Psychedelics Textbook PDF

# Chapter 15 Hallucinogens, Psychedelics, and Club Drugs In this chapter, you will learn about a variety of drugs that profoundly impact users' sensory perceptions and emotions, but do so through diverse mechanisms of action. At one time, these substances were referred to as psychotomimetics, sugge...

# Chapter 15 Hallucinogens, Psychedelics, and Club Drugs In this chapter, you will learn about a variety of drugs that profoundly impact users' sensory perceptions and emotions, but do so through diverse mechanisms of action. At one time, these substances were referred to as psychotomimetics, suggesting (falsely) that they routinely foster a mental state analogous to psychosis. Later, they were rather broadly named the hallucinogens, though, at ordinary doses, many of these drugs do not typically produce hallucinations. Various other monikers have also been applied to this diverse group, each of which attempts to capture a certain feature of the drugs' subjective effects. These titles include phantasticants (substances that induce vivid perceptual experiences), psychedelics ("mind manifesters"), entactogens ("touching within"), and empathogens ("empathy enhancers"). The latter three labels were proposed to describe the enhancing effects of these substances on the mind, such as gaining personal insight or empathy. The individual may feel more in touch and in love, with other people as well as his or her own self, closer to God or the universe, and may experience a state of ecstasy. Due to the nature of these subjective effects, it has been suggested that drugs of this type could be useful tools in psychotherapy, though others have warned of their potential dangers. Some of the compounds included in this chapter tend to be used by teenagers and young adults at nightclubs, concerts, and parties to enhance their pleasure and appreciation of music, dancing, and social interactions. When used in this way, they are referred to as club drugs. Numerous chemical analogs of hallucinogenic and psychedelic compounds have been synthesized. Some of the more popular of these designer drugs will also be discussed in this chapter. ## 15.1: Classic Hallucinogens Hallucinogens are defined as agents that alter thought, perception, and mood without producing memory or intellectual impairment, delirium, or addiction, and that cause minimal autonomic side effects. To distinguish these compounds from others, such as cannabis or ketamine, that have very different chemical structures and mechanisms of action but likewise have hallucinogenic and psychedelic properties, we refer to the drugs discussed in this section as the classic hallucinogens. Classic hallucinogens can be divided into two main structural classes: the indolamines, whose molecular structures bear resemblance to that of serotonin, and the phenethylamines, which are structurally similar to molecules of dopamine or norepinephrine. The chemical structure of LSD, for instance, is similar to that of serotonin and the drug therefore belongs in the indolamine class, whereas mescaline has a molecular structure more closely resembling the catecholamines and therefore belongs with the phenethylamines. Despite their structural differences, the indolamine and phenethylamine classic hallucinogens overlap considerably in their subjective effects, so they will be discussed together in this section. The main differences that exist amongst the classic hallucinogens lie in their selectivity for certain serotonin receptor subtypes, varying potencies, and durations of action. In addition to LSD, members of the indolamine class of hallucinogens include: - lysergic acid amide (LSA)-an ergoline chemical compound (like LSD) found in the seeds of the flowering plant species known as morning glory. - psilocybin-the psychoactive ingredient in "magic mushrooms," or species belonging to the genus Psilocybe, such as those known to the Aztecs as teonanácatl. - bufotenine-contained in the skin secretions of toads of the Bufo genus, as well as in certain plant species. - harmine and harmaline-plant compounds found in the bark of Banisteriopsis caapi, a tropical vine. - N,N-Dimethyltryptamine (DMT)-a compound present in a variety of insect and amphibian species, as well as in more than 50 plant species. In recent years, a lot of media attention has been devoted to a South American hallucinogenic decoction (herbal brew) called ayahuasca, and a related emerging trend known as hallucinogenic tourism-foreigners traveling to South America to partake in the ritual of ayahuasca consumption. Ayahuasca ("vine of the souls") is a brew made from Banisteriopsis caapi in combination with other plants, most often Psychotria viridis. The primary psychoactive ingredient in ayahuasca is DMT (from P. viridis), which stimulates serotonin 5-HT2A receptors. However, when orally administered, DMT is rapidly metabolized in the gut and liver by the enzyme monoamine oxidase A (MAO-A), rendering