A. Historical Use

Psychedelics are a class of drug that cannot be fully understood without reference to a number of other fields of research, including anthropology, ethnopharmacology, psychiatry, psychology, sociology, and others. This review will focus mostly on pharmacology, both preclinical and clinical, but on occasion reference will be made to aspects of some of those other areas.

Psychedelics may be the oldest class of psychopharmacological agents known to man. Important examples of these substances include a substance used in ancient India known as Soma, which was highly revered and is frequently mentioned in the Rigveda, with numerous Vedic hymns written in praise of Soma (Wasson and Ingalls, 1971). In the ancient village of Eleusis, outside Athens, for more than 2000 years there was an annual all-night secret ceremony that is believed to have involved ingestion of a hallucinogenic brew known as κψκεον (Wasson et al., 1978). We know almost nothing about the ceremony other than that profound insights about life could be achieved, and it was apparently a treasured once-in-a-lifetime opportunity for any Greek citizen who had not been convicted of murder.

Psilocybin mushrooms were used by the Aztec shaman in healing and in a variety of religious and divinatory rituals. These mushrooms were known as teonanacatl, meaning “god’s flesh” (Ott and Bigwood, 1978; Schultes and Hofmann, 1979). The use of various psychoactive plant materials and substances was common in pre-Columbian Mesoamerican societies, including the Olmec, Zapotec, Maya, and Aztec cultures (Carod-Artal, 2015). In the Bradshaw rock art in the Kimberly region of Australia and in the Sandawe rock art in the Kolo region of Eastern Tanzania, one finds uniquely shared images such as the “mushroom head” symbol of psilocybin use, suggesting that the two cultures were linked and had shamanic practices that used psychoactive mushrooms (Pettigrew, 2011).

Peyote (Lophophora williamsii) is a small cactus native to the American Southwest and Northern Mexico that has been used for millennia and is consumed as a sacrament during services of the Native American Church.Psychedelic Drug Therapy Adoption In Singapore Essay.  Two peyote samples from a cave on the Rio Grande River in Texas were analyzed and subjected to radiocarbon dating. The average age of the samples, both of which contained mescaline, dated to 3780–3660 BCE (El-Seedi et al., 2005). This evidence supports the use of peyote by Native North Americans as long ago as 5700 years (Bruhn et al., 2002). Classic psychedelics that have been extensively studied include LSD, shown earlier, mescaline, psilocybin, and N,N-dimethyltryptamine (DMT) (Fig. 2).

Ayahuasca, also known as yagé or hoasca, has a long history of use by natives in the Amazon valley of South America (Dobkin de Rios, 1971; Schultes and Hofmann, 1979). Ayahuasca is a decoction prepared from an admixture of two plants: the pounded bark from Banisteriopsis caapi vines and leaves from Psychotria viridis. The latter contains the hallucinogen DMT, a Schedule 1 controlled substance under U.S. law, and it is generally considered that the psychoactive effects of ayahuasca can be attributed to its DMT content. Although DMT is not orally active, B. caapi contains β-carboline alkaloids that inhibit the liver monoamine oxidase (MAO) that normally breaks down DMT; thus, ayahuasca is taken orally as a “tea.” Its use has been incorporated as a sacrament into the religious practices of two syncretic Brazilian churches [União do Vegetal (UDV) and the Santo Daime] that have branches in the United States, with the U.S. Supreme Court rendering a 2006 decision to allow the use of ayahuasca by the UDV under the Religious Freedom Restoration Act.

B. What Are Psychedelics?

In view of the widespread historical use of psychedelics as sacraments in a variety of other cultures, Jaffe’s (1990) definition for the class of psychedelics can perhaps be appreciated: “…the feature that distinguishes the psychedelic agents from other classes of drug is their capacity reliably to induce states of altered perception, thought, and feeling that are not experienced otherwise except in dreams or at times of religious exaltation.” All pharmacologists will recognize that this definition for a class of psychoactive drugs is indeed quite unique!

One of the pioneers of LSD research, the late Daniel X. Freedman, noted that “…one basic dimension of behavior… compellingly revealed in LSD states is ‘portentousness’— the capacity of the mind to see more than it can tell, to experience more than it can explicate, to believe in and be impressed with more than it can rationally justify, to experience boundlessness and ‘boundaryless’ events, from the banal to the profound” (Freedman, 1968). Freedman’s observation is completely consistent with Jaffe’s definition. Psychedelic Drug Therapy Adoption In Singapore Essay.

