory factor synthase (not by allinase !)
• Allium sativum (a.k.a. garlic)

=> alliin : during cooking the membranes separating the alliin compartment and the alliinase compartment within each clove are broken and the latter catalyzes conversion of alliin to allicin, a toxic, but unstable, chemical which breaks down quickly and harmlessly when it is eaten. It has been used as immunotoxin and is effective against MRSA
=> anticoagulants
• Amaryllidaceae
• Narcissus spp.

=> nausea and vomiting
• Asphodelaceae
• Aloe spp.

=> barbaloin (glycoside) => aloe-emodin-9-anthrone (AE-anthrone)
=> aloe-emodin
=> aloenin
• Hyacinthaceae
• Urginea
• Urginea maritima (a.k.a. red squill)

=> bulbs contain scillaren glycosides

• Orchidaceae
• Vanilloid clade
• Vanillinae
• Vanilla spp.
• Vanilla planifolia (vanilla)
=> vanilline

• commelinids
• Arecales
• Arecaceae
• Arecoideae
• Cocoeae
• Butiinae
• Cocos
• Cocos nucifera

=> coconut oil : the fixed oil obtained by expression or extraction from the kernels of seeds; used as an ointment base and edible oil and in soap, chocolate, and candle formulations
• Zingiberales
• Zingiberaceae
• Curcuma
• Curcuma longa (a.k.a. turmeric)

=> curcumin / diferuloylmethane is a specific inhibitor of heme oxygenase 1 (HO-1) and of the p300/CREB-binding protein (CBP) HAT activity but not of p300/CBP-associated factor, in vitro and in vivo. Furthermore, curcumin could also inhibit the p300-mediated acetylation of p53 in vivo. It specifically represses the p300/CBP histone acetyltransferases (HATs) activity-dependent transcriptional activation from chromatin but not a DNA template. It can inhibit angiogenesis by preventing proliferation and migration of endothelial cells^ref. Fresh and dried rhizomes are used as peptic ulcer treatment, carminatives, wound treatment and anti-inflammatory agent^ref. It is effective against HIV^ref, HPV^ref and Plasmodium falciparum^ref
• Elettaria
• Elettaria cardamomum (a.k.a. cardamom or cardamon)

=> cardamom oil : a volatile oil distilled from the seed used as a flavoring agent in pharmaceutical preparations
• Zingiber
• Zingiber officinale (a.k.a. ginger)

=> 6-gingerol
• Liliales
• Colchicaceae
• Colchicum
• Colchicum autumnale (a.k.a. autumn-crocus, meadow-saffron)

=> colchicine
Laboratory examinations (Zeisel's test)
• Melanthiaceae
• Veratrum
• Veratrum californicum (a.k.a. California false hellebore, corn lily)

=> cyclopamine
• Poales
• Poaceae
• Bambusoideae
• Bambuseae
• Bambusa spp. (bamboos)

=> cyanogenic glycosides in shoots
• taxiphyllin
• PACCAD clade
• Panicoideae
• Andropogoneae
• Cymbopogon
• Cymbopogon nardus

=> citronella oil : a fragrant oil used as an insect repellent
• Zea
• Zea mays

=> corn oil : a refined fixed oil obtained from the embryo; used as a solvent and vehicle for various medicinal agents and as a vehicle for injections. It has also been promoted as a source of PUFAs in special diets
• PACC clade
• Arundinoideae
• Arundineae
• Arundo
• Arundo donax (a.k.a. giant reed)

=>
• Pooideae
• Aveneae
• Phalaris
• Phalaris aquatica (Harding or canary grass)
• Phalaris arundinacea (Reed canary grass)
=> N,N-dimethyltryptamine (DMT)
• Stipeae
• Stipa spp.
• Stipa robusta (a.k.a. sleepy grass, Stipa vaseyi)

