Drugs, Society & Human

BghaViOf sevenreenthEdition

Carl L. Hart Co/umbio University

Charles Ksir University of Wyoming

Mc Graw Hilt Education When you hove finished this chaptel you shoulcl be oble to:

. Explain why plants with psychoactive effects have been used in religious practices all over the world.

. Recognize several examples of indole and catechol psychedelics.

Describe the relationship of LSD to the ergot fungus.

Discuss the early research and evidence on LSD for use in interrogation and in psychotherapy.

Understand what is meant by,,hallucinogen persisting Source: Drug Enforcement Administration perception disorder."

. Describe the major active ingredient and some history of use From the soft, quiet beauty of the of psilocybe, morning glories, ayahuasca, peyote, San pedro sacred Psiloc1,be mushroom to the cactus, Amonito, and Solvio divinorum, angry, mottled appearance of the . Understand toxic Anwnita, from the mountains the chemical relationship among DOM, MDA, and MDMA. of Mexico to the streets of Anytown, USA, from before history to the . Compare and contrast PCP effects with those of LSD. 2lst centufy, humans have searched Explain how anticholinergic psychedelics act in for the perfect aphrodisiac, spiritual the brain, experiences, and other worlds. The Compare stories about medieval witches using belladonna to plants have been there to help; contemporary stories about people using marijuana, LSD, or plants have evolved to produce cocaine, chemicals that alter the biochemis- try of animals. if they make us feel sick, we are unlikely to eat them again, and if they kill us, we are certainly not going Animism and Religion to eat them again. But humans long ago learned to "tame" some of these plants, to use them in just the Animism, the belief that animals, plants, rocks, right ways and in just the right amounts to alter streams, and so on derive their special characteris- perceptions and emotions without too many tics from a spirit contained within the object, is a unpleasant consequences. common theme in most of the world's religions.

309 3lO Section Six Restricted Drugs

unbiased term that Plants that are able to alter our perception of the Is there a descriptive and the drugs and then to world and of ourselves fit right into such a view. If will allow us to categorize prejudice? Probably the plant contains a spirit, then eating the plant examine their effects without however, we have transfers that spirit to the person who eats it, and not. As a matter of convention, drugs as psychedelics the spirit of the plant can speak to the consumer, chosen to refer to this class of make her feel the plant's joy or provide her with in this chapter. of these drugs psy- special powers or insights. Although we will call all differences among In early hunter-gatherer societies, certain indi- chedelics, there are important according to their viduals became specialists in the ways of these them. They can be classified plants, learning when to halvest them and how chemical structures, their known pharmacological awareness occurs much to use under what circumstances. These tra- properties, how much loss of they can ditions were passed down from one generation to under their influence, and how dangerous review are the classical another, and colorful stories were used to teach the be. The first types we will percep- principles to apprentices. Our modern term for psychedelics: They are capable of altering in com- these individuals is shaman because of their tions while allowing the person to remain The individual knowledge of drug-containing plants. But because munication with the present world. these drugs will often be they also were the experts on obtaining power from under the influence of and the real the spirit world, their function in hunter-gatherer aware of both the "fantasy" world avidly about societies had as much to do with the origins of reli- world at the same time, might talk and will be able to gion as with the origins of modern medicine' These what is being experienced, these drugs plants and their psychoactive effects were probably remember much of it later. Many of without much important reasons for the development of spiritual can produce psychedelic effects is, there is rela- and religious traditions and folklore in many socie- acute physiological toxicity-that an overdose of ties all over the world.l tively little danger of dying from LSD, psilocybin, or mescaline. The two major classes of psychedelics, the indoles and catechols Terminology and TYPes are grouped according to their chemical There has been some controversy about what to structures. call this group of drugs. Because the drugs are lndoles capable of producing hallucinations and some sero- altered sense ofreality, a state that could be called The basic structure of the neurotransmitter psychotic, they have been referred to as psychoto- tonin is referred to as an indole nucleus. Figure 14' 1 mimetic drugs. This term implies that the illustrates that the psychedelics LSD and psilocybin drugs produce dangerous effects and a form of also contain this structure. For that reason and the mental disorder, which is also a controversial fact that some other chemicals with this structure one conclusion. have similar psychedelic effects, we refer to More recently, proponents have popularized group ofpsychedelics as the indoles. newerterms, such as entheogen and entactogen, to (LSD) most potent describe these substances. For example, entheogen d-Lysergic Acid Diethylamide The these is used to describe substances (e.g., sacred mush- of the psychedelics, and the one that brought found rooms) that are thought to create spiritual or reli- drugs into the public eye in the 1960s, is not gious experiences, whereas entactogen, meaning in nature. Although there are naturally occurring acid "to produce a touching within," is used to describe compounds that lesemble the indole d-lysergic as psychedelics substances, such as MDMA, that are said to enhance diethylamide (LSD), their identity LSD. It feelings of empathy. was not known until after the discovery of Chapter r4 Psychedelics 3tl

Psychedelics: Back in Mainstream Medical Research?

A few years.ago, a headline in lime magazine read appropriate medical supervision was not included in "LSD May Help Treat Alcoholism." Other mainstream some studies. Together, these concerns led policy publications have printed similar enthusiastic pieces. makers to impose greater restrictions on access to The reason for the resurgent optimism about LSD psychedelics, and effectively ended their role in therapy are the findings of a 2c12 study published in research and medical treatment. t t h e Jo urno 1 P o/ sy chphar maco/ogy. Resea rc h e rs ln the last decade or so, however, a new gener- Norway from conducted a retrospective analysis of ation of researchers has been investigating the studies published in the late r96os and early r97os in potential therapeutic benefits of psychedelics. For order to assess the utility of LSD as a treatment for example, studies have shown that 3,4-methylenedi- excessive drinking. Data from six randomized, oxymethamphetamine (MDMA) decreases symp- double-blind trials involving 536 participants were toms of posttraumatic stress disorder (PTSD),3 evaluated. The researchers found that a single dose ayahuasca reduces symptoms of depression,a and LSD of decreased problem drinking to a greater psilocybin facilitates tobacco smoking cessation5 (ephedrine, extent than a control drug amphetamine, and decreases depression and anxiety in patients or placebo). These findings add to a growing number with life-threatening cancer. 6 of studies showing beneficial effects of psychedelics Researchers in this area today emphasize that in the treatment psychiatric of conditions, following psychedelic therapies should be thought of as adjuncts, nearly four decades of limited interest in these or add-ons, to psychotherapies and not stand-alone compounds for medical purposes. treatments. The idea that this class of drugs comprised ln the t95os and t96os, psychedelics were pro- "magic bullets" probably contributed to the backlash moted physicians by as treatments for several medical against their use in research and medicine in the t96os. conditions ranging from anxiety to schizophrenia. ln an effort to move psychedelics back into mainstream Excitement about the potential medical benefits of medical research, researchers are avoiding mistakes this class of drug abruptly ended, as nonmedical use of the past by remaining cautious about the role of became more widespread and associated problems psychedelics in medicine and stressing the importance increased. ln addition, some researcher investigating of proper education for professionals using these drugs the effects of psychedelics began using less than rig- in research and treatment. orous methodology in their studies, which increased

the likelihood of adverse drug effects. For example, Box icon credit: @Glow lnoges RF

was originally synthesized from ergot alkaloids animism: the belief that objects attain certain charac- extracted from the ergot fungw Claviceps purpurea. teristics because of spirits. This mold occasionally grows on grain, especially shaman: a person having access to, and influence in, rye, and eating infected grain results in an illness the world of spirits, especially among certain tribal soci- called ergotism, which can cause headaches, eties. Also known as medicine men/women. psychotomimetic (sy vomiting, diarrhea, and gangrene ofthe fingers and cot o mim et lck): mimicking toes. psychosis. entheogen (en thee o gen): generating the divine within. entactogen (en gen): LSD Discovery ond Eorly Reseorch Dr. Albert tac to generating empathy and openness. Hofmann first synthesized LSD in 1938 when he indole (in dole): a particular chemical structure found was working as a scientist at Sandoz Laboratories in serotonin and LSD. in Basel, Switzerland. It was not until 1943, ergotism: a condition caused by fungal contamination however, that LSD entered the world of of grains resulting in headache, vomiting, diarrhea, and psychopharmacology, when Hofmann recorded his gangrene ofthe fingers and toes. LSD-induced experiences. 112 Section Six Restricted Drugs