The use of psychedelics as a central feature of many religious practices, as well as the profound and unique psychopharmacological effects suggested by Jaffe’s definition and the observations of Freedman, surely makes us aware that psychedelics are an exceptional category of mind-altering substances. Indeed, this knowledge prompted Ruck et al. (1979) to coin the word entheogen as a replacement for the terms hallucinogen and psychedelic, both of which they felt had negative connotations. Entheogen is derived from the Greek roots entheos, meaning “God (theos) within,” and genesthe, meaning “to generate.” The word entheogen thus essentially refers to a substance or material that generates God or the divine within someone. Although the term entheogen is now seeing fairly wide acceptance within the culture of those who use these substances “recreationally,” a search of the term in the National Library of Medicine finds only five hits. Although it seems unlikely that the term entheogen will be adopted within the formal scientific community, the reader should realize that in some circles entheogen is generally synonymous with psychedelic. Nonetheless, it should be appreciated that the effects produced by psychedelics are highly dependent on the set (mental expectation) of the user and the setting (environment). A set and setting designed to facilitate a mystical experience will increase the probability of such an occurrence, whereas an unstructured or party-type setting is less likely to lead to a positive outcome.

Studerus et al. (2012) investigated the importance of 24 predictor variables on the acute response to psilocybin and confirmed that nonpharmacological factors play an important role in the effects of psilocybin. Variables examined included age, sex, education, personality traits, drug pre-experience, mental state before drug intake, experimental setting, and drug dose. Their analysis was based on pooled data from 23 controlled experimental studies involving 261 healthy volunteers who had participated in 409 psilocybin administrations over a 19-year period in the authors’ laboratory. Multiple linear mixed-effects models were fitted for each of 15 response variables. Drug dose was shown to be the most important predictor for all measured response variables, but several nonpharmacological variables significantly contributed to the effects of psilocybin. Specifically, having a high score in the personality trait of absorption, being in an emotionally excitable and active state immediately before drug intake, and having experienced few psychologic problems in past weeks were most strongly associated with pleasant and mystical-type experiences. Psychedelic Drug Therapy Adoption In Singapore Essay.High emotional excitability, young age, and an experimental setting involving positron emission tomography (PET) most strongly predicted unpleasant and/or anxious reactions to psilocybin. Interestingly, in addition to confirming that nonpharmacological variables play an important role in the effects of psilocybin, an experimental setting involving PET most strongly predicted unpleasant and/or anxious reactions to psilocybin.

Two instruments have been most widely used to assess the subjective effects of hallucinogenic drugs. The first of these, the Hallucinogen Rating Scale (HRS) was developed by Strassman et al. (1994) during their studies of the intravenous administration of DMT. The HRS was first drafted based on interviews with 19 experienced DMT users and was modified during the early stages of their study. The final version, used for their double-blind study, contained 126 individual items. HRS items were placed into six conceptually coherent clusters: somaesthesia (interoceptive, visceral, and cutaneous/tactile effects), affect (emotional/affective responses), perception (visual, auditory, gustatory, and olfactory experiences), cognition (alteration in thought processes or content), volition (a change in capacity to interact willfully with themselves, the environment, or certain aspects of the experience), and intensity (strength of the various aspects of the experience). Subjects were asked to recall their experiences from the immediately preceding session. Most questions were scored on a 0–4 scale (0, not at all; 1, slightly; 2, moderately; 3, quite a bit; and 4, extremely).

The second assessment instrument widely used to quantify the subjective effects of hallucinogens is the Abnormal Mental States (APZ) questionnaire, first developed by Dittrich (1994, 1998) to measure altered states of consciousness (ASCs). In a series of 11 experiments using different induction methods in 393 healthy subjects, the hypothesis was tested that ASCs have major dimensions in common, irrespective of their mode of induction. The original version contained 158 items covering a range of phenomena potentially occurring during an ASC. The common denominator of ASCs was described by three primary oblique dimensions, designated as “oceanic boundlessness” (OSE, later as OBN), “dread of ego dissolution” (AIA, and later as DED), and “visionary restructuralization” (VUS, later as VRS). The APZ questionnaire became the international validated standard for the assessment of ASCs and the name was further revised to the OAV scales (Bodmer et al., 1994) and later to the five-dimensional altered states of consciousness (5D-ASC) (Dittrich et al., 2006). Details of the development of the original APZ questionnaire and its further refinements were summarized by Studerus et al. (2010). To overcome a variety of methodological limitations, Studerus et al. (2010)carried out a psychometric evaluation of the OAV and 5D-ASC in a relatively large sample from 43 pooled experimental studies of healthy subjects who had received psilocybin, ketamine, or MDMA.Psychedelic Drug Therapy Adoption In Singapore Essay.  The total sample was composed of 591 drug sessions. After comprehensive and detailed statistical analyses, the authors found that the original OAV scales were multidimensional constructs, and arrived at an improved final model that had 11 factors: experience of unity, spiritual experience, blissful state, insightfulness, disembodiment, impaired control and cognition, anxiety, complex imagery, elementary imagery, audio-visual synesthesia, and changed meaning of percepts. Correlations between the 11 factors and their association with the original OAV scales were presented. The new lower-order scales were proposed to be better suited to assess drug-induced ASCs.

