Psychoactive Plants

Psychoactive Plants Psychoactive plants produce their effects by acting on the nervous system. In general they mimic, block, or affect the normal metabolism of neurotransmitters. They can be classified as stimulants, depressants, or hallucinogens. Stimulants excite portions of the nervous system, promote alertness and activity, reduce fatigue, and suppress appetite. Depressants reduce physical activity and alertness. Typically, the reduced awareness is seen as a near-sleep, dreamlike state. Hallucinogens alter perception, mood and thought patterns.

Most are alkaloids (but not the active ingredient in marijuana). Some have legitimate medical uses (including marijuana), but many are illegal, recreational drugs. The use of these plants and drugs is not new – the use of opium poppy goes back at least 6000 years in Sumerian records. We typically think of these drugs collectively as narcotics, but by definition the name only applies to depressants. Modern usage adds to depressants any other drugs that are addictive. Addictive means that the drugs cause one or more of: psychological dependence, physiological dependence, and tolerance.

Psychological dependence means that the experience of the drug is so pleasurable that the person has an irresistible need to re-experience the sensations produced by taking the drug. Physiological dependence means that the body needs the drug to avoid painful withdrawal symptoms. Tolerance means that it takes more and more of the drug to obtain the same sensations or responses to the chemical. Your text has a fine description of the common neurological mode of addictive drugs…

The mesolimbic pathway links the ventral tegmentum to the nucleus accumbens of the limbic system. This pathway uses the neurotransmitter dopamine, and is involved in both pleasure and psychosis.

Dopamine is released at the nucleus accumbens by axons of neurons of the ventral tegmentum. Normally, those neurotransmitters are recollected after a short time and returned to VT neurons. Different drugs act in different ways to prevent the normal cycle of controlled release and recollection. The end result is accumulation of dopamine at the nucleus accumbens neurons, producing a euphoric sensation, whether in a state of heightened or depressed activity. Stimulant drugs like cocaine prevent the recollection. Depressant drugs like heroin shut down the control pathway that normally reduces or stops the production and release of dopamine.

Above is a cartoon depiction of the normal state of the mesolimbic pathway. A complex dendritic tree of a ventral tegmentum neuron gathers stimulation. It connects to the nucleus accumbens neuron at a synapse that releases dopamine. With addiction, there are physical, as well as control and chemical changes to the pathway. The dendritic tree of the VT neuron simplifies. Without a larger amount of drug, the NA cell is ‘starved’ for dopamine.

What was at first an increase in dopamine becomes a reduced amount with tolerance. The basic molecular biology of tolerance is now understood. Chronically elevated dopamine in the nucleus accumbens causes its neurons to produce cyclic AMP. Cyclic AMP triggers a transcription factor called CREB (cyclic AMP response element-binding protein – sorry!) that, when phosphorylated, triggers genes that inhibit dopamine-producing neurons in the VT. It takes more drug to overwhelm this tolerance.

It is also important to recognize that neurons in our brains have opiate receptors. They respond to endorphins – endogenous opiate-like molecules that enhance pleasure and reduce pain, but also to the various narcotics injected, inhaled, smoked, drunk or consumed. • What are those narcotics, and what plants produce them? • opium – from the opium poppy (Papaver somniferum), • from which morphine, codeine, and heroin are derived. • marijuana – from Cannabis sativa, which is also the • source for hasish (under its various names) and hash oil • cocaine – from Erythroxylum coca

nicotine – from Nicotiana tabacum • peyote – from Lophophora williamsii • kava – from Piper mysticum • caffeine – from many sources • alcohol – from many sources • Starting through this long list, we have already seen a lot about opium. There is more to add here… • Opium • In the dried resin of the poppy’s pod are ~20 alkaloids. Both morphine and codeine are medically important. Both are phenanthrenes. There is another whole class of alkaloids present, in a group called benzylisoquinolines.

The leading producer of opium is Afganistan (>1000 metric tons, 70% of the world’s supply). Other producers supplying the illegal drug trade are Myanmar, Laos, Thailand, Pakistan, Iran, and some countries of Central America and northern South America. The leading producer of legal opium poppies is India. There have been many famous opium addicts: Elizabeth Barrett-Browning, Samuel Coleridge, and Hector Berlioz. Berlioz got the ideas for his Symphonie Fantastique ‘under the influence’ in a dream.