The indole nucleus

Psilocybin (3-[2-{dimethylamino]ethyll - indol - 4 - ol dihydrogen phosphate ester)

Q carbon O o*yg"n d-lyseric acid diethylamide (LSD) O Hydrogen (9, 10 - didehydro - N, N - diethYl - 6 - methyl - ergoline - 8b - carboxamide) O Nitrog"n Q Phosphorus

Figure r4.t lndole Hallucinogens

He wrote, "The first experience was a very At this point the laboratory notes were discontinued weak one, consisting of rather small changes. It had and were continued on a subsequent day: theater quality"'? He a pleasant, fairy tale-magic The last words could only be written with great dif- was sure that the experience resulted from the acci- ficulty. I asked my laboratory assistant to accom- dental absorption, through the skin of his fingers, pany me home as I believed that my condition would of the compound with which he was working. The be a repetition of the disturbance of the previous next Monday morning Hofmann prepared what he Friday. While we were still cycling home, however, the symptoms were much stron- thought was a very small amount of LSD, 0.25 mg, it became clear that ger than the first time. I had great difficulty in and made the following record in his notebook: speaking coherently, my field of vision swayed April 19, 1943: Preparation ofan 0.5% aqueous solu- before me, and objects appeared distorted like tion of dJysergic acid diethylamide tartrate. images in curved mirrors. I had the impression of 4:20 P,M.: 0.5 cc (0.25 mg LSD) ingested being unable to move from the spot, although my orally. The solution is tasteless. assistant told me afterwards that we had cycled at a 4:50 P.M.: no trace of anY effect. good pace.. . . 5:00 P.M.: slight dizziness, unrest, difficulty in A remarkable feature was the manner in which concentration, visual disturbances, marked desire to all acoustic perceptions (e.g., the noise of a passing laugh. car) were transformed into optical effects, every Chapterl4 Psychedelics 313

sound causing a corresponding colored hallucination Institute of Mental Health (NIMH) research task constantly changing in shape and color like pictures force on hallucinogenic research stated: in a kaleidoscope. At about I o'ctock I fell asleep and awakened the next morning somewhat tired but oth- Virtually every psychological test has been used to erwise feeling perfectly wel1.7 study persons under the influence of LSD or other such hallucinogens, but the research has contributed The dose that Hofmann had taken was quite large little to our understanding of the bizarre and potent for someone who had not developed tolerance; effects of this drug.8 the potency of the drug attracted attention. Mes- caline had long been known to cause strange This conclusion, along with the growing public experiences, alter consciousness, and lead to a perception that this class of drug produced unpre- particularly vivid kaleidoscope of colors, but it dictable effects, led to a virtual moratorium on gov- takes 4,000 times as much mescaline as LSD to ernment funding to support LSD research in produce that effect. LSD is usually active when humans. only 0.05 mg (50 pg) is taken, and in some people a dose of0.03 mg is enough to produce psychoac- Secret Army/ClA Reseorch with LSD As had happened tive effects. with amphetamines earlier, various militaries, in- Hofmann's discovery of LSD and his advocacy cluding the U.S. military, experimented with LSD for its responsible use made him a cult hero among and other psychedelics. Between the 1950s and psychedelic enthusiasts. He remained steadfast in 1960s, hundreds of soldiers and civilians were un- his view that LSD is a valuable psychotherapeutic wittingly administered doses of these drugs, The tool and could be used to enhance humans' under- vast majority of these unsuspecting individuals did standing of their place in nature until his death in not have previous experience with this class of April 2008 at age 102. Hofmann's discovery also drug. As a result, drug effects were sometimes spurred a tremendous amount of research on LSD toxic. Many of the unsuspecting victims believed between the early 1950s and 1970s. they were losing their minds. Some suffered long- A fair amount ofresearch in this area centered term psychiatric disturbances and others had diffi- on developing a model of psychoses and accessing culties adjusting to their usual lives. Even by the the "subconscious mind." The focus on the subcon- standards of the day, this practice was unethical; scious mind probably derived from the dreamlike once knowledge of these activities became public, quality of the reports of LSD experiences and the the U,S. government was required to pay repara- long-held psychoanalytic view that dreams repre- tions exceeding hundreds of thousands of dollars to sent subconscious thoughts trying to express them- some victims and their families. selves. Thus, LSD was widely used as an adjunct to Remember back in Chapters 1 and 5 when we psychotherapy. When a psychiatrist felt that a explained that drug effects are not determined by patient had reached a roadblock and was unable to pharmacology alone (drug-receptor interactions)? dredge up repressed memories and motives, LSD Other factors, including the situation in which drug might be used for its "mind-viewing" properties. use occurs and the user's level of experience with Thus, LSD took over as a modern truth serum, the drug, can greatly influence the effects experi- replacing sodium pentothal, scopolamine, and enced. The U.S. Army-LSD experimentations amphetamines. Whether LSD actually helped these highlight this point. Imagine being given a power- patients in the long run or only seemed helpful to ful mind-altering drug without your knowledge the psychiatrists who believed in it is still being prior to taking your final examination. Also, imag- debated. ine not having any experience with the drug you Scientific study ofLSD and other psychedelics were administered. The effects could be horrifying, declined in the 1970s. A 1974 report by a National and you too might think that you were going insane. 9,l,4 Section Six Restricted Drugs

The important point here is that administering any LSD use is thought to have peaked in the late psychoactive drug to individuals without their 1960s but has always remained relatively low. In knowledge is not only unethical, but it can also be 2015, about 350,000 people aged 12 or older extremely dangerous. reported using LSD in the past month, which corre- sponds to about 0.1 percent of the population aged Recreotionol Use of LSD Psychologist Timothy 12 or older. LSD can also be monitored by examin- Leary was another popular advocate for LSD use' ing past-year use. For past-year use, 0.6 percent of In the early 1960s, he conducted research investi- people aged 12 or older in 2015 had used LSD, gating the psychological effects of LSD and psilo- which represents about 1.5 million people. cybin at Harvard University. Leary's research came under increasing criticism due to charges that his LSD Phormocology LSD is usually taken by mouth methods were not rigorous and were unethical. For and is rapidly absorbed from the gastrointestinal example, proper controls, such as carefully screen- tract. Following ingestion, the brain contains less ing subjects prior to administering drugs, were LSD than any of the other organs in the body, so it sometimes omitted, as was proper medical supervi- is not selectively taken up by the brain. Half of the sion. These concerns may have contributed to LSD in the blood is metabolized every three hours, Leary's dismissal from Harvard and the world of so blood levels decrease fairly rapidly. LSD is me- research, but he was instrumental in popularizing tabolized in the liver and excreted as 2-oxy-lysergic LSD use among the general public. acid diethylamide, which is inactive. Tolerance develops rapidly, usually within 3-4 days if the drug is taken daily on multiple occa- sions. Cross-tolerance has been shown among LSD, mescaline, and psilocybin. Physical dependence to LSD or to any psychedelics has not been demonstrated. LSD is a sympathomimetic agent, and the autonomic signs are some of the first to appear after LSD is taken. Typical symptoms are dilated pupils, elevated temperature and blood pressure, and an increase in salivation. The fact that the LSD molecule resembles the chemical structure of serotonin provided a clue that

t, A very small dose of LSD has powerful effects. Liquid LSD Dr. Albert Hofmann was known as the father of LSD because solution may be taken orally; it is often applied to blotter he was the firsi person to synthesize the drug' paper divided into squares containing single OKeystone/Getty lmages doses. Source: Drug EnforcementAdministration Chapter r4 Psychedelics 3lE

the drug might act on serotonin receptors to pro- duce its effects. The best evidence seems to indicate that LSD and several other psychedelics, including mescaline and psilocybin, act by stimulating the serotonin-2A.subtype of receptors. Among a large group ofpsychedelic chemicals, there is a high cor- relation between their potency in binding to this type of receptor in rat brains and their potency in producing psychedelic effects in humans.e