Mechanistically, psychedelics have agonist or partial agonist activity at brain serotonin 5-HT_2A receptors. This molecular characterization will be elaborated in some detail later in this review, and aspects of the anatomic and functional importance of this receptor type will also be extensively explored. Discussions over the years with many colleagues working in the pharmaceutical industry have informed me that if upon screening a potential new drug is found to have serotonin 5-HT_2A agonist activity, it nearly always signals the end to any further development of that molecule.

A recent study by Turton et al. (2014) reported on the subjective experience of intravenous psilocybin administered during a functional magnetic resonance imaging (fMRI) examination. Fifteen volunteers were administered an intravenous infusion of either placebo or 2 mg psilocybin and were blinded as to whether they would receive placebo or drug for a particular experiment. Drug infusion began 6 minutes after the start of a scan in a magnetic resonance imaging scanner. Subjects completed a visual analog scale rating the intensity of the drug experience at the start of the scan and prior to drug infusion, 5 minutes postinfusion, and 12 minutes postinfusion. All subjects subsequently were interviewed about the drug effects, and interviews were analyzed using interpretative phenomenological analysis, a qualitative method. All subjects reported that the onset of drug effect was very rapid and intense, with a duration of effect lasting 10–15 minutes. The investigators identified nine broad categories of phenomenology. Altered somatosensory, visual, auditory, and proprioceptive sensations were reported, with 14 of 15 subjects describing perceptual changes as the primary effect of the drug. Thirteen subjects reported changes in perception of time, either speeding up or slowing down. The report describes a variety of effects on cognition, mood, memory, and spiritual or mystical experiences. Overall, subjects found the experience difficult to describe, yet most found it pleasant and positive. Psychedelic Drug Therapy Adoption In Singapore Essay.

In a new study by Schmid et al. (2015), LSD (200 μg) was administered orally to 16 healthy subjects in a double-blind, randomized, placebo-controlled, crossover study. LSD produced a pronounced alteration in waking consciousness that lasted for 12 hours and included visual hallucinations, audio-visual synesthesia, and positively experienced derealization and depersonalization phenomena. Compared with placebo, LSD increased subjective well-being, happiness, closeness to others, openness, and trust. Increases in blood pressure, heart rate, body temperature, pupil size, plasma cortisol, prolactin, oxytocin, and epinephrine also were measured. On the 5D-ASC scale, LSD produced higher scores than did psilocybin or DMT. The authors also described subjective effects on mood that were similar to those reported for MDMA that might be useful in psychotherapy. No severe acute adverse effects were observed and the effects subsided completely within 72 hours.

In a very recent study by Carhart-Harris et al. (2015a), LSD was shown to enhance responsiveness to suggestion. Their study was prompted by very early reports indicating that LSD increased suggestibility (Sjobergand Hollister, 1965; Middlefell, 1967). Thus, Carhart-Harris et al. (2015a) administered LSD (40–80 μg, i.v.) to 10 healthy volunteers in a within-subject placebo-controlled design. Suggestibility and cued mental imagery were assessed using the Creative Imagination Scale and a mental imagery test. The two instruments were administered between 110 and 140 minutes after drug infusion, at the peak of the drug effect. Subjects scored significantly higher on the Creative Imagination Scale, but not the mental imagery test after LSD administration, compared with placebo. The magnitude of suggestibility enhancement was positively correlated with the subject’s baseline trait conscientiousness. This enhanced suggestibility may have implications for the use of LSD as an adjunct to psychotherapy, but it also indicates that individuals with a high trait conscientiousness are particularly sensitive to the suggestibility-enhancement effect of LSD.

It has been axiomatic among users of psychedelics that music takes on an intensified and more enjoyable quality under the effects of LSD or other psychedelics, yet no modern placebo-controlled study had ever been carried out to confirm that widely held belief. Early studies at the Maryland Psychiatric Research Center found that music was a very effective stimulus and complement to the effect of LSD (Bonny and Pahnke, 1972). Gaston and Eagle (1970) also reported that the presence of music was much preferable to its absence in alcoholic patients undergoing treatment using LSD therapy, both by patient preference and treatment results. Numerous other studies had been reported on the value of music in the context of various shamanic and therapeutic approaches (see references in Kaelen et al., 2015). Psychedelic Drug Therapy Adoption In Singapore Essay. Very recently, therefore, Kaelen et al. (2015) tested the hypothesis that the emotional response to music is enhanced by LSD. Ten participants were administered placebo or various doses of LSD, including 40, 50, 70, or 80 μg, infused intravenously over 3 minutes. They then listened to five different instrumental music tracks on each of two study days: a placebo day followed by an LSD day, separated by 5–7 days. Music tracks were chosen that produced the highest liking and lowest familiarity by a separate sample of nine participants. The question “How emotionally affected were you by the music?” was asked immediately after each track and served as the study’s primary outcome. The nine-category Geneva Emotional Music Scale (Zentner et al., 2008) was also used. Mean scores for all music stimuli in response to the question “how emotionally affected were you by the music?” were significantly higher for the LSD condition than for placebo. In addition, all nine factors on the Geneva Emotional Music Scale were scored higher after LSD administration than after placebo. Emotions related to transcendence also were enhanced by LSD. Specific emotions showing the strongest enhancement included wonder, transcendence, tenderness, and power. Furthermore, there was a significant positive relationship between ratings of the intensity of the LSD effect and emotional arousal to music. The results of Zentner et al. (2008) support the hypothesis that LSD enhances music-evoked emotion.

