This paper (2016) extensively reviews the history, chemistry, and therapeutic evidence of a broad range of hallucinogenic/psychedelic substances.

Abstract

“Hallucinogens fall into several different classes, as broadly defined by pharmacological mechanism of action, and chemical structure. These include psychedelics, entactogens, dissociatives, and other atypical hallucinogens. Although these classes do not share a common primary mechanism of action, they do exhibit important similarities in their ability to occasion temporary but profound alterations of consciousness, involving acute changes in somatic, perceptual, cognitive, and affective processes. Such effects likely contribute to their recreational use. However, a growing body of evidence indicates that these drugs may have therapeutic applications beyond their potential for abuse. This review will present data on several classes of hallucinogens with a particular focus on psychedelics, entactogens, and dissociatives, for which clinical utility has been most extensively documented. Information on each class is presented in turn, tracing relevant historical insights, highlighting similarities and differences between the classes from the molecular to the behavioral level, and presenting the most up-to-date information on clinically oriented research with these substances, with important ramifications for their potential therapeutic value.”

Authors: Albert Garcia-Romeu, Brennan Kersgaard & Peter H. Addy

Summary

Hallucinogens include psychedelics, entactogens, dissociatives, and other atypical hallucinogens. This review will focus on psychedelics, entactogens, and dissociatives, with a particular focus on clinically oriented research with these substances.

Introduction

Hallucinogens include serotonin 2A receptor (5-HT2AR) agonists, mixed serotonin and dopamine reuptake inhibitors and releasers, NMDA antagonists, atypical hallucinogens, and cannabis.

Although they do not share a common primary mechanism of action, hallucinogens exhibit important similarities in their ability to occasion temporary but profound alterations of consciousness. Some have been used for thousands of years in religious sacraments, and some have shown promise in clinical research.

Contemporary research has revisited the potential of hallucinogen-facilitated treatment paradigms, with a focus on psychedelics, entactogens, and dissociatives, for which clinical utility has been most extensively documented.

Psychedelics

Research with 5-HT2AR agonist hallucinogens was marked with controversy from its inception. Many researchers were intrigued by the psychosis mimicking or psychotomimetic properties of these compounds, while others investigated their putative ability to generate insightful, therapeutic, and even spiritual1 experiences.

Clinical psychedelic research began in the mid-20th century and focused almost exclusively on LSD, mescaline, and psilocybin. These compounds were seminal in the field of neurochemistry and helped advance our understanding of serotonin.

After extensive experimentation in humans, it became apparent that the expectations and personal experiences of the individual taking psychedelics as well as the external environment were vitally important in influencing users’ experiences. This helps explain the widely varied reactions to these substances observed across different studies.

Lysergic Acid Diethylamide (LSD)

LSD was first synthesized in 1938, but its psychoactive properties were not discovered until five years later. It remained relatively obscure in the public sphere for nearly 20 years, until magazine articles chronicling the experiences of highly visible journalists and movie stars were published.

In the early 1960s Harvard psychologists Richard Alpert and Timothy Leary began their now infamous experiments with LSD and psilocybin, and in 1965 Sandoz Laboratory halted the production and distribution of LSD.

Prior to this, a large body of human subjects research with LSD was accumulated, including over 1,000 published papers by 1961. This research centered on its psychotomimetic properties, but some argued that these compounds did much more.

Researchers in the late 1950s and 1960s examined LSD’s efficacy in the treatment of a broad variety of conditions including alcoholism, opioid dependence, pain, neurosis, and cancer-related anxiety.

Researchers found that individuals receiving a single dose of LSD in the context of alcoholism treatment exhibited significantly reduced alcohol misuse at initial follow-up compared with patients receiving non-psychedelic control treatments.

LSD is a semi-synthetic tryptamine derived from the naturally occurring ergot alkaloid ergotamine. It acts primarily as a serotonergic agonist, but also shows action at dopaminergic and adrenergic receptor sites.