The LSD Experience In the past 40 years, hundreds of studies investigating the direct effects of mari- juana, opioids, sedatives, and stimulants on human behavior have been published in the scientific liter- ature. Far fewer empirical investigations of psyche- delics have taken place in this same period, in part because ofprevious research abuses involving these agents. As a result, much of our knowledge about the effects of LSD and other psychedelics in hu- mans is anecdotal. Fortunately, this situation is primary changing, and an increasing number ofLSD studies The active ingredient ln so-called magic mushrooms is psilocybin, an indole psychedelic. @tT Stock/age fotostock are being conducted using human subjects. RF One of the most prominent LSD-related effects is the modification of perception, particu- Flashbacks have been widely discussed in the larly of visual images. Other commonly reported popular press as a common adverse effect of psy- effects include an altered sense oftime, changes in chedelics, Unfortunately, the term flashback has the perception of one's own body, and some alter- multiple meanings, making it difficult to investigate ations of auditory input. A particularly interesting its occurrence with any precision. As a result, the phenomenon is that of synesthesia, a "mixing of termflashback has been replaced in the DSM-5 by senses," in which sounds might appear as visual the phrase "hallucinogen persisting perception dis- images (as reported by Hofmann on the first-ever order." An individual diagnosed with this disorder LSD trip), or the visual picture might alter in has not used the drug recently, but has re-experienced rhythm with music. one or more of the perceptual symptoms experi- enced while intoxicated, such as geometric halluci- nations, false perceptions of movement, intensified Adverse Reoctions The adverse reactions to LSD in- colors, and so on. In general, although psychedelics gestion have been repeatedly emphasized in the are reported to have been consumed by millions, popular press. Because there is no way ofknowing few cases of flashbacks have been reported. This how much illegal LSD is being used or how pure the LSD is that people are taking, there is no possi- bility of determining the true incidence of adverse synesthesia (sin ess thees ya): the blending of reactions to LSD. Adverse reactions to the street different senses, such as "seeing" sounds. use of what is thought to be LSD can result from flashbacksl in a nondrug state, reexperiencing ofone many factorS. Drugs obtained on the street fre- or more ofthe perceptual alterations that occurred quently are not what they are claimed to be-in during psychedelic intoxication. purity, chemical composition, or quantity. 3t6 Section Six Restricted Drugs

using rigorous number is even lower when individuals who were case and needs to be confirmed administered psychedelics under carefully con- experimental procedures. l0 trolled laboratory conditions are assessed. Mexico have A more common adverse effect that can occur Psilocybin The magic mushrooms of ceremonial use' while under the influence of LSD (or other psyche- a long history of religious and dropped from West- delics) is the panic reaction. The intensity of these These plants, as well as peyote, use) for 300 years reactions can range from a mild case of increased ern sight (but not from native system- anxiety to a full-blown panic attack. In general, after the Spanish conquered the Aztecs and Use they are not life threatening and, in less severe atically destroyed their writings and teachings' particularly suppressed' cases, can be dealt with by calmly talking the per- of the mushrooms was was clearly shown that son through the experience. In more severe cases, In the late 1930s, it being used by natives in the individual might require medical attention, and these mushrooms were still many species was benzodiazepines or another sedative might be southern Mexico and the first of came in 1955' indicated. identified. The real breakthrough During that year a New York banker turned ethno- with a Betiefs About LSD One of the most widely occurring botanist and his wife established rapport religious cer- beliefs is that these psychedelics increase creativity native group still using mushrooms in first outsider or release creativity that our inhibitions keep bot- emonies. Gordon Wasson became the eat the tled inside us. Several experiments have attempted to participate in the ceremony and to of experiences in a to study the effects of LSD on creativity, but there magic mushroom. He wrote of his knowledge of is no good evidence that the drug increases it. 1957 Life magazine article, spreading properties Another belief is that LSD has therapeutic use- the mushrooms and their psychoactive fulness, particularly in the treatment of alcohol and religious uses. mushroom dependence. The publication of a study that reana- The most well-known psychoactive in lyzed data published in the 1960s and 1970s sug- is Psilocybe mexicana. The primary active agent dis- gest that LSD is effective at decreasing problem this mushroom is psilocybin, an indole that the 1958 drinking.2 This has reignited interest in the thera- coverer of LSD, Albert Hofmann, isolated in peutic potential of LSD in the treatment of psychi- and later synthesized. atric disorders. LSD has also been reported to Another psilocybin-containing mushroom, along the reduce the number of cluster headaches in those Psilocybe cubensis, grows on cow dung questions who suffer from this disorder and decrease anxiety U.S. Gulf Coast. Aside from the obvious t'12 manure' identify- associated with life-threatening illnesses.l These about eating something found on findings are preliminary and need to be replicated ing the correct psilocybin-containing mushrooms in larger controlled studies' More recently, the in the field can be tricky. Most Psilocyfis species and author Ayelet Waldman published a memoir detail- are described as "little brown mushrooms," ing her apparent successful use of LSD to treat a there are several toxic look-alikes. debilitating mood disorder't' Waldman took 10 The dried mushrooms ate 0'2 to 0.5 percent psilocybin micrograms of LSD every 3 days for 30 days. This psilocybin. The psychedelic effects of the catechol dose is about one-tenth of the typical dose taken by are quite similar to those of LSD and exists a recreational user seeking notable LSD-induced psychedelic mescaline, and cross-tolerance mood and perceptual alterations. Ten micrograms among these three agents. taken regulady, observes Waldman, did not pro- Effects Over the past duce noticeable acute perceptual changes but was Acute ond Long-Term Subiective studies have transformative in treating her mood disorder. Of decade or so, a growing number of on research course, Waldman's experience is but one anecdotal examined the effects of psilocybin Chapter 14 Psychedelics 3,17