it inactive. Harmine and harmaline (from B. caapi) are MAO inhibitors. While not particularly psychoactive on their own, their presence in ayahuasca prevents MAO-A from metabolizing DMT, thereby allowing the drug to enter the bloodstream and reach the brain. Ayahuasca's hallucinatory effects are therefore contingent upon the combination of active ingredients found in both plants. The hallucinogenic effects of ayahuasca usually appear within 1 hour of ingestion and last approximately 4 hours. ### LSD: #### 15.1.1: History of LSD LSD is an odorless, colorless, and tasteless synthetic drug. A number of compounds similar to LSD exist naturally in the ergot fungus that infects grains. During the Middle Ages in Europe, there were outbreaks of what is now called ergotism, a reaction caused by eating fungus-infected grain. The symptoms of ergotism usually take one of two forms. One set of symptoms involves vasoconstriction and a severe restriction in blood flow to the extremities, making the person feel excessively warm. This eventually leads to gangrene and the loss of fingers, toes, or entire limbs. In 1039, a religious order was formed in France to treat people afflicted with this kind of ergotism. The patron saint of this order was St. Anthony, and the disease became known as St. Anthony's fire because of the sensation of heat. The other set of symptoms seen in ergotism is characterized by convulsions, delirium, and hallucinations. That these afflictions were caused by the ergot fungus was not discovered until more than 700 years later, in 1777. In fact, St. Anthony's fire is caused by derivatives of lysergic acid produced by the ergot fungus. The story of LSD begins in the twentieth century. One of the effects of the lysergic acid derivatives in ergot was contractions of the uterus, a fact that was well known to midwives who used it to aid women in childbirth. The potential medical use of LSD prompted Albert Hofmann of the Sandoz Laboratories in Basel, Switzerland, to experiment with the derivatives of lysergic acid in the hope of finding a new pharmaceutical. He had no idea at the time that he was dealing with a hallucinogen. In 1938, Hofmann synthesized a series of lysergic acid compounds, but found none of them particularly interesting and moved on to other priorities. Five years later, in 1943, Hofmann made a fresh batch of the 25th derivative (which he called LSD-25) and conducted some new experiments, but he began to feel very peculiar and decided to go home. Hofmann suspected that the reason for his strange sensations lay in his accidental ingestion of some of the LSD-25. To test his theory, a few days later Hofmann deliberately ingested 0.25 mg, which he believed to be an extremely small dose of the drug. His plan for testing the drug's effects was to begin by taking a dose so small that it would have no discernable consequence and then to slowly increase the dose. Hofmann was unaware of the extreme potency of LSD and the fact that a quarter of a milligram is, in fact, a rather large dose. This amount of LSD is more than sufficient to produce a significant hallucinatory effect, causing Hofmann to experience the first LSD "trip." Sandoz Laboratories, unsure of what to do with this new compound, distributed LSD to laboratories in Europe and the United States for testing. Government agencies in the United States wondered whether LSD could be used in intelligence gathering or as a weapon to temporarily incapacitate the enemy without bloodshed or loss of life. Its similarities to serotonin, both in chemical structural and mechanism of action, led researchers to hypothesize that LSD may prove useful in the treatment of mental disorders and alcoholism, or at least as a tool for studying psychotic behavior. Some researchers believed that LSD had the power to evoke great personal insight and possessed considerable psychotherapeutic potential. Based on the Alcoholics Anonymous (AA) philosophy that the induction of a spiritual experience can facilitate recovery from the disease of alcoholism, Osmond gave high doses of LSD to his patients and reported a 40-50% success rate in quitting alcohol use (although most patients relapsed due to a lack of follow-up counseling). The potential of hallucinogens, including LSD, as psychotherapeutic tools in the treatment of alcoholism and other substance use disorders continues to be investigated and remains a contentious topic. LSD was used in experiments in mental hospitals and laboratories until the mid-1960s, when it broke out of the laboratory and hit the street. Timothy Leary, a research professor in the Department of Social and Human Relations at Harvard University, had long been thought of by his colleagues as rather unconventional in his views. The psychedelic revolution began for Leary in 1960. While visiting Mexico, Leary ate mushrooms containing psilocybin, causing him to have a "full-blown conversion experience." Upon his return to Harvard, Leary