=> D-lysergic acid amide (LSA)
=> isolysergic amide
=>8-hydroxylsergic acid amide
=>ergonovine
=> chanoclavine-I
=>N-formylloline
• Poeae
• Lolium
• rye grass poisoning : poisoning of an animal or occasionally a human by eating rye grass, usually consisting of mycotoxicosis when the grass is moldy. Common types are darnel poisoning and rye grass staggers. See also endoconidiotoxicosis.
• Magnoliales
• Myristicaceae
• Myristica
• Myristica fragrans (a.k.a. nutmeg, mace)

=> elemicin
=>eucalyptol
=> eugenol
=> myristicin (3-methoxy,4,5-methylendioxy-allylbenzene)
=> safrole
=> nutmeg poisoning : severe toxic symptoms produced by ingestion of powdered nutmeg
Symptoms & signs : narcosis with periods of delirium and excitability
• magnoliids
• Laurales
• Lauraceae
• Cinnamomum
• Cinnamomum cassia

=> cinnamon oil / cassia oil : a volatile oil distilled with steam from the leaves and twigs used as a flavoring agent for pharmaceuticals and formerly used as a carminative
• Sassafras
• Sassafras albidum (a.k.a. white sassafras)

=> sassafras oil : the volatile oil distilled from the root; it is the source of the beverage root beer and is used as a pharmaceutical flavoring agent. It is also applied to insect bites and stings and has been used as a topical antiseptic, pediculicide, and carminative. It contains safrene and safrole
• Piperales
• Piperaceae
• Piper
• Piper methysticum (a.k.a. kava, kawa, kava-kava) is an ancient crop of the western Pacific. Other names for kava include 'awa (Hawaii), 'ava (Samoa), yaqona (Fiji), and sakau (Pohnpei). The word kava is used to refer to both the plant and the beverage produced from it. The extract is an emulsion, consisting of suspended kavalactone droplets in a starchy suspension. The taste is slightly pungent, while the distinctive aroma varies depending on whether it's been prepared from dry or fresh material, and by variety. The colour is grey to tan to opaque greenish. Various sources incorrectly state that preparation technique of mastication potentiates the psychoactive effects of kava because of the action of saliva enzymes on the plant. Although chewing kava does produce a more powerful effect than any other form of preparation, this is not the result of any chemical process; rather, this is due to the much finer particles produced in this method. Fijians commonly share a drink called Grog that is prepared by pounding sun-dried kava root into a fine powder and mixing it with cold water. Traditionally, Grog is drunken from the shorn half-shell of a coconut, called a bilo. Despite tasting very much like dirty water and perhaps starting with dirty water, Grog is very popular in Fiji, especially among young men, and often serves to bring people together for storytelling and socializing. The effects of drinking kava, in order of sensation, are slight tongue and lip numbing caused by the contraction of the blood vessels in these areas (the lips and skin surrounding may appear unusually pale); mildly talkative and euphoric behavior; anxiolytic (calming) effects, sense of well-being, clear thinking; and relaxed muscles. Sleep is often restful and there are pronounced periods of sleepiness correlating to the amount and potency of Kava consumed. When drunk to excess, kava can cause vomiting and a feeling of nausea that will subside usually by the end of the day after consumption. In Vanuatu, drinking strong kava is normally followed by a hot meal or tea. Meals consumed along with kava traditionally follow some time after the beverage so that the psychoactives are absorbed into the bloodstream more quickly. A drink of high potency results in a faster onset with a lack of stimulation, somnolence, and then deep, dreamless sleep within 30 minutes. Unlike alcohol-induced sleep, after wakening the drinker does not experience any mental or physical after effects. Heavy consumption of kava can produce dermatological effects ranging from light, red bumps to heavy, scaly, ulcerous skin. Kava contains lactones that bind to skin proteins forming antigens, which then lead to the allergic response. Discontinuation or reduction of consumption resolves the effects. There have been indications of severe liver toxicity, including liver failure in some people who had used dietary supplements containing kava extract. The severity of liver damage consequently prompted action of many regulatory agencies in some countries.