There have also been many famous heroin addicts. During the 1950s and 1960s heroin addiction was common among the leading jazz musicians: Charlie ‘Yardbird’ Parker, Miles Davis, and Billie Holiday among many others. Heroin is 6 times more addictive than morphine. As well, withdrawal from heroin addiction is much more severe than from morphine. So much more severe that withdrawal from heroin addiction is very difficult. Instead of withdrawal ‘cold turkey’ (the descriptive term comes from the tendency to feel cold and get ‘goose bumps’ during withdrawal), medicine has found that slow reduction in the dose of methadone, a synthetic opiate that is less addictive, can make withdrawal manageable.

Overdoses of either heroin or morphine can be fatal. The opiates are central nervous system depressants, and can, in overdose, completely suppress the respiratory center in the brain. Morphine as a prescription medicine is still used to treat intense pain, for example following surgery or in the case of severe burns, for those in the pain of terminal cancer, and for kidney stones. Both morphine and heroin were once in commonly available, over-the-counter remedies, like cough syrups, but the dangers were recognized early in the 20th century, and those products were no longer available by 1920.

Marijuana – The species is a dioecious (separate sexes) annual. The active ingredient is -9-tetrahydrocannabinol. It is present at low concentrations even in the leaves of hemp grown for rope, but is in much higher concentration in the resin from unfertilized pistillate (female) flowers and adjacent leaves. It takes about 5 mg of THC to have a detectable psychological or physiological effect.

THC is a phenolic molecule, in its own class called cannabinoids. There are two receptor types for cannabinol, called CB1 and CB2 types. CB1 receptors are in the brain, including the limbic system, hippocampus (short term memory) and amygdala (emotional memory), but are absent in the medulla oblongata. CB2 receptors are in the immune system (particularly the spleen), and are probably responsible for anti-inflammatory response.

Much like endorphins, we produce endogenous cannabinols. After discovering cannabinol receptors in animal brains in 1988, endogenous cannabinols were discovered in 1992. This is the structure of the first one found: It’s called anandamide, which comes from the Sanskrit word for bliss, with the suffix for its structure as an amide. It is approximately as potent as THC and binds to both receptor types.

Cannabis has been used for at least 5,000 years for its ‘drug’ properties, beginning in China, then India and among the Scythians of central Asia. Use spread from there into Asia Minor (the Arabic and Persian countries) and northern Africa. It was used as a hallucinogen and in religious ceremony. It is still used in religious ceremony in India (it is one of the five sacred plants), and is the preferred ‘relaxant’ in alcohol-free Muslim countries like Pakistan and Bangladesh, smoked in hookahs. Estimates suggest at least 20% of the populations of the U.S. and Canada have used cannabis. Is that accurate? An underestimate? An overestimate?

Symptoms and effects of marijuana: • sporadic, uncontrollable laughter • often the (mistaken) impression their • conversation is witty and brilliant • limbs feel light.... • decreased sperm count; decreased Testosterone levels • ‘the munchies’…hunger, usually for snack foods • an altered (distorted) sense of time and space • smoke may damage lungs as cigarette smoke • does

However, there are valuable medical uses for marijuana. It is used to treat glaucoma – a high intraocular pressure that can be caused by advancing age, diabetes, and other factors – THC reduces intraocular pressure. It is used to treat the nausea, vomiting, and loss of appetite brought on by cancer chemotherapy. It is used to reduce or eliminate spastic movements in patients with multiple sclerosis and Parkinson’s disease. It is used to counteract the wasting syndrome that is part of terminal AIDS.

In Canada marijuana is a “schedule II” drug, meaning that it can be prescribed for approved medical conditions when necessary. The medical marijuana is all produced under contract to the federal government by Prairie Plant Systems in Manitoba and Saskatchewan. In the U.S. there is no parallel federal approval system for medical marijuana; it is a schedule I drug (with heroin). In a (conflicted) situation, some states have a licensed mechanism to distribute medical marijuana. The AMA is significantly more ‘liberal’ than government, and wants marijuana reclassified as a schedule II drug.