and his colleague, Richard Alpert, distributed psilocybin to as many people as they could persuade to try it. In 1961, Leary and Alpert experimented with LSD, started a new religion, and adopted LSD as a sacrament. In 1963, the men were dismissed from Harvard, a move that generated considerable publicity, both for them and for the drug. They coined the phrase that was to become the mantra of the hippie movement of the 1960s: "Turn on, tune in, drop out." LSD experienced its heyday during the 1960s and early 1970s-the era of the hippie movement, which reached its peak at the Woodstock Music Festival in 1969. In 1970, LSD was classified in the United States as a Schedule I (illegal) drug. Over the past 50 years, LSD has not vanished from the recreational drug scene but its pattern of use is now rather different. In the 1960s, LSD was used as a true psychedelic-high doses were taken in order to achieve vivid hallucinations and personal or cosmic insight. The use of such high doses did not always lead to a pleasurable experience. It has been suggested that today's drug users are not as interested in personal insight as they are in pleasure. LSD is now taken in much smaller doses and used more as a phantasticant or entactogen than as a hallucinogen. The resultant effect is a euphoric high similar to that of marijuana. The powerful mind-altering properties of LSD are neither achieved nor desired. #### 15.1.2: Route of Administration and Pharmacokinetics LSD is typically sold as hits to be taken orally. In the 1970s, the average hit contained about 100 mg of LSD. However, there has always been great variation in the dosage available in a single hit; some may contain as much as 300 mg of LSD. The effective oral dose of LSD is about 20-80 mg. The dose required to produce a full psychedelic experience with intense visual hallucinations is approximately 200 mg. Hits of LSD are most commonly sold in the form of tiny squares of paper called blotter. The paper, which may be plain or decorated with cartoons, mosaic patterns, or other artwork, is perforated, submerged in liquid LSD solution, and then dried. Each square comprises one hit to be dissolved on the tongue. Hits may also be sold in the form of gel tabs, which consist of LSD encapsulated in gelatin and set in molds of various shapes. Similarly, window panes are flat gelatin squares. Gelatin products usually contain a larger dose of LSD compared to that found on blotting paper because the gelatin protects the drug from deterioration caused by exposure to light and air. LSD is also available as tiny pills called microdots; as sugar cubes or candy (often Gummy Worms, Sweet Tarts, Altoids, or Pez) soaked in drug solution and dried; and in gel wraps, which look like blue bubble-wrap packing material. Small bottles of liquid LSD are sold under the guise of breath-freshening drops. Following ingestion, LSD takes effect within 30-60 minutes. Only about 1% of the drug ever reaches the brain. The elimination half-life of LSD is approximately 175-300 minutes and the drug's effects can be felt for 10-12 hours. LSD is metabolized extensively in the liver, and its many metabolites are secreted from the body through the digestive system and kidneys. Mescaline is acquired from the dried heads of cactus flowers and can be eaten or soaked in water to create an intoxicating drink. The typical effective dosage of mescaline is 200-400 mg. Mescaline is readily absorbed from the digestive tract and has a half-life similar to that of LSD. #### 15.1.3: Neuropharmacology Although LSD and other classic hallucinogens have a relatively long history of use and have been studied extensively, their effects on the central nervous system are still not entirely clear. LSD is known to act as a serotonin receptor blocker in the peripheral nervous system, but in the central nervous system it acts as a serotonin receptor agonist. Likewise, the phenethylamine hallucinogens agonize serotonin receptors in the central nervous system, demonstrating highly selective binding for 5-HT2A as well as 5-HT2B and 5-HT2c receptor subtypes. LSD and other indolamine hallucinogens, such as psilocybin and DMT, also act as 5-HT2 receptor agonists, but they are far more promiscuous in their binding and stimulate additional serotonin receptor subtypes, such as the 5-HT₁ receptor series. In cortical neurons, LSD and other hallucinogenic compounds trigger a particular intracellular signaling cascade that is distinct from that triggered by other 5-HT2A receptor agonists. This neuropharmacological action appears to be one of the reasons why these compounds cause hallucinations. Additionally, the ergot hallucinogens (LSD and LSA) exert actions at dopaminergic and adrenergic receptors. Three regions of the brain appear to be involved in the effects of the classic hallucinogens: the locus coeruleus (LC), the cortex, and the raphe nuclei. The LC is the source of nearly all noradrenergic projections in the central