LSD can cause subjective effects in humans that last up to 12 hours and include altered mood, perception, cognition, the occurrence of elementary and complex hallucinations, as well as experiences described as insightful, transcendent, and/or mystical in nature.

LSD does not produce physiological toxicity, and there have been no documented human deaths from LSD overdose. However, in rare cases, ongoing psychotic symptoms and other psychological sequelae have been reported.

HPPD or “flashback” is a potential persisting effect of LSD that occurs with very low prevalence. Individuals who received LSD on 10 or more occasions were more likely to report such effects.

A more recent review of 20 studies confirmed that HPPD was indeed reported as an adverse effect in some early studies of LSD, but prevalence appears higher among recreational psychedelic users than those administered the drugs in controlled settings.

Early research found evidence suggesting that LSD may cause chromosomal damage, creating considerable concern about its use as a therapeutic agent. However, risks related to these early findings were later thought to be overstated.

A double-blind, randomized, active placebo-controlled study investigating LSD-assisted psychotherapy for anxiety associated with life-threatening illnesses was published in 2014. Results showed that 200 g LSD significantly reduced state measures of anxiety up to 12 months post-treatment.

Recent pilot studies have found that LSD increases suggestibility and creative imagination in healthy volunteers, and can evoke heightened emotional responses to music. This research may contribute to guiding more refined application of musical stimuli in LSD-facilitated treatments.

Psilocybin is found in over 100 species of mushrooms and was first isolated in 1958. It has been used in religion since 500 BCE and is referred to as “divine flesh” in Nahuatl.

Psilocybin is a prodrug that is dephosphorylated by hepatic first pass metabolism into the 5-HT2A, 1A and 2C receptor agonist psilocin. It has a largely benign safety profile, but may cause disorientation, anxiety, or fear responses.

In the 1950s and 1960s, clinical research with psilocybin was nowhere near that of LSD. However, several landmark psilocybin studies were conducted, including the Good Friday experiment, which found that psilocybin was significantly more effective than an active placebo at increasing measures of mystical experience.

Doblin (1991) provided a notable long-term follow up and methodological critique of the Good Friday experiment, which found that 25 years after the experiment two volunteers had challenging experiences and were administered thorazine as a tranquilizer.

In 1965, 32 male inmates at the Massachusetts Correctional Institute at Concord underwent a psilocybin-facilitated group therapy program focused on reducing subsequent recidivism. However, in a subsequent long-term follow-up study, recidivism rates were similar to that of the larger prison population.

Leary maintained that the results were not due to treatment failure per se, but to lack of structured support after parole, which makes it difficult for such programs to have lasting effects.

A recent study of over 25,000 individuals in the criminal justice system in the Southeastern US found that hallucinogen use was significantly associated with reduced rates of supervision failure.

Psilocybin has received renewed attention in the 21st century with multiple studies in various populations. These studies have found that psilocybin facilitates mystical-type experiences with sustained meaning and persisting beneficial effects, and that psilocybin-occasioned mystical experiences are significantly correlated with persisting increases in the personality domain of openness.

A recent meta-analysis of 8 double blind, placebo-controlled experiments conducted in a single laboratory over the course of 10 years found that 60% of volunteers rated their psilocybin experience “very enriching” and 90% rated it enriching to at least a medium degree between 8 and 16 months after administration.

Regarding Hallucinogen-Persisting Perception Disorder (HPPD), no significant increase in spontaneous perceptual disturbances was observed in a sample of 110 volunteers with 60% hallucinogen naieve individuals and 40% volunteers with prior hallucinogen use.

A meta-analysis of 23 trials of psilocybin found that dose, personality absorption, positron emission tomography scanning environment, and age were significant factors predicting response to psilocybin. Participants’ gender was not found to have any significant effects on psilocybin response.