A. General Issues of Safety and Mental Health in Psychedelic Users

Although there is a general public perception that psychedelic drugs are dangerous, from a physiologic standpoint they are in fact one of the safest known classes of CNS drugs. They do not cause addiction, and no overdose deaths have occurred after ingestion of typical doses of LSD, psilocybin, or mescaline. Cohen (1967) and Jaffe (1985) have both stated that death due to direct LSD toxicity is unknown. Indeed, recreational users who have consumed massive doses of LSD have survived. For example, eight individuals who believed they had cocaine accidentally insufflated an extremely high dose of LSD. Their plasma LSD levels were reported as between 1000 and 7000 μg/100 ml (recall that a typical total oral dose of LSD might be 100–200 μg). These individuals all became comatose, with hyperthermia, vomiting, light gastric bleeding, and respiratory problems. With hospital treatment, however, all eight survived and without apparent residual effects (Klock et al., 1974).

Although the classic psychedelics have not been directly responsible for causing death, the judgment of users is certainly impaired while under the influence of these drugs. This is a particular concern when hallucinogens are used in unsupervised settings. Users may believe that they are invincible or possess superpowers and may do things they would not normally consider, such as believing they can fly (Reynolds and Jindrich, 1985), jumping from buildings (Keeler and Reifler, 1967), or incurring severe ocular damage by prolonged staring at the sun (Schatz and Mendelblatt, 1973; Fuller, 1976).

Studerus et al. (2010) analyzed acute, short-, and long-term subjective effects of psilocybin in healthy humans. Again, using pooled raw data from eight double-blind placebo-controlled experimental studies conducted between 1999 and 2008, their analysis included 110 healthy subjects who had received between one and four oral doses of psilocybin (45–315 μg/kg body weight). Psilocybin dose-dependently induced profound changes in mood, perception, thought, and self-experience, but most subjects described the experience as pleasurable, enriching, and nonthreatening. Psychedelic Drug Therapy Adoption In Singapore Essay. Acute adverse reactions were characterized by strong dysphoria and/or anxiety/panic, but occurred only at the two highest doses of psilocybin in a relatively small number of subjects. All acute adverse drug reactions were successfully managed through interpersonal support and did not require psychopharmacological intervention. Follow-up questionnaires indicated no subsequent drug abuse, persisting perception disorders, prolonged psychosis, or other long-term impairment of functioning in any of the subjects. The results indicate that the administration of modest psilocybin doses to healthy, high-functioning, and well prepared subjects in the context of a carefully monitored research environment carries an acceptable level of risk.

The recent resurgence of interest in the clinical uses of psychedelics led Johnson et al. (2008) to propose appropriate procedures for using them in clinical practice. The guidelines they outline have certain parallels with ritual uses of hallucinogens by older indigenous cultures. In particular, Johnson et al. (2008) cite the need for structured use (expressed as ritual in indigenous use) and restrictions on use, including the need for guidance and appreciation of the powerful psychologic effects of hallucinogens (expressed as reverence in indigenous use). Psychedelic administration in humans results in a unique profile of effects and potential adverse reactions that need to be appropriately addressed to maximize safety. The primary safety concerns with psychedelics are largely psychologic rather than physiologic in nature. Somatic effects vary but are relatively insignificant, even at doses that elicit powerful psychologic effects. The proposed guidelines extend and complement the recommendations of Fischman and Johanson (1998) for high-dose hallucinogen research. The guidelines include 1) the presence of two “monitors” with some medical knowledge, knowledge of ASCs, and a degree of clinical sensitivity; 2) a physical environment that is safe, aesthetically pleasing, and comfortable; 3) careful subject preparation, including several meetings to establish rapport and trust with the monitors; 4) a detailed consent form and explanations of the study procedures, detailed discussions about the range of potential experiences, and time of onset and duration of the effects; and 5) an available physician in the event of an untoward medical reaction. Anyone contemplating carrying out a clinical research program with a psychedelic is strongly encouraged to read the detailed guidelines presented by Johnson et al. (2008). Psychedelic Drug Therapy Adoption In Singapore Essay.

Krebs and Johansen (2013) evaluated any association between lifetime use of psychedelics and current mental health in the adult population. Data were analyzed for 2001–2004 for 130,152 randomly selected NSDUH respondents; 21,967 respondents (13.4% weighted) reported lifetime psychedelic use. The authors found no significant association between lifetime use of any psychedelic and increased rate of any mental health outcomes. Indeed, they discovered that psychedelic use was associated with a lower rate of mental health problems in several cases. Johansen and Krebs (2015)subsequently analyzed a new data set of 135,095 randomly selected U.S. adults that included 19,299 users of psychedelics. Data were from the NSDUH for 2008–2011. As in their earlier study, the authors found no significant associations between lifetime use of psychedelics and increased likelihood of past-year serious psychologic distress, mental health treatment, depression, anxiety, or suicidal thoughts, plans, or attempts. Johansen and Krebs (2015) failed to find any evidence that use of psychedelics is an independent risk factor for mental health problems. Indeed, they report that lifetime use of psychedelics was associated with decreased inpatient psychiatric treatment.