volunteers. Following acute administration of oral Psilocybin occasioned a mystical experience, doses ranging from 0.045 to 0.315 mgkg,psilocy- whereas nicotinic acid did not. However, an im_ bin dose dependently induces intense changes in portant methodological concern associated with the mood, perception, and thought. Most individuals Pahnke study was that parricipants were explicitly describe the experience as pleasurable, enriching, told that they would receive psilocybin, and it was and nonthreatening. The most frequently reported conducted in a group setting. These features com- acute negative drug reactions are strong feelings of promised blinding procedures and undoubtedly in_ dysphoria and anxiety. These effects are more likely fluenced the findings. when the drug dose is increased but occur only in a In a series of follow-up studies, Roland Grif- relatively proportion small of individuals. Another fiths and colleagues used rigorous double-blind common adverse effect reported after taking larger clinical pharmacology methods to investigate both doses ofpsilocybin is headache. The onset is about the acute and longer-term psychological effects of seven hours after drug administration; they are psilocybin.rT'18 They found that psilocybin acutely transient, lasting no more than a day after psilocy- increased mystical experience. One and two months bin la'15 administration. after drug administration sessions, participants Less information is available regarding the rated the psilocybin experience as having substan- long-term effects psilocybin, of although at least tial personal and spiritual significance, and one literature review has been published. Studerus attributed to the experience sustained positive and colleagues (2012) analyzed pooled data from changes in attitudes, mood, and behavior. These eight double-blind placebo-controlled experimen- effects were undiminished 14 months later. Find- tal studies conducted between 1999 and 200g.14 A ings from the Griffiths study replicated and major focus of the literature review was the exam- extended Pahnke's results, and raised questions ination of data collected from a follow-up question- about why so few studies evaluating the effects of naire. The questionnaire probed subjective psychedelics in human volunteers have appeared in experiences and psychological functioning 8-16 the literature in the past half century (see the Tak- months after participants had received 1-4 oral ing Sides box). doses of psilocybin in a srudy. The data indicated no subsequent drug abuse, persisting perception Morning Glories and Hawaiian Baby Woodroses Of disorders, prolonged psychosis, or other long-term the psychoactive agents used freely in Mexico in impairment of functioning in any of the partici- the l6th century, ololiuqui, seeds of the morning pants. Together, the growing body of evidence sug- glory plant Rivea corymbosa, perhaps had the gests that psilocybin produces predictable effects greatest religious significance. These seeds tie when the drug is administered to healthy individu- America to Europe even today. When Albert als in carefully monitored research environments. Hofmann analyzed the seeds of the morning glory, he found several active alkaloids as well as Psilocybin ond Mysticol Experiences 1963, In as part d-lysergic acid amide, which is about one-tenth as of his Ph.D. requirements, pahnke Walter con- active as LSD. The presence of d-lysergic acid ducted the classic "Good Friday Experiment," in amide is quite amazing (to botany majors) because which the ability of psilocybin ro induce meaning- before this discovery in 1960, lysergic acid had ful religious experiences was investigated.l6 Twenty Christian theological seminary students were as- signed to two groups: one group received psilocy- acute: abrupt or immediate onset of effects. bin (30 mg); the other, nicotinic acid (200 mg) as a psilocybin (sill o sy bin): the active chemical in "placebo." Following drug administration, the stu- Psilocybe mushrooms. dents attended a Good Friday religious service. 318 Section Six Restricted Drugs been found only in much more primitive groups of the fuzzy outer coating contains toxic cyanogemc plants, such as the ergot fungus.le glycosides (which can make one sick). The recreational use of seeds fuom Argyreia nervosa, commonly known as Hawaiian baby DMT Dimethyltryptamine (DMT) has never been woodrose, has also.been reported.2o These seeds widely used in the United States, although it has a contain higher levels of d-lysergic acid amide than long, if not noble, history. On a worldwide basis, morning glories. However, recreational use of these DMT is one of the most important naturally occur- in many seeds often has adverse effects, probably because ring psychedelic compounds, and it occurs

Taking Sides

I Do You Think the Federal Government Should Fund Psychedelic Research?

Findings from a zoo6 study indicate that psilocybin produces positive mystical experiences, which may last at least two months.tT This may not be a surprise to anyone who remembers the tg6os, but the study by Roland Griffiths and colleagues at Johns Hopkins University represented one of the few rigorous investigations in the past 40 years. ln response to widespread psychedelic misuse and poorly con- ducted studies of these compounds, laws were enacted and federal funding was terminated, virtu- ally ending clinical research on this class of drugs for more than four decades. As a result, from a mod- ern clinical scientific perspective, relatively little was known about psilocybin and other psychedelics. Proponents of this type of research argue that understanding how psilocybin-induced mystical and altered consciousness states arise in the brain might inform us about basic neurobiology and could have therapeutic implications such as ameliorating pain and suffering of the terminally ill. ln an unprece- Roland Griffiths, ofJohns Hopkins University' lead author on psilocybin in dented editorial in the journal P sychopharmacology, the landmark study evaluating the effects of where the Griffiths et al. study was published, Dr. humans. Ocarl Hart Harriet de Wit remarked, "lt is time for psychophar- Dr. Volkow noted, "Psilocybin can trigger psychosis macologists . . . to consider the entire scope of in susceptible individuals and . . its adverse effects human experience and behavior as legitimate tar- ' well known." - Some have interpreted this as an gets for systematic and ethical scientific investiga- are indication that NIDA will not fund clinical research tion. Griffiths et al. set an excellent example for investigating the effects of psychedelics, although such a venture."'t the institute currently spends nearly a billion dollars Critics are less enthusiastic about the study each year supporting research on other psychoac- and its results. They point out that the positive find- tive drugs, including cocaine, heroin, marijuana, and ings might increase experimentation with these methamphetamine. Do you think the federal gov- drugs by young people. ln response to the Griffiths ernment should fund this type of research? et al. study, Dr. Nora Volkow, Director of the U.S. National lnstitute on Drug Abuse (NIDA), released a statement underscoring the risks of psychedelic use. Box icon credit: @Novo Developnent RF Chapterl4 Psychedelics 3lg

plants. DMT is the active agent in cohoba snuff, combining the v ine B an i s t e r io p s i s c aap i w ith leav es which is used by some South American and Carib- of Psychotria viridis, which contains DMT. Recall bean indigenous people in hunting rituals. Although that we stated that MAO metabolizes oral DMT rap- DMT was synthesized in the 1930s, its discovery as idly before the drug reaches the brain, So, how does the active ingredient in cohoba first led to human ayahuasca produce psychoactive effects? The vine examination of its psychoactive properties in 1956. Banisteriopsis caapi contains harmaline, an MAO DMT is normally ineffective when taken orally inhibitor. The monoamine-oxidase-inhibiting prop- because it is metabolized by monoamine oxidase erties of harmaline prevent the degradation of oral O4AO) before reaching the brain. As a result, the drug DMT, thereby allowing DMT to reach the brain, is usually snuffed, smoked, or injected. The effective where it produces psychoactive effects. intramuscular dose is about I mglkg body weight. Intravenously, psychedelic effects are seen within two Other Tryptamines There seems to be an endless minutes after doses of 0.2 mg/kg or more and last for list of indole psychedelics, but many are infre- less than 30 minutes. Classic psychedelic effects are quently used. Two that have received some atten- observed following acute adminisffation. DMT pro- tion recently are 5-methoxy DIPT (known as "foxy duces alterations of visual, auditory, and tactile percep- methoxy") and alpha-methyltryptamine (AMT). tion. At larger doses, auditory (e.g., music, whispering The prevalence of their use remains limited, but voices) and visual (e.g., complex geomeffic pafterns they are usually taken orally. on walls) hallucinations may occur. Mood can vary from anxious to expansive and euphoric. Data from at Catechols least one controlled study suggest that DMT is unique The second group ofpsychedelics, although having among classic psychedelics in that tolerance to its psy- psychological effects quite similar to those of the chological effects does not develop.23 indole types, is based on a different structure, that of the catechol nucleus. That nucleus forms the basic Ayahuasca Ayahuasca is a psychoactive tea that structure of the catecholamine neurotransmitters, was originally used by indigenous cultures in South norepinephrine and dopamine. Figure 14.2 shows America for shamanic, religious, and medicinal the catechol structure and the structures of some purposes. It is now used worldwide for a variety of catechol psychedelics. Look for the catechol nucleus reasons ranging from ceremonial to medicinal to in each ofthe psychedelics, and then compare these recreational. The main psychoactive component structures with the structure of the amphetamines of the tea is DMT and it is usually prepared by and other stimulants shown in Chapter 6.

Mescaline Peyote (from the Aztec peyotl) is a small, spineless, carrot-shaped cactus, Lophophora williamsii-Lemaire, which grows wild in the Rio Grande Valley and the Southwest. It is mostly sub- terranean, and only the grayish-green pincush- ion-like top appears above ground. In pre-Columbian times, the Aztec, Huichol, and other Mexican indigenous people ate the plant ceremonially either in the dried or green state, producing psychological effects lasting an entire day.