nervous system. It is involved in fear and emotional responses and appears to function as a novelty detector, as it is extremely responsive to sensory stimuli that are novel or highly arousing. The LC receives input from many sensory sources throughout the body, including the raphe nuclei. It sends axons to almost every area of the brain, including the cortex where it promotes the release of NE. Stimulation of 5-HT2A receptors by both indolamine and phenethylamine hallucinogens can suppress output of the LC, although it occurs through different mechanisms. In addition, these drugs enhance the response of the LC to novelty. This might explain the common effects of hallucinogenic drugs on perception. After taking mescaline, for example, people often report that it is like seeing things for the first time. In the cortex, hallucinogenic drugs alter the response of large glutamatergic neurons to synaptic input by increasing the duration of excitatory action potentials. This effect is mediated through serotonin synapses and is most prominent in the medial prefrontal cortex, where 5-HT2A receptors are densely concentrated. This area of the cortex is instrumental in information processing and perception and an important site of action for the hallucinogens. The raphe nuclei are clustered in the brainstem and release serotonin throughout the rest of the brain. LSD acts as a 5-HT1A receptor agonist in the raphe system, where it inhibits neuronal firing and serotonin release. Because the LC receives input from the raphe nuclei via serotonin neurons, suppression of the raphe system by hallucinogenic drugs may be the precursor to LC suppression and resulting effects. #### 15.1.4: Effects of Classic Hallucinogens on Human Behavior The effects of LSD on the body are highly dependent upon the dose taken by the user; higher doses produce more pronounced or even adverse physiological effects. Symptoms may include pupil dilation, nausea, vomiting, diarrhea, abdominal pain, an increase in body temperature, profuse sweating, increased heart rate and blood pressure, tachycardia, loss of appetite, sleepiness, dry mouth, and tremors. These effects are, however, rarely life threatening. ##### Hallucinogenic Effects How does a researcher go about studying hallucinations? Hallucinations are, by definition, in the realm of subjective experience, and one of the first principles of scientific inquiry is that all data must be public and observable to anyone who looks for it. It is, however, possible to study the verbal reports of people who are experiencing or have experienced hallucinations. Compared the reports of participants in his mescaline experiments with those of other researchers and noticed that there were strong consistencies. Mostly, people described vivid visual images that were not real. If participants closed their eyes, they would see these images against a black background; if they opened their eyes, the images would be projected onto whatever they were looking at. Klüver noticed that the images were frequently geometric, and he identified some common patterns: a grating or lattice; a cobweb; a tunnel, funnel, or cone; and a spiral. Klüver remarked that images of these types also appear in fever deliriums, insulin hypoglycemia, and states that occur just before drifting off to sleep (hypnogogic states). Unfortunately, Klüver went only as far as to describe the first of two stages of imagery; the second stage, described by other researchers, is more complex and involves meaningful images of people, animals, and places. Even during this second phase, there are some common elements between individuals. For example, 60-70% of research participants report seeing small animal or human figures that are friendly and caricature-like, and 72% of all participants report religious imagery. Despite great interest in these observations, no comprehensive, systematic, or scientific work on them was attempted until the 1970s. The problem was tackled by Ronald Siegel. Siegel adopted a variation of the technique of trained introspection, which was used by the early German schools of psychology. Siegel trained his observers to use a code to describe their experiences. They were able to code images, colors, and movement by using a series of letters and numbers that could be quickly expressed. Following this training, Siegel gave participants a series of blind tests in which they were administered placebos or any of a number of drugs in random order and left in a darkened room to report their experiences. Neither the participants nor the researchers scoring the imagery codes knew what drug had been given. Whereas the participants who took placebos saw a predominance of random forms, those administered hallucinogenic drugs saw far more lattice and tunnel forms, confirming the observations Klüver had documented. During control sessions, participants saw primarily black and violet forms, but in hallucinogenic sessions, they saw