Hendricks et al. (2014) analyzed data from 2002–2007 for 25,622 individuals charged with a felony in the Southeastern United States and under community corrections supervision in the Treatment Accountability for Safer Communities program, which is a case management intervention program for individuals with a history of substance involvement. The authors examined relationships between any hallucinogen use disorder (versus no hallucinogen use disorder) and all available sociodemographic and psychosocial variables. They report that any hallucinogen use disorder was associated with a decreased probability of supervision failure. They note the contrast with any cannabis, cocaine, alcohol, opiate, or amphetamine use disorder, each of which was associated with an increased probability of supervision failure. Their results suggest that hallucinogens may promote alcohol and other drug abstinence and prosocial behavior in a population with high rates of recidivism.

In a more recent report by Hendricks et al. (2015), the authors evaluated any relationship between use of a classic psychedelic and psychologic distress and suicidality among more than 190,000 U.S. respondents pooled from the NSDUH for 2008–2012. Lifetime use of a psychedelic was associated with significantly reduced odds of past-month psychologic distress, past-year suicidal thinking, past-year suicidal planning, or past-year suicide attempt. By contrast, lifetime use of other illicit drugs was associated with an increased likelihood of these outcomes. Psychedelic Drug Therapy Adoption In Singapore Essay. The authors suggest that classic psychedelics may hold promise in the prevention of suicide. These findings are consistent with the surveys of Krebs and Johansen (2013) and Johansen and Krebs (2015); in all three studies, the authors suggest that their data are not compatible with the highly restricted legal status of psychedelics and that more extensive clinical research is warranted.

B. Adverse Reactions

Use of high doses of psychedelics can lead to vascular problems because the 5-HT_2Areceptor is associated with vascular smooth muscle contraction, platelet aggregation, thrombus formation, and coronary artery spasms (Nagatomo et al., 2004). Acute vasoconstriction caused by serotonin is usually shared by activation of 5-HT_1B and 5-HT_2A receptors; however, in intracranial arteries, only the 5-HT_1B receptor mediates constriction (Kaumann and Levy, 2006). Both 5-HT_2A and 5-HT_1B receptors can mediate coronary artery spasm. 5-HT_2A receptors also constrict the portal venous system, including esophageal collaterals in cirrhosis. Data from studies by Ootsuka et al. (2004) suggest that spinal 5-HT_2A receptors contribute to sympathetically induced cutaneous vasoconstriction regulated by the raphe/parapyramidal neurons in the brainstem.

Balíková (2005) reports a fatal and nonfatal overdose after ingestion of the psychedelic phenethylamine 2,5-dimethoxy-4-bromoamphetamine (DOB) by two male individuals. Gas chromatography–mass spectrometry was used to detect the presence of DOB in both gastric and urine samples of the two men. Although one subject survived, the other suffered convulsions and metabolic acidosis and died 6 days after admission.

Psilocybin, when administered in a controlled setting, has frequently been reported to cause transient, delayed headache, with incidence, duration, and severity increased in a dose-related manner (Johnson et al., 2012). Bickel et al. (2005) reported the case of a 25-year-old hepatitis C–infected man, who presented with severe rhabdomyolysis and acute renal failure after Psilocybe mushroom ingestion. He later developed encephalopathy with cortical blindness. Respiratory and cardiovascular support, mechanical ventilation, continuous venovenous hemodialysis, and corticosteroid treatment led to improvement and the patient recovered completely over several months. Psychedelic Drug Therapy Adoption In Singapore Essay.

Psilocin was identified in the urine of a subject who was investigated for driving under the influence (Tiscione and Miller, 2006). The subject apparently did not exhibit any response to the crash of his automobile, seemingly unaware of the severity of his situation or immediate surroundings.

Although very rare, there have been reports of rhabdomyolysis after ingestion of LSD (Berrens et al., 2010). A newer tryptamine, 5-methoxy-N,N-diisopropyltryptamine (“foxy”) also produced rhabdomyolysis and transient acute renal failure in an otherwise healthy 23-year-old man (Alatrash et al., 2006).

Although many ergot alkaloids are known to produce vasospasm, especially after chronic use, LSD has rarely been associated with this adverse effect. Nevertheless, Raval et al. (2008) reported on a 19-year-old woman who experienced severe lower-extremity ischemia related to a single use of LSD 3 days prior to presentation. After intra-arterial nitroglycerin and verapamil failed, balloon percutaneous transluminal angioplasty therapy led to rapid clinical improvement in lower-extremity perfusion. As of the date of the report, the patient had not required a major amputation.