Though they are controversial, there are local regulations in some jurisdictions (e.g. Ann Arbor, MI) that make possession of personal use amounts of marijuana a civil offense like a traffic ticket. State laws concerning Cannabis: Blue-medical marijuana Red-decrimilization Purple-both

Even where marijuana is available for medical use, smoking it, as noted with effects, can do much the same damage as smoking tobacco (see below). An inhaler for THC would be much better medically, but has not become available. One last point: modern growth systems have increased the THC content of marijuana in two ways: one is classical selection, the other is the production of sinsemilla plants that are seedless hybrids of C. sativa and C. indica. Artificial growth systems clone pistillate plants of the hybrid that are dwarfed in size, but have abundant flowers and resin. One of the products of this new growth method is a larger yield of hashish (hash, hash oil, etc.)

The origin of the term “Hashish” is from Hashishin, which is the Arabic word for ”assassin” or, possibly more likely, from the Arabic for grass. • The source for the term assassin, and the reason for its association with marijuana is the Hashshashin, the medieval Shia sect of militants founded by Hassan-i-Sabah. They were said to have been inspired to commit murder under the influence of hashish • Hashish normally means the compressed trichomes from upper leaves which are the source of the resin that is the most concentrated source for THC. The current ‘product’ is a much stronger material today than in the 1960s and 1970s; the THC content has increased by about 10x.

Cannabis trichomes hashish

Cocaine – coca leaves have been chewed by natives in Peru and the pre-Columbian Andes for hundreds of years. Cocaine has been used in western culture for more than a century. Among famous users (neglecting the many models (Kate Moss) and musicians) have been: Arthur Conan Doyle, Sigmund Freud (where do you think those dreams for analysis came from?), and Ulysses S. Grant. You know that Coca-cola once contained cocaine, and still contains a non-narcotic extractive of coca leaves grown under government control in New Jersey. Cocaine may be taken by injection, consumption, smoking, or ‘snorting’ (formally insufflation). Effects occur fairly rapidly (seconds to less than one hour).

Cocaine is a powerful stimulant, producing a euphoria and a burst of energy and alertness. However, after that short-term ‘high’ there is a period of depression and lethargy. All this happens because cocaine blocks the transporter protein involved in re-uptake of dopamine. Long term users may suffer from a psychosis like schizophrenia.

Cocaine is extracted from the coca leaves by processing with sulfuric acid. Leaves are macerated (stomped like grapes or otherwise crushed), and mixed into the acidic solution. After maceration, the water is evaporated, leaving a brown mush that is dried into impure cocaine sulfate. That product is sold in South America. What is transported to North America is much more concentrated cocaine hydrochloride. This is the white powder sometimes called ‘snow’. From this ‘base’ cocaine, the many more dangerous forms are made: crack cocaine, freebase cocaine, etc.

‘lines’ for insufflation Cocaine hydrochloride ‘crack’

Tobacco – tobacco is a product of a New World genus, and only two species are commonly used: Nicotiana tabacum and N. rustica. Both are tetraploid hybrids of closely related Nicotiana species. As members of the nightshade family, they have certain properties that are particularly interesting (and another reason not to smoke) for Canadians.

Members of the nightshade family accumulate soil cadmium in their leaves (but not fruits). Canadian soil (at least where tobacco was mostly grown around Delhi, Ont.) is high in cadmium, a toxin for kidneys (second only to Japan in Cd concentration). We eat the fruits of other Solanaceae: e.g. tomatoes, green peppers, potatoes, eggplants, but what we use of tobacco is the leaves, the parts with high cadmium. The use of tobacco isn’t new; it was used by native Americans long before Europeans arrived. It was smoked in large quantities as a hallucinogen by shamans. It was also chewed, eaten, and drunk. Missionaries saw the effects, and sent seeds back to Europe, initially Spain.