Clinical research has shown promising results with psilocybin for the treatment of anxiety, obsessive-compulsive disorder, treatment-resistant depression, smoking cessation, and alcoholism. Additionally, MRI studies have shown decreased activity in the medial prefrontal cortex in healthy volunteers during psilocybin administration.

A pilot study examining psilocybin in nine individuals with treatment-resistant obsessive-compulsive disorder found significant improvement on measures of OCD symptoms at four, eight and twenty-four hours post-psilocybin administration. A recent study in 12 individuals with unipolar treatment-resistant major depression found sustained therapeutic benefits.

Pilot studies of psilocybin have shown promise in treating substance use disorders. These studies used two to three doses of psilocybin in combination with cognitive-behavioral therapy for smoking cessation, and one to two administrations of psilocybin in the context of motivational enhancement therapy for alcoholism.

Mescaline was isolated from a small cactus in 1896 and is the first naturally occurring psychedelic alkaloid. It is used by the Native American Church, and is constitutionally protected under the US constitution.

Aldous Huxley stimulated interest in mescaline by writing about his experiences with the drug in The Doors of Perception, but contemporary research has remained limited relative to the other psychedelics.

Alexander Shulgin created many hallucinogens by modifying the mescaline molecule, including 2,5-Dimethoxy-4-Methylamphetamine (DOM), which are becoming increasingly popular as recreational drugs in recent years.

Mescaline is a naturally occurring psychedelic found in cacti including peyote and San Pedro cactus. It has effects and risks comparable to those of LSD and psilocybin, but has not been studied as a potential therapeutic aid.

Early research suggested that religious use of peyote by the Native American Church was safe and may prove effective in the treatment of alcoholism. More recent data suggests that mescaline, and possibly other phenethylamines, may be useful as therapeutic agents.

DMT was discovered in 1956 and is now becoming increasingly visible in popular media outlets. It is almost always vaporized and inhaled when not prepared as ayahuasca, a South American DMT containing brew.

DMT is similar to LSD and psilocybin in many regards, including molecular composition and affinity for the 5-HT2AR, but also possesses many unique characteristics. It has been detected in the body fluids of both schizophrenics and healthy individuals.

Indolethylamine-N-methyltransferase (INMT) is widely expressed in the body and is responsible for synthesizing DMT from tryptamine. It has been implicated in consciousness and perception, particularly visual perception.

Researchers have suggested that DMT may have an immunomodulatory role, potentially through sigma-1 receptor mediated pathways. This is consistent with preclinical data showing that DMT may be useful in the treatment of allergic asthma.

Early human subjects research with DMT focused largely on basic psychopharmacology, and psychotomimetic effects of this substance. However, research with DPT revealed some promise as an adjunct to psychotherapy, particularly with alcoholics and those with anxiety associated with a terminal cancer diagnosis.

Human subjects research with DMT resumed in 1990 after a long hiatus, and several experiments were performed to assess the basic pharmacological and subjective effects of DMT in experienced hallucinogen users.

Researchers have administered DMT and ketamine to experienced drug users to better characterize serotonergic and glutamatergic models of psychosis. They found that DMT was associated with positive symptoms of schizophrenia, while ketamine was associated with negative symptoms, suggesting differentially mediated effects of serotonin and glutamate in the manifestation of psychotic disorders.

Ayahuasca is a loosely defined admixture of more than 90 different plant species from 38 plant families that was first described by pioneering botanist Richard Spruce on a botanical expedition to the Amazon. It was legalized in Brazil in 1987 and was granted religious freedom in 2006.

DMT is the only major alkaloid present in the leaves of Psychotria viridis, and the -carboline alkaloids harmine, tetrahydroharmine, and harmaline are potent MAO inhibitors, preventing the first-pass oxidative deamination of DMT. The concentration of DMT and -carboline alkaloids in ayahuasca varies widely by batch, but a high dose of 0.85 mg / kg bodyweight of DMT, 1.4 mg / kg of harmine, 0.09 mg / kg of harmaline and 1.16 mg / kg of tetrahydroharmine produced significant increases in diastolic blood pressure.