Sunness (2004) described a 15-year-old female patient with a 2-year history of afterimages and photophobia after a history of drug use that included LSD, marijuana, and other illicit drugs. She had discontinued LSD 1 year prior to examination. Although the author connected her visual problems with her prior LSD use, it is not at all clear from the report that her LSD use was the cause of her visual problem.

Bernhard and Ulrich (2009) reported a case of cortical blindness in a 15-year-old girl. She had headache and nausea 5 days after taking LSD and suddenly developed complete blindness in both eyes. The blindness persisted for 48 hours. Over the next 3 months, the subject had three more episodes of complete blindness that lasted 12–36 hours, with no visual disturbances between episodes. The authors suggested that the temporary blindness might be a correlate of “flashbacks” caused by LSD.

Toxicity also has been noted for several of the so-called designer drugs. For example, Jovel et al. (2014) reported the case of a healthy young male individual who ingested 5-methoxy-N,N-diallytryptamine, one of the emerging new tryptamine-type research chemicals. Psychedelic Drug Therapy Adoption In Singapore Essay. The patient was admitted with extreme agitation, tachycardia, diaphoresis, and combativeness that required physical restraint and intravenous sedation, but the patient did recover.

Andreasen et al. (2009) reported a fatality involving the potent synthetic psychedelic phenethylamine compound 1-(8-bromobenzo[1,2-b; 4,5-b′]difuran-4-yl)-2-aminopropane, known commonly as Bromo-Dragonfly. An 18-year-old woman was found dead after ingesting 1 ml of a “hallucinogenic liquid.” She and her boyfriend had ingested it between 10 and 11 PM on the previous evening and then they both fell asleep. On awakening at 5 AM the next morning, the woman’s boyfriend discovered that she was dead. Autopsy findings 3 days after her death included edema of the lungs, slight edema of the brain, spleen enlargement, irritation of the mucous membrane in the stomach, and ischemic changes in the kidneys. Her femoral blood concentration of the drug was 4.7 μg/kg. The bottle containing the hallucinogenic liquid was recovered and analyzed by ultraperformance liquid chromatography time-of-flight mass spectrometry, high-performance liquid chromatography diode array detection, ¹H nuclear magnetic resonance, and ¹³C nuclear magnetic resonance and found to contain a solution of almost pure Bromo-Dragonfly. Based on the solution concentration and the amount of solution consumed, it was estimated that she had ingested approximately 700 μg. Although that would seem to be a relatively small dose, no other drugs were discovered in her system, including the absence of ethanol.

It is often difficult to establish whether the drug is pure or has been coingested with other unknown drugs of unknown purity. For example, Ovaska et al. (2008) reported a case of “sympathomimetic toxicity” in a patient who was reported to have ingested 2,5-dimethoxy-4-chloroamphetamine (DOC), yet toxicological screening showed the patient had ingested both DOC and MDMA.

Data for 2005 to 2006 from the Texas Poison Control Centers were reviewed for mushroom exposures (Barbee et al., 2009). There were a total of 742 exposures, which were all acute and intentional. Of those, 59 individuals were admitted to a hospital, with 17 requiring admission to a critical care unit. Nonetheless, only 10 of the admissions that were identified involved psilocybin. Of all of the admissions, major toxic reactions were uncommon, with no deaths reported. Psychedelic Drug Therapy Adoption In Singapore Essay.

C. Hallucinogen Persisting Perception Disorder

One adverse effect of hallucinogen use, particularly associated with LSD use, is hallucinogen persisting perception disorder (HPPD). This term has displaced an earlier somewhat more nonspecific one known as “flashbacks,” which was a re-experiencing of one or more of the perceptual effects induced by a hallucinogen at some later time, after the acute drug effects had worn off. HPPD is composed of afterimages, perception of movement in peripheral visual fields, blurring of small patterns, halo effects, and macro- and micropsia long after the drug has been used.

The Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV), Text Revision lists the following three criteria for HPPD: A) re-experiencing, after the use of a hallucinogen, of one or more of the perceptual symptoms that were experienced while intoxicated with the hallucinogen; B) the symptoms in criterion A cause clinically significant distress or impairment in social, occupational, or other important areas of functioning; and C) the symptoms are not due to a general medical condition and are not better accounted for by another mental disorder.

Halpern and Pope (2003) noted that when LSD was used in a therapeutic or research setting, HPPD appeared less frequently than when LSD was used recreationally. The authors concluded, however, that some individuals, especially users of LSD, can experience a long-lasting HPPD syndrome with symptoms of “persistent perceptual abnormalities reminiscent of acute intoxication.” Nevertheless, the incidence of HPPD is very small given the many tens of millions of persons who have taken LSD, most often in a recreational setting. Litjens et al. (2014) provided a recent comprehensive review on the subject of HPPD. The actual incidence of HPPD is not known and depends on the prevalence of use in different countries, but epidemiologic information is scarce.