From Spain use spread to France, then England. It is argued that the desire for tobacco fueled the European colonization of North America. John Rolfe came to Jamestown in 1609, and became the first person to successfully raise tobacco (N. tabacum) as a crop, replacing the inferior N. rustica. He later married Pocahontas. He became rich on tobacco export to England, and continued to improve the crop quality by selection. Tobacco also drove the initial slave trade, bringing the first slaves to Jamestown in 1619. King James I disliked tobacco intensely, wrote a polemic about that, and imposed a high tariff on imported tobacco.

Here are those characters: John Rolfe with an imagined Pocahontas King James I Pocahontas as painted in England

Tobacco is an annual plant. It is grown from seeds that are started in special beds. In the U.S. these beds are fertilized with apatite, a mineral that causes the plants to be partially starved for nitrogen – the object is taste. When the seedlings reach sufficient size, they are transplanted into fields and grown. To maximize leaf area of tobacco plants, they are generally not allowed to flower or to branch laterally. Harvesting occurs by pulling mature leaves off the plants, beginning at the bottom and working upward over time as leaves mature. The leaves are hand-picked. Alternatively, harvest can wait until most leaves are mature, then the whole plant is cut.

The cut leaves are then moved to barns to cure. Curing is basically ‘fermentation’ and drying. This is the time when the flavors develop; the leaves turn from green to brown as the chlorophylls break down and carotenoids degrade. Tobacco leaves can be air-cured, smoke-cured, or flue-cured (heated without exposure to smoke).

The cured leaves are aged for weeks to years before manufacturing the final product (cigarettes, cigars, pipe tobacco, chewing tobacco). Each product involves a mixture of leaves of different cures as well as additives. Cigarettes are the most recent of these products, only having been marketed after the Crimean War (1854-6) pitted Russia against an alliance of France, England and the Ottoman Empire. Mass marketing only followed the development of machinery that could manufacture cigarettes cheaply, beginning in 1881. Cigarette consumption peaked in 1963 in the U.S., when 42% of the population were at least occasional smokers. Today numbers have declined, but there are still more than 1 billion smokers worldwide.

Why are we concerned about smoking? Because tobacco contains the most widely used addictive drug – nicotine. All means of consuming tobacco result in the absorption of nicotine in varying amounts into the user's bloodstream, and over time the development of tolerance and dependence, i.e. addiction.

The addiction has significant health consequences. Among the statistics: • 85% of lung cancer in men and 75% of lung cancer in women is caused by smoking • 30% of all cancer deaths can be linked to smoking • Male smokers die 13 years and women 14.5 years earlier on average than otherwise similar non-smokers. • Coronary heart disease and stroke, leading killers, are • caused by smoking. 120,000 deaths from coronary • artery disease are attributed to smoking annually. • Smokers having double the risk of dying.

Chronic obstructive pulmonary disease (bronchitis, • asthma, emphysema) is next on the list of leading • causes of death. 90% of these deaths are due to • smoking. • Second-hand smoke is now recognized as dangerous. • Exposed babies have higher risk of SIDS. Asthma, • emphysema and cancer risk is increased in exposed • children.

Public recognition of the danger took a long time. In 1964 the US Surgeon General’s Office reported links between smoking and lung cancer, heart disease emphysema etc. In 1998 California became the first state to ban smoking in bars. In that same year settlements with the five major cigarette manufacturers in the U.S. gave damages to the states totaling $200 billion to recover costs of medical treatments for smokers. Today most states and Canada ban smoking in public buildings. Bans are currently being extended more broadly.

States in red are members of one or more of the suits against tobacco manufacturers.

Nicotine is the addictive component, but not necessarily the most dangerous compound in tobacco. Table 20.1 in your text lists some of the 2000 compounds in tobacco smoke. Check them out. Many are carcinogens and/or toxic. Nicotine comprises 0.3 – 5% of the dry weight of tobacco leaves. It is a potent neurotoxin. You get about 1mg absorbed nicotine/cigarette (non-filtered).