=>kavalactones / kavapyrones
• dihydrokawain / marindinin
• kawain (5,6-dihydro-4-methoxy-6-(2-phenylethenyl)-2H- pyran-2-one) / kavain / gonosan
• methysticin
• DHM (dihydromethysticin / pseudomethysticin)
• yangonin
• Winterales
• Canellaceae
• Canella
• Canella winteriana (a.k.a. Canella winterana, Canella alba, barbasco, wild cinnamon, curbana)

=> canellal, a sesquiterpene dialdehyde

• veratridine : it binds to site 2 (or 4 ?) on voltage gated Na⁺ channel and blocks Na⁺ flux.
• cevadine
• sabacilline.

Good news for lovers of extra-virgin olive oil: besides being delicious on salads, it also contains a compound that mimics the effects of ibuprofen. So a Mediterranean-style diet might give you the supposed long-term benefits of that drug, such as a reduced cancer risk. A daily dose of 50 g or 4 tablespoons of olive oil confers the equivalent of around 10% of the recommended ibuprofen dose for adult pain relief, say researchers led by Paul Breslin of the Monell Chemical Senses Center at the University of the Sciences in Philadelphia, who discovered the effect. So although it won't cure a headache, it may give you some of the long-term benefits of repeated ibuprofen use, including helping to ward off Alzheimer's disease. The compound, called oleocanthal, acts in the same way as ibuprofen to stifle components of the prostaglandin system. This is in spite of the 2 chemicals' very different structures^ref. The compound should be present in any extra-virgin oil, but concentrations will vary depending on a range of factors, such as the variety of olive, and the age of the olives at pressing. So how do you know which olive oil will give you the biggest dose? Simple, just go for the authentic Mediterranean taste. Most supermarket-style extra-virgin olive oils will be relatively low in this compound, but there are inexpensive olive oils available that have high levels. There's a simple rule of thumb to help you out: oleocanthal is also responsible for the throat-stinging sensation of a good extra-virgin oil. The way to check is to sip the oil neat and see how strongly it stings the throat. The greater the sting the greater the oleocanthal level. Does the discovery help to explain the folklore that a Mediterranean diet is good for a healthy, long life? Probably. The long-term benefits of ibuprofen have only been demonstrated for doses that are much larger than the amount of oleocanthal provided by 4 tablespoons of oil a day. But smaller daily doses might have the same effect. The long-term side-effects of ibuprofen can also include damage to the kidneys and digestive system. But as oleocanthal has a different chemical structure, it is unclear whether these effects would also occur with a diet rich in olive oil. Of course, other dietary factors, such as overall calorie intake, are important too. After all, there's no point dousing your healthy salad in healthy olive oil if you chase it down with a bottle of wine and a cheesecake. Weight gain is a factor that needs to be held in check, but the traditional Mediterranean diet, such as on Crete, involves lots of fresh vegetables and is not a high-calorie diet overall

Palm wine is also known as toddy, or palm toddy. It is made from the sap of certain palm trees, which is fermented into an alcoholic beverage. It is most common in South India and places in Africa. The amount of alcohol depends upon the location and the specific species of palm trees. Generally yeast is added to the fermenting mixture, so it would also be possible to add a contaminant that would be camouflaged by the acidic flavor of the finished product.

flavonoid fisetin activates ERK and induces cAMP response element-binding protein (CREB) phosphorylation in rat hippocampal slices, facilitates long-term potentiation in rat hippocampal slices, and enhances object recognition in mice. Together, these data demonstrate that the natural product fisetin can facilitate long-term memory, and therefore it may be useful for treating patients with memory disorders^ref

Web resources :

• SCOP family : plant cytotoxins
• Poisonous Plant Database by D.Jesse Wagstaff
• Poisonous Plants at Cornell University
• Plants toxic to animals at University of Illinois
• alkaloide : an alkaloids database

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