Hermle et al. (2008) reviewed MEDLINE data for 1997–2007, searching for reports of hallucinogen-induced psychosis, flashbacks, and HPPD. The authors reported that adolescent intoxication with psychedelic drugs rarely produced acute psychotic syndromes, further stating that “The clinical relevance of flashback phenomena as a post-hallucinogenic psychiatric disorder has to be disputed.”

Although LSD was most widely used and therefore has led to the greatest number of HPPD cases, it is clear that other hallucinogens also can evoke the syndrome. For example, Espiard et al. (2005) reported HPPD in an 18-year-old man after mixed intoxication with psilocybin and cannabis.  Psychedelic Drug Therapy Adoption In Singapore Essay.The symptoms persisted for more than 8 months. Ikeda et al. (2005) reported flashbacks after use of 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) by a 35-year-old man without a previous psychiatric history. He had used the substance six or seven times over 5 months but discontinued it after he had a bad trip, with anxiety, palpitations, auditory oversensitiveness, and visual distortions. Treatment with oral risperidone ameliorated his symptoms. Another case study described a 33-year-old woman who developed HPPD after LSD use for a year. Although treatment with antidepressants and risperidone did not ameliorate her symptoms, treatment with the antiseizure drug lamotrigine almost completely abolished her visual disturbances (Hermle et al., 2012).

A. Evidence for Agonist or Partial Agonist Action at Serotonin 5-Hydroxytryptamine 2A Receptors

It was only a decade after the discovery of the remarkable psychopharmacology of LSD that the presence of serotonin was demonstrated in the mammalian brain (Twarog and Page, 1953). A comparison of the chemical structures of LSD and serotonin (shown earlier) led to early hypotheses that the action of LSD was due to an interaction with serotonin systems in the brain. Ten years after the discovery of LSD, Gaddum (1953)reported that LSD antagonized the action of serotonin in peripheral tissues. Only 1 year later, Gaddum and Hameed (1954) and Woolley and Shaw (1954) independently proposed that the effects of LSD might result from serotonin receptor blockade in the CNS. Shaw and Woolley (1956) later modified their hypothesis to include the possibility that LSD might mimic the actions of serotonin. Numerous studies in the subsequent decade examined the possibility that LSD blocked the actions of serotonin, but it was a concept that proved untenable. It was clear, however, that LSD did have a potent effect on brain serotonin systems, elevating whole brain serotonin content (Freedman, 1961) and reducing brain levels of the major metabolite of serotonin, 5-hydroxyindole acetic acid (Rosecrans et al., 1967).

Ultimately, Andén et al. (1968) suggested that LSD might have direct agonist actions at serotonin receptors in the brain. Subsequently, studies from numerous laboratories provided support for that idea, with an initial focus on serotonin 5-HT_1A receptors (see discussion in Nichols, 2004). When serotonin receptor–selective antagonists became available, it was Glennon et al. (1983, 1984) who demonstrated in a rat drug discrimination model that the 5-HT₂ antagonists ketanserin and pirenperone blocked the discriminative cue of a psychedelic. Further studies in numerous laboratories over the next 2 decades, primarily with rodents, then focused attention on the 5-HT_2A receptor as the primary target for psychedelics. Agonist or partial agonist activity at the serotonin 5-HT_2A receptor was ultimately concluded to be a necessary pharmacology for psychedelic effects, but it may not be sufficient to explain all of the qualitative differences between different drugs. As Ray (2010) pointed out, different molecules may also have significant affinity for other types of brain receptors.

The first definitive experiment pointing to the central role of the 5-HT_2A receptor for the action of psychedelics in humans came from a clinical study by Vollenweider et al. (1998), who showed that the effects of psilocybin were blocked by the 5-HT_2A receptor–selective antagonist ketanserin or the atypical antipsychotic risperidone but were enhanced by the dopamine antagonist and typical antipsychotic haloperidol. These data provided the first evidence that psilocybin-induced effects in humans were due to 5-HT_2A receptor activation. Subsequently, Vollenweider and colleagues have carried out several additional clinical studies, discussed later, of various aspects of the action of psilocybin and have shown that ketanserin can block most of those effects. Psychedelic Drug Therapy Adoption In Singapore Essay.

Kometer et al. (2012) carried out a randomized, double-blind study in 17 healthy human subjects. On 4 separate days, subjects received placebo, psilocybin (215 μg/kg), the 5-HT_2A antagonist ketanserin (50 mg, p.o.), or psilocybin plus ketanserin. Mood states were assessed, and behavioral and event-related potential measurements were used to quantify facial emotional recognition and goal-directed behavior toward emotional cues. Psilocybin was found to enhance positive mood and attenuate negative facial expression recognition. Furthermore, psilocybin increased goal-directed behavior toward positive compared with negative cues, facilitated positive but inhibited negative sequential emotional effects, and valence-dependently attenuated the P300 component. Ketanserin given alone had no effect but blocked the psilocybin-induced mood enhancement and decreased recognition of negative facial expression. This study demonstrated that psilocybin shifts the emotional bias across various psychologic domains and that activation of 5-HT_2A receptors is central in mood regulation and emotional face recognition in healthy subjects. The authors suggest that their findings have implications not only for the pathophysiology of dysfunctional emotional biases, but they may also provide a framework to delineate the mechanisms underlying psilocybin’s putative antidepressant effects.