Nicotine acts on acetylcholine receptors. In small concentrations it increases their activity, among other things leading to an increased flow of adrenalin, a stimulating hormone. The release of adrenaline causes an increase in heart rate, blood pressure and respiration, as well as higher glucose levels in the blood. However, in higher doses, nicotine causes a blocking of acetylcholine receptors, which is the reason for its toxicity (higher than cocaine) and its effectiveness as an insecticide. In addition, nicotine increases dopamine levels in the reward circuits of the brain. Studies have shown that smoking tobacco inhibits monoamine oxidase, an enzyme responsible for breaking down dopamine.

In this way, it generates feelings of pleasure, similar to that caused by cocaine and heroin, thus causing the addiction. The same dependence and tolerance effects are observed. Breaking the addiction, just as with the ‘hard’ drugs, is difficult. Transdermal nicotine patches are being used successfully. They wean the person off smoking by providing a steady, but slowly decreasing supply of the alkaloid.

Peyote and Mescaline Peyote is the cactus Lophophora wiliamsii that is native to southwestern Texas and Mexico. It is a spineless cactus.

It is slow growing, taking 10 – 30 years in the wild to reach adult, flowering size. What is harvested is the above ground ‘button’. It contains a number of phenethylamine alkaloids, the most important of which is mescaline. Overharvesting has made Lophophora an endangered species. The effective dose is 300 – 500 mg mescaline, or about 5g of dried peyote. It is a hallucinogen.

The hallucinogenic visions vary widely, from LSD-like light shows to frightening visions of snakes, demons and feelings as if trapped in a cave. There are, additionally, many side effects, including nausea, vomiting, and tremors. Those effects typically precede the hallucinatory phase of effects. In Canadian law, mescaline is a prohibited (illegal) substance, but peyote is exempt. In the U.S., after a protracted series of legal challenges, use of peyote by a religious group, the Native American Church, was permitted, but the Supreme Court also upheld the rights of individual states to outlaw peyote. The situation might now be described as a morass, with conflicting regulations in different states.

Kava - is a soporific derived from Piper mysticum. The plant is native to the western Pacific and was transported from island to island by Polynesians. The name kava refers both to the plant and the beverage made from it. The active ingredients are lactones. There are 15 – 20 lactones in the leaves and roots, but only 6 are pharmacologically active. Fresh roots contain about 15% lactones, while leaves contain ~5%. Exact proportions of different lactones differ among the many sources across the South Pacific. The effects vary similarly. Overharvesting of roots has meant population decline and the harvesting of younger and younger plants.

The most potent kava is produced by grinding or pounding fresh roots, adding cold water, and drinking the emulsion that results. It can also be prepared by chewing, which is the traditional Polynesian method.

The effects of consuming kava occur within an hour or two of consumption. Initially blood vessels of the lips and tongue constrict, some numbness occurs there. Then there is a somewhat euphoric period, and finally there is an anxiolytic effect (reduced anxiousness, calming, friendliness) and, typically, sleep. Stronger beverages produce somnolence, then deep, dreamless (??, there are also reports of vivid dreams) sleep. Either mild or stronger effects have the advantage that this ‘drug’ is not addictive, has no aftereffects, and, unlike alcohol, does not affect reaction time. Use in Europe and North America has been directed towards reduction of anxiety and as a sleep aid. However, there is conflicted evidence of liver disease.

Kava has been the subject of an FDA alert, but has not been banned. The difference between a lack of liver disease in Polynesian users and occurrence in Europe and North America is suggested to be due to difference in extraction/preparation methods. Commercial preparation has used ethanol extraction of lactones from roots versus the traditional method that uses only water. However, there is tentative evidence that methanol extracts of kava roots may be useful in treating leukemia and ovarian cancer.

A few last pharmacoactive plants – Other plants from among the Solanaceae also produce alkaloids that can be poisonous, but used are used medically in small amounts. The plants are: deadly nightshade (Atropa belladonna) and jimsonweed (Datura strumonium) Both species contain atropine and scopolamine. Both chemicals are hallucinogens and are dangerously toxic, but also have medical applications. Symptoms of atropine poisoning are tachycardia, hallucinations, loss of balance, confusion, and constipation. Atropine completely blocks acetylcholine neurotransmission (and function of the parasympathetic system).

Psychoactive Plants