Contemporary research shows that ayahuasca use is medically safe and may even have a protective psychological effect. A study of 15 adult male members of the UDV found that they experienced a near complete remission of all pathological behaviors after their long-term involvement with the UDV.

Initial research on the long-term neuropsychological effects of ayahuasca has shown decreases in measures of psychopathology and increases in performance on cognitive tasks in Brazilian adult ayahuasca users as compared to matched non-ayahuasca using controls at baseline and 1 year follow up.

A recent study of 22 regular ayahuasca users and 22 matched controls found that ayahuasca users exhibited significantly greater self-transcendence and significantly less cortical thickness in the posterior cingulate than non-users, suggesting a compelling link between psychedelic use, brain structure, and spiritual attitudes.

Ayahuasca may be used to treat addiction, as evidenced by decreased rates of alcohol use among current users of ayahuasca and a decrease of problematic substance use upon initiation of religious ayahuasca use. However, larger, more carefully controlled studies are necessary before results can be deemed conclusive.

Ayahuasca may be useful in the treatment of major depressive disorder (MDD) due to its influence on serotonergic neurotransmission.

Ayahuasca has been shown to affect several biological systems implicated in depression, including the hypothalamic-pituitary-adrenal (HPA) axis, which regulates hormones such as cortisol and adrenaline. Ayahuasca has also been shown to inhibit rapid eye movement (REM) sleep and increase slow-wave activity without reducing subjective sleep quality.

Ayahuasca use has been shown to reduce hopelessness and panic-like symptoms, reduce depression scores, and increase mindfulness related capacities in a small sample of religious ayahuasca users and healthy volunteers.

While most research suggests ayahuasca use is safe, there are methodological shortcomings and the possibility of self-selection bias. Future research should make an effort to study individuals who used ayahuasca in religious contexts for a period of time before abandoning the practice.

Entactogens

The term entactogen was coined by Nichols (1986) to describe the psychoactive effects of the synthetic drugs 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxy-N-ethylamphetamine (MDEA). MDMA is the most widely studied and recreationally used entactogen.

3, 4-methylenedioxymethamphetamine (MDMA)

3,4-methylenedioxymethamphetamine (MDMA) was first synthesized in 1912 and became popular among therapists in the second half of the 20th century, when Dr. Leo Zeff became the first psychotherapist in the United States to incorporate MDMA into his private practice psychotherapy.

MDMA gained popularity for recreational use during the late 1970s and early 1980s, and was classified as a Schedule I controlled substance in 1985. It was accompanied by a new youth culture, the rave and electronic dance music culture.

MDMA is a potent releaser of catecholamine neurotransmitters and a potent releaser of pre-synaptic serotonin. It is usually taken orally, but limited i.v. use has been observed among some experienced users with an eventual return to oral use in most cases.

MDMA safety is an area of intense controversy, but there is a distinction between medical risks of controlled MDMA use and recreational risks, such as prolonged dancing and physical exertion, lack of proper hydration, and poly-drug use.

MDMA exposure is associated with increased heart rate, increased blood pressure, accelerated breathing, jaw clenching, thirst and increased core body temperature. This can lead to hyperthermia and even death.

Recreational ‘Ecstasy’ use has been associated with cognitive deficits, including memory deficits. However, the study by Halpern et al. (2004) may have overstated the association, as the study used a large number of measures in a relatively small sample.

Two studies examined cognitive function in current and ex-‘Ecstasy’ users, poly-drug users, and drug-naive controls, and found no significant differences in cognitive processing between current and ex-‘Ecstasy’ users and drug-naive controls, suggesting that impulsivity may be a mediator of vulnerability to cognitive deficits in chronic ‘Ecstasy’ users.