Quednow et al. (2012) investigated the role of 5-HT_2A receptors in automatic (sensorimotor gating) and controlled (Stroop interference) inhibition processes in a model psychosis approach using psilocybin (260 μg/kg) in 16 healthy humans pretreated either with the 5-HT_2A–selective receptor antagonist ketanserin (40 mg) or placebo, using a placebo-controlled, crossover, counterbalanced, and double-blind design. They found that psilocybin-induced deficits in automatic and controlled inhibition were significantly attenuated by ketanserin. They also replicated their previous findings that most of the subjective hallucinogenic effects of psilocybin were abolished by ketanserin.

Kometer et al. (2013) assessed the effects of psilocybin (215 μg/kg) on both αoscillations that regulate cortical excitability and early visual evoked P1 and N170 potentials in 16 healthy human subjects. They employed a double-blind, placebo-controlled, within-subject, randomized design. Psilocybin generally significantly increased 5D-ASC scores after placebo pretreatment, but not after ketanserin pretreatment. Psilocybin strongly decreased both prestimulus parieto-occipatal α power and decreased N170 potentials associated with the appearance of visual perceptual alterations, including visual hallucinations. Preadministration of the 5-HT_2A antagonist ketanserin (50 mg) blocked all of these effects. The authors conclude that 5-HT_2Areceptor activation by psilocybin profoundly modulates the neurophysiological and phenomenological indices of visual processing. They further propose that 5-HT_2Areceptor activation may induce a processing mode in which stimulus-driven cortical excitation is overwhelmed by spontaneous neuronal excitation through modulation of αoscillations.

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Indirect evidence for a role of 5-HT_2A receptors in mediating psychedelic-induced hallucinations comes from a study by Huot et al. (2010). In that study, [³H]ketanserin binding was used to compare 5-HT_2A receptor density in postmortem brains of patients with Parkinson’s disease (PD) who experienced visual hallucinations with the brains of PD patients who did not experience hallucinations. Six brains from patients with idiopathic PD who experienced visual hallucinations were compared with six PD patients without visual hallucinations and five healthy, age-matched controls. In PD patients with visual hallucinations, [³H]ketanserin binding was increased 45.6% in inferolateral temporal cortex compared with PD patients who did not have visual hallucinations. The authors suggest that increased 5-HT_2A density in the inferolateral temporal cortex may be the basis for visual hallucinations in PD patients and that 5HT_2Aantagonists may alleviate this symptom. Psychedelic Drug Therapy Adoption In Singapore Essay.

Similarly, Ballanger et al. (2010) measured 5-HT_2A binding in vivo using [¹⁸F]setoperone PET in brains of seven PD patients with visual hallucinations and seven age-matched PD patients without visual hallucinations. Patients with visual hallucinations had significantly increased 5-HT_2A receptor binding in several cortical regions and one subcortical region. These increased levels of 5-HT_2A receptor expression were clustered mainly in the ventral visual pathway. With the evidence of increased 5-HT_2A receptor expression as a possible basis for visual hallucinations in PD patients, a serotonin 5-HT_2A inverse agonist, perhaps not surprisingly, demonstrated phase 3 clinical efficacy in treating several symptoms of PD psychosis, including visual hallucinations (Hacksell et al., 2014).

Halberstadt et al. (2011a) examined the effects of several psychedelics on the mouse head twitch response (HTR) in wild-type (WT) male C57BL/6J or 5-HT_2A knockout (KO) mice. They also assessed investigatory and locomotor activity in the mouse behavioral pattern monitor (BPM). Psilocin and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) produced the HTR in WT mice but not in KO mice. Psilocin and 5-MeO-DMT reduced locomotor activity, investigatory behavior, and center duration in the BPM, and these effects were blocked by the selective 5-HT_1A antagonist WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]- N-(2-pyridyl)cyclohexanecarboxamide), indicating that psilocin and 5-MeO-DMT act as mixed 5-HT_1A/5-HT_2A agonists. Halberstadt and Geyer (2011) reviewed the extensive literature covering various indoleamines as well as LSD and concluded that although the phenethylamines primarily exert their effects through activation of 5-HT_2A receptors, indoleamines can have a significant behavioral component mediated by activation of 5-HT_1A receptors.

Quednow et al. (2010), using [¹⁸F]altanserin PET, found that the intensity of psilocybin-induced subjective effects measured using the 5D-ASC was directly correlated with the level of 5-HT_2A receptor occupation by psilocin in the ACC and medial prefrontal cortex (mPFC). Psychedelic Drug Therapy Adoption In Singapore Essay.