more colors, ranging into the yellow, orange, and red end of the color spectrum. Finally, in all conditions, aimless and pulsating movement was reported, but in hallucinogenic sessions there was an increase in "explosive" movement. After demonstrating that all of these drugs appeared to evoke similar types of images, Siegel was also able to show that, at higher doses, people sometimes go through a phase where they see themselves being swept up into their own hallucination. This is followed by a stage where the images lose their geometric quality and become meaningful pictures of real objects. These images can change rapidly, as fast as 10 times per second, but the changes are not without a pattern. Each image appears to be related to the one before it. Siegel also noted that the images during this stage were related to the participant's surroundings; for example, sounds such as footsteps induced an image of someone walking. Another interesting finding was that the colors appeared to shift from the blue end of the spectrum to the red end as the effect of the drug increased in intensity. Because all the classic hallucinogen drugs have such similar effects, Siegel wondered whether the similarities might be due to cultural factors, since all his subjects came from a similar culture. To answer this question, he visited a remote tribe of Huichol Indians in the Sierra Madre range of Mexico. The Huichols use dyed yarn to make brightly colored depictions of their peyote visions. Siegel found that the experiences represented by the Huichols in their yarn images were very similar to those reported by the participants in his laboratory. Siegel then postulated that the nature and structure of hallucinations must be determined by the nature and structure of the visual system and the brain, not by the drug, because (a) these hallucinatory experiences are similar among vastly different drugs; (b) the experiences resemble the effects produced by other nondrug hallucinations, such as those from fever, hypoglycemia, and migraine headaches; and (c) the experiences are similar between cultures. In other words, the hallucinations are a result of nonspecific interference in brain functioning; the drug intensifies what might be considered normal background noise in the perceptual systems, and this noise is then organized, by the normal processes of perception and cognition, into images and patterns. Siegel's study addressed only the visual property of the hallucinogenic experience, but LSD can cause entactogenic and empathogenic effects as well. These experiences often have a profound effect on emotions, insight, and feelings, which are not as easily studied and can be conveyed only by less scientific modes of expression, as we shall see. ##### Phantasticant and Perceptual Effects Hallucinogenic drugs can cause users to feel as though the experiences they are having are of great emotional or worldly significance. Often, these experiences are of a spiritual nature. For this reason, classic hallucinogens like psilocybin and DMT have been used for thousands of years in traditional religious ceremonies. The spiritual nature of the hallucinogenic experience is described by R. Gordon Wasson: *It permits you to see more clearly than our perishing mortal eyes can see, vistas beyond the horizons of this life, to travel backwards and forwards in time, to enter other planes of existence, even (as the Indians say) to know God. It is hardly surprising that your emotions are profoundly affected and you feel that an indissoluble bond unites you and the others who have shared in this sacred agape. All that you see during this night has a pristine quality; the landscape, the edifices, the carvings, the animals-they look as though they had come straight from the Maker's workshop. *(p. 197)* Another commonly reported experience is the greatly enhanced pleasure derived from viewing art and, especially, listening to music: *Ordinarily I am not particularly susceptible to music. This time, lying on the cot, I became acutely aware of the Montoya record playing. This was more than music: the entire room was saturated with sounds that were also feelings-sweet, delicious, sensual-that seemed to be coming from somewhere deep down inside me. I became mingled with the music, gliding along with the chords. Everything I saw and felt was somehow inextricably interrelated. This was pure synesthesia, and I was part of the synthesis. I suddenly "knew" what it was to be simultaneously a guitar, the sounds, the ear that received them, and the organism that responded, in what was the most profoundly consuming aesthetic experience I have ever had. *(Richardson in Aaronson & Osmond, 1970 1, p. 53)* ##### Entactogenic and Empathogenic Effects Another commonly reported effect is that the classic hallucinogens seem to provide insight into one's past and mind, revealing repressed thoughts and unrecognized feelings. Such insights are similar to those that