The debate on MDMA neurotoxicity goes back over 20 years, but many unresolved questions cloud interpretation of the literature, including the validity of using extremely high doses and exposing the test animal to multiple doses in a short amount of time. Baumann and colleagues review the rodent literature and conclude that doses of MDMA do not necessarily need to be adjusted between species. However, moderate doses of MDMA do induce anxiety-like behavior in rats.

Researchers have proposed that chronic recreational ‘Ecstasy’ users may experience some lasting functional impairment, though these effects are not known to generalize to individuals undergoing limited exposure to MDMA.

In recent years, laboratory data have begun to accumulate on the subjective effects of MDMA, and in particular social cognitive effects of potential clinical relevance. These effects include acute reduction in the recognition of fearful faces and identification of negative emotions in an ‘eyes only’ emotion recognition task.

MDMA has been found to have significant sex differences in human subjects, with female volunteers experiencing greater perceptual changes, thought disturbances, and fear of loss of body control, as well as more adverse effects and sequelae post-drug administration.

Multiple studies in rodents have reported significant prosocial effects after MDMA exposure, including decreased aggressive behavior and increased social interaction. Recent neurobiological models for MDMA in the treatment of anxiety disorders have drawn on this body of work.

MDMA-assisted psychotherapy was proposed to reduce or eliminate the neurophysiological fear response to a perceived threat to one’s emotional integrity, thereby facilitating therapeutic outcomes. Follow-up data collected from 29 subjects who underwent MDMA-assisted psychotherapy found positive changes in attitudes, expanded mental perspective, increased insight into personal problems, and positive changes in relationships.

A team of Swiss researchers collected long-term follow up data on 121 patients who had undergone at least one session of MDMA-assisted psychotherapy. They reported decreased drug use and increased quality of life after MDMA-assisted psychotherapy.

Recent clinical MDMA research has focused on treatment-resistant posttraumatic stress disorder (PTSD), with three double-blind, placebo-controlled pilot studies published since 2008 and one long-term follow up study underway.

The first study administered MDMA to individuals with chronic PTSD during two 8-10 hour sessions, and found that 10 of 12 participants showed clinically significant reductions in CAPS score, as opposed to 2 of 8 participants in the placebo condition.

The long-term follow-up to this study showed no significant differences in CAPS scores between 16 individuals who agreed to repeat the CAPS, and 89% of subjects endorsed increased self-awareness and understanding as a persisting benefit.

A recent study found that MDMA treatment for PTSD did not reach statistical significance, but a secondary outcome measure did show significant post-treatment reductions. No serious drug-related adverse events were reported in any of the three clinical trials of MDMA for PTSD.

Dissociative Anesthetics

Dissociative anesthetics include phencyclidine (PCP), ketamine, dextromethorphan (DXM) and nitrous oxide, among others, and act as antagonists at the N-methyl-D-aspartate (NMDA) glutamate receptor as a key mechanism of action. They have earned important roles in medicine, but have also made them popular with recreational users.

Ketamine is an N-methyl-D-aspartate receptor (NMDAR) antagonist used for anesthetic, analgesic, and hallucinogenic purposes, and was first synthesized in 1962 from phencyclidine. It was classified as a schedule III drug in the US in 1999.

Ketamine can be administered via oral, intravenous, and intramuscular routes, though the majority of recreational users report intranasal use. The subjective effects of ketamine last between ten minutes and four hours, depending on the route administered.

Ketamine abuse can cause serious health problems, including ulcerative cystitis, hepatic dysfunction and abdominal cramps. Withdrawal symptoms include craving, sweating, shaking and palpitations, but controlled administration of ketamine in medical and research settings has not been linked to lasting complications.

Ketamine induces visual distortions, mild dissociative and stimulant effects, and at higher doses, complete mental dissociation from the physical body. The most appealing aspects of ketamine use are melting into the surroundings, visual hallucinations, out-of-body experiences, and “giggliness”. Ketamine’s psychedelic-like effects were systematically characterized by Bowdle and colleagues (1998), who found a strong correlation between ketamine plasma concentration and subjective drug effects, and a psychometric profile on the Hallucinogen Rating Scale comparable to that of DMT.