Only the top of peyote the cactus appears above ground, but peyote (pay oh tee): a type of psychedelic cactus. the entire plant is psychoactive, Source: US Fish & Witdtife 320 Section Six Restricted Drugs

The basic catecholamine structure (dopamine)

2', 5'dimethory -4'- methylamphetamine (DOM)

3, 4 methylenediory amphetamine (MDA)

3, 4, 5 trimethoxyphenylethylamine (mescaline)

Q caroon Q o*ygen e Hydrogen Q Nitrog"n 3, 4 methylenedioxy methamphetamine (MDMA)

Figurel4.2 CatecholHallucinogens

Near the end of the 19th century, Arthur Several writers have written about their peyote Heffter isolated several alkaloids from peyote and experiences, good and bad. William James had showed that mescaline was the primary psychoac- been told about the unique visions that the cactus tive agent found in peyote. Mescaline was synthe- could inspire, but as can be seen from the letter he sized in 1918, and most experiments on the wrote to his brother, Henry, one must sometimes psychoactive effects since then have used synthe- rely on faith: sized mescaline. More than 30 psychoactive com- I ate one but three days ago, was violently sick for pounds have now been identified in peyote, but twenty-fout hours, and had no other symptoms whaG mescaline is believed to be the agent responsible for ever except that and the Katzenjammer the following the vivid colors and other visual effects. day. I rvill take the visions on trust. Chapter r4 Psychedelics i321

Aldous Huxley's 1954 percep- The Doors of For many years the use of peyote as a sacra_ rions details his experiences with peyote.2a He too ment by the Native American Church was protected warned that peyote's effects were mixed: by the constitutional guarantee of freedom of reli- gion. However, 1990 Along with the happily transfigured majority of mes- in the Supreme Court ruled caline takers there is a minority that finds in the drug that the State of Oregon could prosecute its citizens only hell and purgatory. for using peyote, and the freedom of religion argu- ment was not allowed. In response, the U.S. Con_ There was evidence that the use ofpeyote had gress passed an amendment to the American Indian moved north into the United States as early as 1760. Religious Act of 1978 (i.e., rhe American Indian In the late 19th century, a group of Native Ameri- Religious Freedom Act Amendments of 1994), cans in the Plains became known for its use of pey- which in essence reversed the Supreme Court's rul- ote during religious ceremonies. From that time to ing. The relevant portion of the amended Act stated: the present, Native American missionaries have "the use, possession, or transportation ofpeyote by spread the peyote religion to almost a quarter of a an Indianfor bonafide traditional ceremonial pur- million Native Americans, some as far north as poses in connection with the practice of a tradi- Canada. The Native American Church of the United tional Indian religion is lawfitl, and shall not be States was first chartered in Oklahoma in 1918. It is prohibited by the United States or any State. No an amalgamation of Christianity and traditional Indian shall be penalized or discriminated against beliefs, incorporating peyote use into its ceremo- on the basis of such use, possession or transporta- nies. This is sometimes referred to as peyotism. tion, including, but not limited to, denial of other- Peyotism continues to be an important reli- wise applicable benefits under public gious practice among Native assistance Americans between programs." the Rocky Mountains and the Mississippi. peyote is also used in other ways because the Native Ameri- Son Pedro Cocfus Another mescaline-containing cans attribute spiritual power to the peyote plant. cactus, Trichocereus pachanoi, whose common As such, peyote is believed to be helpful, along name is the San Pedro cactus, is native to the Andes with prayers and modern medicines, in curing ill- Mountains of Peru and Ecuador and has been used nesses. It is also worn as an amulet, much as some for thousands of years as a religious sacrament.2s Christians wear a Saint Christopher's medal, to The San Pedro is a large, multibranched cactus, of- protect the wearer from harm. ten growing to heights of 10 to 15 feet. Its mesca- line content is less than that of peyote, and its recreational use more often results in adverse ef- fects rather than in the desired psychedelic experience.

Phormocology of Mescoline Mescaline is readily ab- sorbed if taken orally but does not readily pass the blood-brain barrier (which explains the high doses required). There is a maximal concentration of the drug in the brain after 30 to 120 minures. About half of it is removed from the body in six hours, and

Peyotism remains an important religious practice among mescaline (mess ka lin): the active chemical in the Native Americans in certain areas of the United peyote cactus. States, @Hemis/Alamy Stock photo 322 Section Six Restricted Drugs there is evidence that some mescaline persists in the brain for up to 10 hours. Similar to the indole psychedelics, the effects obtained with low doses, about 3 mglkg body weight, are primarily euphoric, whereas doses in the range of 5 mglkg give rise to a full set of hallucinations. Most of the mescaline is excreted unchanged in the urine, and the metabo- lites identified thus far are not psychoactive. A dose that is psychoactive in humans causes pupil dilation, pulse rate and blood pressure increases, and an elevation in body temperature. All of these effects are similar to those induced by Some evidence suggests that Ecstasy may be neurotoxic, LSD, psilocybin, and most other alkaloid psyche- affecting serotonin neurons in the btain. Source: Drug Enforcement Administration delics. There are other signs of central stimulation, such as EEG arousal, after mescaline intake. In rats the LD5s is about 370 mglkg body weight, 10 to 30 amphetamine and methamphetamine than those of times the dose that causes behavioral effects' Death classical psychedelics. From a psychological per- results from convulsions and respiratory arrest. spective, the drug increases sociability and eupho- Tolerance develops more slowly to mescaline than ria. Physiologically, it increases blood pressure, to LSD, but there is cross-tolerance between the pulse, and body temperature but decreases appetite two drugs. and sleep. There are also reports of the drug caus- Although mescaline and the other catechol ing teeth grinding (bruxism), but this effect has psychedelics have a structure that resembles the been less well studied. catecholamine neurotransmitters, they act indi- Anecdotal reports suggest that MDMA users rectly on the serotonin 2,A. receptor. report substantially more negative or depressed mood states in the days immediately following Amphetamine Derivatives A large group of syn- MDMA administration. Colloquially, this phenom- thetic psychedelics is chemically related to the enon is frequently referred to as "Suicide Tuesday'" amphetamines. Anecdotally, it has been said that Some have speculated that initially MDMA admin- the effects produced by this class of agents were istration causes a substantial release of serotonin, more similar to those produced by mescaline' This followed by a marked reduction of the neurotrans- view was probably motivated by the observation mitter, lasting several hours to days after the last that the molecular structures of MDMA' MDA' dose. Because serotonin plays a major role in mood DOM, and mescaline are similar. regulation, it is thought that this "reduction" in serotonin produces the depressed mood state MDMA ond MDA Perhaps the best known of these reported by MDMA users in the days following agents is MDMA (sometimes referred to as Ecstasy drug use. But there are no empirical evidence to or molly). Prior to July 1985, the drug could be support this position. In fact, unpublished data col- used legally in the United States. Some psychia- lected in our laboratory at Columbia University do trists used it as a therapeutic aide, arguing that it not indicate the emergence of depressed mood facilitated communication by increasing the pa- states in the days after MDMA use, even when the tient's openness and empathy. Data supporting such drug is given repeatedly. arguments, however, are limited. Studies that have Another frequently mentioned potential nega- evaluated the effects of MDMA in young adults in- tive consequence of MDMA is damage to brain dicate that its effects are more similar to those of cells. Several investigators have shown that large Chapter t4 Psychedelics 323