psychoanalysis attempts to achieve through psychotherapy. It was this effect that inspired Humphry Osmond to suggest that hallucinogens might be useful tools in psychotherapy, a belief that still exists today. This effect also prompted the use of the term entactogenic ("touching within"). Here is a description of the experiences of psychologist Bernard Aaronson, who took LSD as part of an experiment: *We sat on the bench under the trees and talked about the loneliness of being, and talked about how people are forever needing things they expect you to provide. For what seemed a long time, I cried as I have not cried since I was a baby, for all the people in the world who need things and whose needs cannot be met. I cried too for all the people around me that I botched in the giving or to whom I cannot give because I am depleted .. I expressed great hostility toward both my parents and with H's help analyzed my feelings as they derived from my relationship with each of them. I analyzed my relationship with my next older brother, and examined the meaning in my life of my relationship with that friend whom I love the most. *(Aaronson & Osmond, 1970 pp. 47-48)* A complete account of the subjective experiences of hallucinogens is beyond the scope of this text, but a good selection of accounts of drug experiences may be found in Grinspoon and Bakalar (1979b). ##### Effects on Perception As you have learned, people who use LSD frequently report that their perceptions are much keener and that their sight and hearing have become more acute. There have been a few studies of the effects of LSD on visual sensory thresholds, but their results are inconsistent. In general, however, impairments in sensory functions attributable to LSD are reported more often than improvements. ##### Tolerance In humans, tolerance to the effects of LSD and related drugs develops extremely rapidly. When LSD is taken repeatedly at daily intervals, tolerance is observed after 1-3 days and a near-complete loss of response eventually ensues so that the drug no longer produces any desired effect. The ability of LSD to disrupt the operant behavior of nonhumans also shows rapid tolerance. Such tolerance appears to be mediated by an acute downregulation of serotonin 5-HT2A receptors and is one reason why classic hallucinogens are seldom taken continually. The abrupt tolerance to hallucinogens dissipates quickly, however, and sensitivity returns within a week. Cross-tolerance has been observed between LSD, psilocybin, and mescaline but not between LSD and d-amphetamine or THC. As an exception to the rule, tolerance does not build to the effects of DMT, nor does the repeated administration of this drug lead to a downregulation or desensitization of 5-HT2A receptors. During ayahuasca ceremonies, the decoction may be taken repeatedly across multiple nights, and is each time capable of producing psychedelic effects. ##### Withdrawal No withdrawal symptoms for LSD or any similar drugs have been documented. This may be because the drugs are seldom taken continuously for any period of time and do not lead to physical dependence. However, adverse effects of the hallucinogens can persist for some time after cessation of use. One such effect is a rare perceptual disorder called hallucination persisting perception disorder (HPPD; colloquially known as "flashbacks"). HPPD is discussed further in Section 15.1.6. ##### 15.1.5: Self-Administration The use of consciousness-altering substances, including classic hallucinogens like DMT, mescaline, and psilocybin, is an ancient and near-universal practice in human cultures. However, the use of these drugs is quite different from that of most others. First, classic hallucinogens are never consumed in a continuous manner. They are indulged in sporadically and on special occasions. The use of hallucinogens in most societies is usually associated with religious ceremonies, cultural practices, or therapeutic interventions. In many cultures, these drugs are taken only by priests and shamans for the purpose of divination, talking to the dead, or seeking direction from a deity. Even in modern Western culture, hallucinogens are usually taken episodically. Unlike other heavily used drugs such as alcohol or nicotine, the use of classic hallucinogens does not usually escalate over time. This is likely due, in part, to the rapid development of tolerance that occurs with repeated use. ##### 15.1.6: Harmful Effects The classic hallucinogens are unlikely to cause life-threatening cardiovascular effects or to damage the functioning of the liver or kidneys, as they have little affinity for these or any other biological targets that play a role in drug toxicity and overdose. There are no known cases of anyone dying from an overdose of a classic hallucinogen. This is not true, however, of certain designer hallucinogenic drugs, such as 5-MeO-DIPT, 5-MeO-DALT, and AMT (all psilocybin-like compounds), or MDMA (a mescaline-like