Ketamine’s psychedelic-like effects were first noted in the scientific literature around 1970. In the 1980s and 90s, over 1,000 alcoholic patients were treated with ketamine psychedelic therapy (KPT) without any complications such as psychosis or ketamine abuse. Follow-up data showed that the KPT group had increased rates of alcohol abstinence at one year post-treatment, and continued abstinence at two years post-treatment and three years post-treatment.

In two studies, high dose ketamine was found to be more effective than low dose ketamine in reducing craving for heroin. The high dose was also found to be more effective in reducing withdrawal symptoms than the low dose.

Eight non-treatment seeking cocaine-dependent volunteers received a single i.v. ketamine infusion and experienced increased motivation to quit cocaine and decreased cue-induced cravings for cocaine. Four out of eight achieved biologically verified abstinence from cocaine two weeks after their ketamine infusions.

Ketamine produced dose-related increases in mystical experience, which were significantly correlated with changes in motivation to quit. Furthermore, mystical experience predicted motivation to quit with greater accuracy than dissociative symptoms.

Current methods of evaluating hallucinogen effects are still in need of further refinement, and qualitative approaches may provide a more nuanced understanding of the role of mystical and other types of drug experiences in hallucinogen-facilitated treatments.

Ketamine has shown promise as an antidepressant, with effects lasting from 3 to 7 days. It is largely eliminated from the body within 3 hours of administration, suggesting a significant role for downstream mechanisms triggered by ketamine in mediating its antidepressant effects.

Ketamine’s antidepressant effects are due in part to a cascade of activity beginning with a surge of glutamate, leading to activation of AMPA receptors and neuroplastic changes including synaptogenesis. Ketamine has additionally been linked to increases in brain-derived neurotrophic factor and enhanced cortical excitability.

Ketamine’s hallucinogenic properties have been implicated as a mediator of antidepressant effects in some research, but not all. The acute psychotomimetic effects of ketamine may be linked to later efficacious treatment outcomes, consistent with preliminary results from related hallucinogen-facilitated addiction treatment paradigms.

Ketamine may be useful as a treatment for obsessive-compulsive disorder and post-traumatic stress disorder, and is being studied as a potential new anti-obsessive drug.

Ketamine showed a significant and rapid decrease in PTSD symptoms compared to midazolam, and was clinically significant for as long as 2 weeks. This suggests that ketamine deserves consideration for further clinical development and proliferation for a number of conditions.

Dextromethorphan (DXM)

Dextromethorphan (DXM) is an analogue of the opioid analgesic levorphanol, and is an effective cough suppressant at low doses. It has a high margin of safety, and low abuse liability at recommended antitussive doses.

Human laboratory research has shown that DXM exhibits psychedelic-like effects at supratherapeutic doses, and that high doses of DXM can elicit acute cognitive impairment in attention, memory, and metacognition comparable to a large dose of the benzodiazepine triazolam.

Clinical research with high-dose DXM has shown safety and preliminary feasibility as an aid in pain management, attenuating opioid withdrawal, and as a treatment for agitation in Alzheimer’s patients and pseudobulbar affect in dementia patients.

DXM may possess rapid-acting antidepressant properties based on its pharmacological similarities to the NMDA antagonist ketamine. Furthermore, recent preclinical data have demonstrated that DXM exhibits antidepressant effects in animal models mediated by its activity at Sigma-1 and glutamatergic AMPA receptors.

Atypical Hallucinogens

Atypical hallucinogens include the indole alkaloid ibogaine, the kappa opioid receptor (KOR) agonist salvinorin A, and the anticholinergics atropine and datura, also known as deliriants. Cannabis is also sometimes attributed psychedelic-like properties.