Drugs in Depth

Extrapolating Findings from Animals to Humans: what you Need to Know "The amount of the drug Ecstasy that some recre- The study's findings generated a wave of con- ational users take in a single night may cause perma- troversy. But in an embarrassing turn of events, nent brain damage and lead to symptoms like those Ricaurte and colleagues were forced to retract their of Parkinson's disease," read an article published in paper one year after its publication because they Ihe New YorkTimes on September zT,zooz.This discovered that larger doses of methamphetamine and similar statements were based on assertions had been mistakenly given, rather than MDMA.'8 made in a scientific paper that appeared in the jour- This was deduced after several unsuccessful nal Science.'6 George Ricaurte and colleagues gave attempts by the researchers to replicate their origi- nonhuman primates three doses of MDMA over the nal findings. lt is noteworthy that the studies that course of six hours and, then, a couple of weeks failed to replicate the neurotoxic findings were later evaluated neuroanatomical and neurochemical never published. This highlights another important changes. They found damage to dopamine and point: There is a bias toward publishing results that serotonin neurons as well as reduced levels of these show drug-induced neurotoxicity. Together, these neurotransmitters in the brain. observations raise questions about the relevancy of What made these results intriguing was that drug-induced neurotoxicity findings collected in lab- the doses of MDMA used and the pattern of drug oratory animals. administration were claimed to be comparable to As a student trying to evaluate drug-related those used by recreational human users. The data, which sources are credible? ln your attempt to researchers injected MDMA at a dosage of z mg/kg, evaluate the research, you should ask a few simple three times, at three-hour intervals, for a total dose questionsr (t) What was the drug dosing regimen of O mg/kg. This dosing regimen does not corre- used, and is it similar to regimens used by humans? spond with those typically used by humans, (r) Most (z) What was the route of drug administration used, people do not take three large doses in one eve- and do humans use the drug in this manner? (:) Was (z) ning; and most people do not inject MDMA. the drug self-administered or administered by the Recall from Chapter 5 that drugs administered by experimenter? (a) Were the animals administered injection result in greater brain concentrations of escalating doses prior to receiving a larger dose? All the drug and increase the potential for toxicity, of these factors potentially impact neurochemical especially in naive users. Potential toxicity is findings and should be considered when making decreased, by contrast, when a drug is self-adminis- extrapolations about data collected in laboratory tered compared to experimenter-administered.2T animals to humans. Thus, these factors increased the likelihood of observing toxicity in the Ricaurte study. Box icon credit: @lngrom Publishing/SuperStock RF doses of MDMA given to laboratory animals can toxicity. This does not, however, suggest that illicit destroy serotonin neurons, but the relevance ofthis MDMA use is safe. As is the case with most illicit and related findings for human recreational use is drugs, there is the potential for contamination with unclear (see the Drugs in Depth box). Recreational adulterants, which are sometimes more toxic than MDMA users do not typically use doses as large as the compound of interest. those used in animal experiments, and when the MDA, known on the street as the love drug, has cognitive abilities of these users is compared with received considerably less research attention. From education- and age-matched counterparts, they per- what little is known, the drug appears to produce form equally well. These observations raise serious effects similar to those seen with MDMA, although questions about the relevance of data collected in there has yet to be a human study that directly com- laboratory animals demonstrating MDMA-induced pares the two drugs. 324 Section Six Restricted Drugs

DOM (STP) DOM is 2,5-dimethoxy-4-methylam- circulation or respiration and did not produce irreg- phetamine. In the 1960s and 1970s, DOM was ularities in heartbeat. Loss of sensation occurred called STP, and street talk was that the initials stood within two or three minutes of beginning the intra- for serenity, tranquility, and peace. Its actions and venous infusion, after about 10 mg ofthe drug had effects are similar.to those of mescaline and LSD, been delivered. The patients later had no memory spoken with a total dose of 1 to 3 mg yielding euphoria and of the procedure, did not remember being 3 to 5 mg a six- to eight-hour psychedelic period' to, and remembered no pain. Compared with exist This makes DOM about a hundred times as potent ing anesthetics, which tend to depress both respira- as mescaline but only one-thirtieth as potent tion and circulation through general depression of as LSD, the CNS, this type of "dissociative" anesthetic seemed to be quite safe. However, the psychologi- 2-CB ond 2-C-T7 lt's happened before and it will cal reactions to the drug were unpredictable' happen again: As federal and state agencies work Thus, by 1960, PCP had been characterized as to limit access to one drug, another arrives to fill an excellent anesthetic for monkeys, a medically the gap. In this case, two drugs have arrived to safe but psychologically troublesome anesthetic for share the rave scene with MDMA: 4-bromo-2, humans, and a psychedelic different from LSD and 5-dimethoxyphenethylamine (known as 2-CB) mescaline, with profound effects on body percep- and 4-propylthio-2, 5-dimethoxyphenethylamine tion. Parke, Davis withdrew Sernyl as an investiga- (2-C:17). As phenylethylamines, both are chemical tional drug for humans in 1965 and in 1967 licensed cousins to the amphetamine series of psychedelics. another company to sell Sernylan as an animal Along with the recently popularized tryptamine de- anesthetic. It was primarily used with primates, in rivatives AMT and "foxy methoxy" (see page3L9), both research laboratories and zoos. Also, because a confusing array of chemicals is being made avail- of its rapid action and wide safety matgin, Sernylan able to "ravers," who may find themselves trying was used in syringe bullets to immobilize stray, unknown amounts of unfamiliar drugs more often wild, or dangerous zoo animals. Because of the than they'd like. popular term tranquilizer gun for this use, PCP became popularly, and inaccurately, known as an animal "tranquilizer." N - ltlethyl - D t-Aspe rtate (1{lrlDAl Antagonists Recreational Use of PCP In the early 1970s, it was said that PCP crystals were sometimes sprinkled PCP onto oregano, parsley, or alfalfa and sold to unsus- In the 1950s, Parke, Davis & Company investigated pecting youngsters as marijuana. In this form, it a series of drugs in the search for an efficient intra- became known as angel dust. Because PCP can be venous anesthetic. On the basis of animal studies, made inexpensively and relatively easily by ama- the company selected 1-(1-phenylcyclohexyl) teur chemists, when it is available it usually doesn't piperidine hydrochloride (PCP' generic name cost much. Eventually, the rapid and potent effects phencyclidine) for testing in humans. The studies of angel dust made it a desired substance in its own on monkeys had indicated that PCP was a good right. Joints made with PCP sometimes contained analgesic but did not produce good muscle relax- marijuana, sometimes another plant substance, and ation or sleep. Instead, the animals showed a sort of were known as "killer joints" or "sherms" (because "dissociation" from what was happening' In 1958, they hit the user like a Sherman tank). the first report was published on the use of PCP At some point in the 1970s, it was reported that (Sernyl) for surgical anesthesia in humans. Sernyl PCP users became violent when under the influ- produced good analgesia without depressing blood ence of the drug. Police narratives claiming to Chapter t4 Psychedelics 328

experience great pCp-intoxi- difficulties subduing primarily restricted to Europe. The fourth genus, cated individuals further cemented the association Datura, is worldwide and has many species con- of PCP and violence. One frequently reported taining the active agents. police story about is the PCP user who was so vio- The family of plants in which all these genera lent, had such superhuman strength, and was so are found is Solanaceae, "herbs of consolation,,' insensitive to pain that he was shot 28 times (or a and three pharmacologically active alkaloids are similarly large number of times) before he fell. responsible for the effects ofthese plants. Atropine, Although there is no evidence that this actually which is dl-hyoscyamine, scopolamine, or happened, the story continues to live and is repeated l-hyoscine, and l-hyoscyamine are all potent central as factual. if What's worse is that this and similar and peripheral cholinergic blocking agents. These stories may contribute to the notion that extraordi- drugs occupy the acetylcholine receptor site but do nary use of force justified is when apprehending a not activate it; thus, their effect is primarily to block suspected PCP user. One such example occurred in muscarinic cholinergic neurons, including the para- March 1991 when Los Angeles police officers were sympathetic system. videotaped beating Rodney King. During their These agents have potent peripheral and cen- trial, the officers said that they used such force tral effects, and some ofthe psychological responses because they believed King might have been to these drugs are probably a reaction to peripheral pCp. "dss1sd"-g11der the influence of He wasn't. changes. These alkaloids block the production of Alcohol was the only drug found in his system. And mucus in the nose and throat. They also prevent regarding the science and PCP-induced violence, a salivation, so the mouth becomes uncommonly dry, comprehensive clinical literature review concluded and perspiration stops. Temperature can increase to that assumptions about PCP and violence are sim- fever levels (109'F has been reported in infants ply not warranted.2e PCP produces many of its effects by selectively blocking the NMDA subtype of glutamate receptor. In other words, PCP is a selective NMDA receptor antagonist. Ketamine, memantine, and dextro- methorphan also act as NMDA receptor antagonists, but their effects at the NMDA receptor are less selective than PCP's. One of the most recent excit- ing lines of research investigates the ability of ket- amine to treat major depressive disorders. A growing body of evidence indicates that the drug not only is effective but also produces antidepres- sive effects at a much more rapid rate than tradi- tional antidepressant drugs.30 The therapeutic effects of ketamine are observed within 24 hours, whereas the beneficial effects oftraditional antide- Belladonna, or deadly nlghtshade, is a poisonous plant that pressants are not seen for 7-I4 days. contains an anticholinergic psychedelic. Osteven p. Lynch RF Anticholinergic Psychedelics PCP: phencyclidine; originally developed as an The potato family contains all the naturally occur- anesthetic; has psychedelic properties. ring agents to be discussed in this section. Three of angel dust: the street name for pCp sprinkled on plant the genera-A t ro p a, Hy o s cy amus, and M andra g o ra material. a single species of importance -have and were 326 Section Six Restricted Drugs