compound). There are many incidences in which users experience non-life-threatening adverse reactions to the use of classic hallucinogens. The subjective effects of these drugs very much depend on the personality and mood of the user, as well as on the environment in which the substance is taken. Sometimes, people experience a "bad trip" or psychedelic crisis, marked by a sense of anxiety, panic reactions, or terror evoked when the user loses sight of the fact that the experience is drug-induced. Panic reactions do not normally occur in experienced users, are frequently the result of an unusually high dose (or a mixture) of drugs, and do not constitute a serious medical emergency. Panicked users can usually be calmed down when someone talks calmly to them and reassures them that their state is drug-induced. When the user's attention is concentrated on this fact, the panic often dissipates. In individuals with preexisting vulnerability for psychopathology, more prolonged psychotic or depressive symptoms may be experienced. One additional adverse outcome of classic hallucinogen use is that their perceptual effects may briefly reoccur, days, months, or even years after using the drug, an experience that is often (understandably!) accompanied by panic. Whereas the acute perceptual alterations caused by hallucinogens typically wear off as the drug is metabolized and excreted from the body, for a subset of individuals, these perceptual alterations do not fade away. These episodes are commonly known as flashbacks, and the condition is listed in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (the DSM-5) as Hallucinogen Persisting Perception Disorder (HPPD). Symptoms of HPPD are similar to those perceptual changes experienced while intoxicated with a hallucinogen, and may include: geometric or kaleidoscopic visual images; false perceptions of movement in peripheral visual fields; flashes of color; an intensification of colors; trailing phenomena, in which a moving object is followed by a series of stationary images that trail along its trajectory; palinopsia, in which a moving object leaves a continuous "smear" in its path; positive afterimages, in which objects continue to be "seen" after they have gone; the appearance of "halos" around objects; macropsia, in which objects appear larger than they actually are; and micropsia, in which objects appear smaller than they really are. These symptoms of HPPD may occur unpredictably and in short episodes that last a few seconds or minutes, rather than continuously. They can be triggered by entering a dark room, acute alcohol or cannabis intoxication, anxiety, fatigue, stress, or by worrying or thinking about flashbacks. Sometimes, however, the perceptual disturbances are unrelenting. In Internet surveys, more than 60% of respondents with extensive histories of drug use reported at least one type of recurring visual experience, and 24-40% reported experiencing HPPD symptoms on a constant or near-constant basis. Yet, less than 5% of respondents reported having considered seeking treatment for their symptoms, suggesting that they did not feel their level of impairment was severe. ### Salvinorin A: Salvinorin A is a psychoactive compound found in a single species of plant belonging to the mint family named Salvia divinorum-the "diviner's sage." The compound is compartmentalized in the glandular trichomes (fuzzy, hair-like strands) of Salvia, in the same way that phytocannabinoids are stored in the Cannabis plant. Salvia divinorum is indigenous to a small region in Mexico's state of Oaxaca where it has been used for centuries by Mazatec shamans in healing and divination ceremonies. It is known as "the leaf of the prophecy" owing to the plant's ability to induce visions. The Mazatecs also train medical practitioners in the use of Salvia divinorum as a treatment for anemia, diarrhea, headache, rheumatism, and an illness known as swollen belly, which they believe is a curse resulting from black magic. Salvia divinorum produces hallucinogenic and dissociative effects that share some similarities with symptoms of intoxication resulting from the cannabis, ketamine, or high doses of classic hallucinogens. However, experienced hallucinogen users report that intoxication by salvinorin A is unique and particularly intense. Salvinorin A is indeed unique, as it is the first known diterpene hallucinogen. Chemically, it does not resemble other psychedelic compounds like LSD or mescaline, which are alkaloids. Dried Salvia divinorum leaves contain about 0.18% salvinorin A which, by weight, makes this compound the most potent of the natural hallucinogens. The effects of salvinorin A can be felt after doses as small as 200 micrograms, which is comparable to the effective dose of a synthetic or semisynthetic psychoactive drug, like LSD. Street names for the drug include magic mint, Sally D, lady sally, Maria Pastora, and puff. The use of Salvia divinorum is controlled in many countries