with atropine poisoning), and heart rate can show a "flying ointments" (e.g., Tlte Book o.f tlre Sacred 50-beat-per-minute increase with atropine. Even at Magic of Abremelirt the Mage, 1458), and one moderate doses these chemicals cause considerable ingledient often included in these ointments was dilation of the pupils of the eyes, with a lesulting deadly nightshade. The idea is that this ointment inability to focus on nearby objects. With large was spread upon the body and/or on a stick, or enough doses, a behavioral pattern develops that "staffe," which was straddled. This is certainly the resembles toxic psychosis; there is delirium, mental origin of our notion that witches flew about on confusion, loss of attention, drowsiness, and loss of broomsticks, though in many accounts it seems that memory for rccent events. These two chalacteristics- the sticks were used more as phallic symbols and a clouding of consciousness and no memory for the were perhaps ridden in a different manner. What is period of intoxication-plus the absence of vivid actually known about witches and witchcraft of this sensory effects separate these drugs from the indole era is confused considerably by what was written and catechol psychedelics. The anticholinergics are about witches by Catholic priests during the the original deliriants. Inquisition. During the Middle Ages, all such pagan rituals Belladonna Atropine, which was isolated in I 83 I, is were considered to be heresy, and practitioners the active ingredient in the deadly nightshade,Atropct were tortured and killed. Admissions by witches belladonncr. The name of the plant reflects two of its that they "flew" long distances to celebrate Black major uses in the Middle Ages and before. The genus Mass were extracted during tol'ture and were likely name reflects its use as a poison. Deadly nightshade to have reflected the beliefs of the inquisitors more was one of the plants used extensively by both pro- than the history of the person being tortured. Some fessional and amateur poisoners; 14 of its berries incredibly lurid accounts of the practices of witches contain enough ofthe alkaloid to cause death. associated drugs, sex, and human sacrifice. Similar Belladonna, the species name, meaning "beau- lurid accounts linking other drugs (marijuana, tiful woman," comes from the use of the extract of LSD, cocaine) to sexual abandon and criminal vio- this plant to dilate the pupils of the eyes' Interest- lence have appeared during more recent years, also ingly, ancient Roman and Egyptian women knew promoted by those plotecting the established order. something that science did not learn until more The facts are usually not so exciting. Anticholiner- recently. In the 1950s, it was demonstrated, by gics can make people feel light-headed, and in con- using pairs of photographs identical except for the junction with the power of suggestion one might amount of pupil dilation, that most people judge the get the sensatiort of floating, or flying, but it's not a girl with the more dilated eyes to be prettier. realistic way to get from New York to Laramie. Of more interest here than pretty girls or poi- soned men is the sensation of flying reported by Mandrake The nnndruke plant (Mandragora offic- some usels of belladonna. The origin of this story inorunt) contains all three alkaloids. Although goes back at least to the Middle Ages in Europe, many drugs can be traced to the Bible, it is particu- and in particular to descriptions of witches and larly important to do so with mandrake because its witchcraft. Every early society for which we have close association with love and lovemaking has any history has a tradition of people with special persisted from Genesis to recent times: knowledge of useful plants. In Europe, the people In the time of wheat-harvest Reuben went out and who were consulted for their special arcane knowl- found some mandrakes in the open country and most often women, and edge of plant potions were brought them to his mother Leah. Then Rachel asked their traditions are kept alive in our modern concept Leah for some ofher son's mandrakes, but Leah said, of "witches." Among the rich folklore about witches "Is it so small a thing to have taken away my hus- are several accounts from the 1400s describing band, that you should take my son's mandrakes as Chapterl4 Psychedelics 327

well?" But Rachel said, ,,Very well, let him sleep preaches a sermon, the heavens bedew the petals of with you tonight in exchange for your son's man_ this plant with rain drops."32 drakes." So when Jacob came in from the country in the evening, Leah went out to meet him and said, Halfway around the world, 2,500 years before "You are.to sleep with me tonight; I have hired you the Chinese text, virgins sat in the temple to Apollo with my-.son's mandrakes.,, That night he slept in Delphi and, probably under the influence of with her.3l Datura, mumbled sounds that holy men interpreted as predictions that The mandrake root is forked and, if you have a always came true. Engraved on .,Know vivid imagination, resembles a human body. The the temple at Delphi were the words thyself." root contains the psychoactive agents and was endowed with all sorts of magical and medical Datura is associated with the worship of Shiva properties. The association with the human form is in India, where it has long been recognized as an ingredient alluded to in Shakespeare's Juliet's farewell speech: in love potions and has been known as "deceiver" 'And shrieks like mandrakes torn out of the earth, and "foolmaker." In Asia the practice of That living mortals hearing them run mad." mixing the crushed seeds of Datura metel in tobacco, cannabis, and food persists even today. One interesting Henbane Compared with deadly nightshade and use of Datura stramonium, which is native mandrake, Hyoscyamus nigerhas had a most unin- and grows wild in the eastern United States, teresting life. This is strange, because it is pharma- was devised by the Algonquin Indians. They used the plant cologically quite active and contains both to solve the problem of the adoles_ scopolamine and l-hyoscyamine. Other plants of cent search for identity, allowing male youths to consume this genus contain effective levels of the alkaloids, only concoctions of the plant for a period of two but it is Hyoscyamus niger that appears throughout to three weeks, during which time it was believed these history as henbane, a highly poisonous substance that youths would forget their former lives and and truly the bane of hens, as well as other leave boyhood behind.32 The same plant is animals. Pliny in AD 60 said, "For this is certainly known, that, if one takes it in drink more than four leaves, it will put him beside himself.,' Shake_ speare's Hamlet's father must have had more than four leaves because it was henbane that was used to poison him.