around the world, including Italy, Japan, Russia, Spain, Sweden, Australia, Canada, and some U.S. states. #### 15.4.1: Routes of Administration and Pharmacokinetics When used traditionally by Mazatecs, Salvia divinorum is taken orally, either by chewing fresh leaves or by crushing them, blending their juices with water, and ingesting the liquid mixture. Salvinorin A is absorbed through buccal membranes, but any drug that is swallowed is fully degraded within the gastrointestinal tract and fails to reach the bloodstream. When salvinorin A is administered sublingually in liquid form, it produces no effect on the user, suggesting a lack of bioavailability via this route. When used recreationally, Salvia divinorum leaves are sometimes chewed, but it is much more common to smoke the plant material using a pipe or bong, or to vaporize it and inhale the aerosol mixture into the lungs. When chewed, users typically retain the plant material in the mouth for 15-20 minutes before spitting or swallowing it. When smoked from a pipe, users hold the smoke in their lungs for more than 20 seconds, as is also typical of cannabis smokers. In an average session, users will smoke 0.25-0.75 grams of plant material. When salvinorin A is absorbed through buccal membranes, its effects are detected within about 5-10 minutes, build gradually and are maintained over the next 60 minutes, and then slowly decline during the following 60-minute period. When smoked, a 200-500 mg dose of salvinorin A produces rapid effects that onset within about 30 seconds, peak in intensity after 5-10 minutes, and then gradually decline over the next 20-30 minutes, though lingering perceptual effects may last for an additional hour. Double-blind, placebo- controlled studies of the effects of vaporized salvinorin A report that participant-rated maximal "drug strength" is reached even faster, peaking at 2 minutes (the first measurement time point) post-inhalation, and then gradually diminishing over the ensuing 20-minute period. Salvinorin A is rapidly distributed throughout the body. A non-human primate PET imaging study using radiolabeled salvinorin A revealed that the drug very quickly crosses the blood-brain barrier and achieves maximum brain concentrations within about 40 seconds of intravenous administration. The highest concentrations of salvinorin A occur in the cerebellum and in the visual cortex. Clearance of salvinorin A from the brain is also astonishingly rapid; the half-life from peak is reached in 8 minutes in non-human primates, which is consistent with the short duration of peak subjective effects reported by humans. It appears that salvinorin A is cleared from the brain by an active transport mechanism, however its high lipophilicity also means that its molecules can diffuse rapidly and passively through the blood-brain barrier. Salvinorin A is metabolized by both the liver and the gallbladder to its principle (inactive) metabolite, salvinorin B. Both phase 1 metabolism, which involves the cytochrome P450 family of enzymes, and phase 2 metabolism, which involves the UGT2B7 conjugation enzyme, are responsible for salvinorin A metabolism. The half-life of salvinorin A elimination from the body is 56.6 minutes in rhesus monkeys. Levels of salvinorin B are undetectable in the urine of rhesus monkeys, even shortly after ingestion, suggesting that the metabolite is either immediately cleared or stored in organs and body tissue. #### 15.4.2: Neuropharmacology Despite the strong association between a drug's hallucinogenic properties and its capacity to stimulate the serotonin 5-HT2A receptor subtype, salvinorin A does not bind to serotonin receptors. Instead, it is a highly selective kappa (к)-opioid receptor agonist. This is remarkable, not only because its hallucinogenic effects are purportedly mediated through the opioid system, but because salvinorin A shares little structural similarity with the endogenous k-receptor ligand, dynorphin, or any other known compound that binds to к receptors. Some researchers have reported that salvinorin A directly affects other neurotransmitter systems, including that it allosterically modulates the mu (u) opioid receptor and that it acts as a partial agonist at the D₂ dopamine receptor, but no independent replications of these findings have since been published. There is strong evidence that salvinorin A interacts indirectly with other neurotransmitter systems, including dopamine, norepinephrine, and endocannabinoids. In animal research, salvinorin A has been found to inhibit the release of DA in the mouse striatum and prefrontal cortex as well as in the rat nucleus accumbens. It also inhibits the release of 5-HT and stimulates the release of NE in the hippocampus. Impairment of the mesolimbic dopamine system is postulated to be involved in salvinorin A induced dysphoria whereas a decrease in 5-HT activity might be involved in the sedating effects of the drug. #### 15.4.3: Effects of Salvinorin