Datura The distribution of the many Datura spe- cies is worldwide, but they all contain the three alkaloids under discussion-tropine, scopolamine, and hyoscyamine-in varying amounts. Almost as extensive as the distribution are its uses and its his- tory. Although it is not clear when the Chinese first rtsed Datura metel as a medicine to treat colds and nervous disorders, the plant was important enough to become associated with Buddha:

The Chinese valued this drug far back into ancient The red- and white-speckled mushroom Amon ito muscorio times. A comparatively recent Chinese medical text, played a major role in the early history of lndo.European and published in 1590, reported rhat ,bhen Buddha Central American religions. Olngram publishing RF 328 Section Six Restricted Drugs

solution now called Jamestown weed, or jimsonweed, as a rites of the god Dionysius in Greece was a And based on paintings result of an incident in the 17th century, recorded in of the Amanila mushroom. ancient the book The History and Present State of Virginia, representing the "tree of life" found in that during which soldiers ate the plant and "turn'd nat- European cave paintings, it has been suggested for the cult ural fools upon it for several Days."33 Arnanita muscaria use formed a basis today Although there has been some recent abuse of that originated about 2,000 years ago and jimsonweed, the unpleasant and dangerous side calls itself Christianity.34 them to alcohol, effects of this plant limit its recreational use. Until the Russians introduced many of the isolated nomadic tribes of Siberia had Synthetic Anticholinergics Anticholinergic drugs no intoxicant but Amanita. these mushrooms are were once used to treat Parkinson's disease (before In the frozen northland, are the introduction of L-DOPA) and are still widely expensive; sometimes several reindeer of the mush- used to treat the pseudoparkinsonism produced by exchanged for an effective number months they might antipsychotic drugs (see Chapter 8). Particularly in rooms. During the long winter them- older people, there is concern about inadvertently be worth the price. While the mushrooms gone), producing an "anticholinergic syndrome," charac- selves are not reusable (once eaten, they're in the urine' terized by excessive dry mouth, elevated tempera- the psychedelic is excreted unchanged Amanita was also used ture, delusions, and hallucinations. Anticholinergic There is evidence that groups in the Amer- drugs such as trihexyphenidyl (Artane) and benz- as a holy plant by several tribal the Great Lakes to tropine (Cogentin) have rarely been abused for their icas, ranging from Alaska and and Central America. In several of the leg- delirium-producing ProPerties. Mexico ends, its origin is associated with thunder and Amonito Muscsrio lightning.r in this mush- The Amanita muscaria mushroom is also called For many years the active agent (for which the "fly agaric," probably because of what it does to room was thought to be rnuscarine flies. It doesn't kill them, but when they suck its muscarinic cholinergic receptors were named). juice, it puts them into a stupor for two to three This substance activates the same type of acetyl- the anticholiner- hours. It is one of the common poisonous mush- choline receptor that is blocked by with other rooms found in forests in many parts of the world. gics. However, pharmacological studies similar psy- The older literature suggests that eating 5 to 10 cholinergic agonists did not produce Amanita mushrooms results in severe effects of choactive effects. Next, attention focused on bufo- high concentrations intoxication, such as muscular twitching, leading to tenin, alindole that is found in psychedelic twitches of limbs and raving drunkenness, with agi- in the skins of toads. However, the doubt, and tation and vivid hallucinations. Later follow many properties of bufotenin have been in amounts of it' hours of partial paralysis with sleep and dreams' Amanita species contain only small two When the ancient Aryan invaders swept down In the mid-1960s, meaningful amounts of and from the north into India 3,500 years ago' they took chemicals were found: ibotenic acid soma, itself considered a deity. The cult of Soma muscimol. not simi- ruled India's religion and culture for many years- The effects of Amanita ingestion are psychedelics, and that helped the poems of the Rig Veda celebrate the sacramen- lar to those of other regard to the mechanism' tal use ofthis substance. It has only been within the confuse the picture with past 30 years that scholars have discovered and Muscimol can act as an agonist at GABA receptors, throughout the cen- agreed on the identity of soma as Amanitq.l which are inhibitory and found potent than The suggestion has been made that the ambro- tral nervous system. Muscimol is more sia ("food of the gods") mentioned in the secret ibotenic acid, and drying of the mushroom, which a Chapter 14 Psychedelics 32g

is usually done by those who use promotes it, the measure that consists of six subscales assessing transformation of ibotenic acid to muscimol. Mus_ various aspects of psychedelic effects. In addition, cimol has been given to humans, resulting in confu_ salvinorin A occasioned mystical-type effects simi_ sion, disorientation in time and place, sensory lar in magnitude to those seen with psilocybin, disturbances, muscle twitching, weariness, fatigue, These results were replicated and extended, demon_ and sleep.le strating that there was no evidence of persisting Amanita muscaria and other related poisonous adverse effects one month following drug mushrooms are found in North America, and they administration.38 are a particularly dangerous type of plant with The findings from rhese studies markedly dif_ which to experiment. fer from the uncontrolled effects seen in online vid_ eos of Salvia divinorutn Sulvia Divinorum use. This observation underscores the importance of the user's history This member of the mint family is known by its and the setting in which drug use occurs. As is the botanical name, which is translated as ,.diviner,s case with all psychoactive drugs, adverse conse_ sage." It has been used for centuries by theMazatec quences are more likely when inexperienced users people of Oaxaca, Mexico, in religious ceremonies. take drugs in chaotic and uncontrolled settings The traditional methods of using the plant include compared with use by experienced users in care_ chewing the leaves, drinking a tea made from the fully controlled settings. crushed leaves, or smoking the dried leaves. Recre_ ational users in the United States and in Europe have cultivated the plant for the past several years Summary and use it via the smoking route. The U.S. govern_ ment does not list Salvia divinorum as a controlled . Psychedelic plants have been used for many substance, but multiple states have taken matters centuries, not only as medicines but for spiri_ into their own hands by banning the substance. tual and recreational purposes as well. The plant was identified in 1962 by Wasson and . LSD, a synthetic psychedelic, alters perceptual Hoffman, and the active agent, salvinorin A, was processes and enhances emotionality, so that identified in 1982. Salvinorin A is a kappa opioid the real world is seen differently and is receptor agonist. The drug produces no effect on the responded to with great emotion. serotonin-2A receptor, the main target for classic . Other chemicals that contain the indole nucleus, psychedelics such as LSD, mescaline, and DMT.35 such as psilocybin (from the Mexican mush- Given its pharmacological profile, one might room), have effects similar to those of LSD. predict that the drug would produce effects differ- . Mescaline, ent from the classical psychedelics. At least two from the peyote cactus, and syn- thetic studies have been published investigating the derivatives of the amphetamines repre- sent effects of salvinorin A in human users: the first by the catechol psychedelics. They have psychological Matthew Johnson and colleagues and the second by effects quite similar to those of the indole types. Peter Addy.36'37 In both studies, the drug was inhaled and doses ranged from 0 to 21 pglkg. Salvi- . PCP, or angel dust, produces more changes in norin A produced dose-dependent effects on partic_ body perception and fewer visual effects than ipant ratings of drug strength. The drug also LSD. increased ratings of euphoria and did not increase . Anticholinergics are found in many plants dysphoric ratings. At the larger doses, salvinorin A throughout the world and have been used not produced a profile of effects similar to DMT and only recreationally, medically, and spiritually psilocybin on the Hallucinogen Rating Scale, a but also as poisons. It

330 Section Six Restricted Drugs

7. Hofmann, A. "Psychotomimetic Agents." In A. Burger, ed. Review Ouestions Drugs Affecting the Central Nervous Systern (Vol 2). New York: Marcel Dekker, 1968. 1. Why was LSD used in psychoanalysis in the 8. Segal, 1., ed. Research in the Service of Mental Heahh, on Mental Health, 1950s and 1960s? How does this relate to its Research on DrugADrse. National Institute Pub. No. (ADM) 75-236, U.S. Department of Health, Educa- proposed use by the ArmY and the CIA? tion, and Welfare. Washington, DC: U.S. Government Printing 2. Describe the dependence potential of LSD in Office, 1975. 9. Julien, R, M. A Primer of Drug Action, 10th ed. New York: terms tolerance, physical dependence, and of Worth, 2005. psychological dePendence. 10. Halpern, J. H., and others. "Hallucinogen Persisting Percep- Years?" Drrrg & 3. What is the diagnostic term for flashbacks? tual Disorder: What Do We Know after 50 Alcohol Dependence 69 (2003), pp. 109-19. agent in the "magic mush- 4. What is the active I l. 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