Ibogaine is an indole alkaloids found in the root and root cortex of the African shrub Tabernathe iboga, and has been used as an opioid detoxification agent since the early 20th century.

The National Institute of Drug Abuse initiated its ibogaine research program in 1991, but discontinued all federally funded human trials in 1995 due to concerns of neurotoxicity and fatalities. Medical ibogaine treatment centers opened their doors in 1994 in Panama and 1996 in St. Kitts.

Ibogaine’s neuropharmacology is complex and remains incompletely understood, but it is thought to act by agonism at the mu opioid receptor and normalization of accumbal dopamine increases associated with the rewarding effects of morphine, nicotine, and amphetamine.

Clinical ibogaine use is controversial because of concerns of neurotoxicity and cardiac toxicity. However, at dosages of 40 mg / kg, no cerebellar toxicity was found.

Concerns over possible cardiac toxicity have come from reports of human fatalities associated with the ingestion of ibogaine. 14 of the 19 deaths included adequate postmortem data with which to infer cause of death.

Ibogaine has been shown to reduce animal self-administration of morphine, cocaine, amphetamine, methamphetamine, alcohol, and nicotine, possibly by dampening dopamine efflux in the nucleus accumbens in response to opiates and nicotine.

Many of these findings have been replicated with a synthetic ibogaine congener, 18-Methoxycoronaridine (18-MC), which has not shown evidence of cerebellar toxicity or tremors in animals. It has also been shown to dampen dopamine efflux in the nucleus accumbens in response to opiates and tobacco.

To date, there are three published case studies of ibogaine treatment, including one opioid detoxification. The results suggest feasibility of ibogaine as a treatment for opioid dependence, though concerns over toxicity and adverse events remain.

A retrospective analysis of 75 alcohol, cannabis, cocaine, and crack cocaine users who sought treatment at a Brazilian substance abuse clinic using cognitive behavior therapy in combination with ibogaine treatment found that ibogaine may be safely administered by experienced professionals in a hospital environment to medically screened volunteers.

Salvia Divinorum

J.B. Johnson, the first anthropologist to observe a traditional mushroom ceremony, was also the first scientist to write on the indigenous Mazatec use of a sacred plant drug, Salvia divinorum, which is controlled in 20 US states and listed as a “drug of concern” by the US DEA. Recreational SD use is sporadic, with most users reporting less than 20 lifetime uses. Most recreational SD use occurs via smoking commercial preparations of SD leaves fortified with additional SA.

SA has no affinity for the 5-HT2AR receptor, contains no nitrogen, and acts selectively as an agonist at the kappa opioid receptor. This has been further demonstrated in humans in a double-blind placebo-controlled study.

Acute activation of the KOR by SA leads to decreased synaptic dopamine within the nucleus accumbens and caudate-putamen, and decreased intracranial self-stimulation. SA may also have downstream effects on the endocannabinoid system, but this has not yet been demonstrated in primates.

Recent controlled studies have shown that inhaling SA leads to acute psychotomimetic effects, intense perceptual alterations, dissociative effects, elevated cortisol and prolactin, decreased resting state EEG spectral power, and no significant changes in physiology such as heart rate or blood pressure.

SA effects on reward circuitry may explain why recreational SD use is not associated with dependence. No respondents met criteria for SD use disorders based on self-report, and no respondents sought out SD subsequent to experimental SA exposure.

Laboratory data indicate that SA administration can lead to experiences with mystical or spiritual qualities, and several surveys of recreational SD users report “spiritual purposes” as a common reason for use. These experiences include “out of body travel” and “contact with other entities”.

Cannabinoids

Cannabis sativa (cannabis) is among the oldest of cultivated plants known to mankind and has been used medicinally, as a food source, and most importantly as a source of fiber. It has also played a prominent role in the religious and ceremonial life of many peoples both past and present.

The plant genus Cannabis is commonly divided in two species, Cannabis sativa and Cannabis indica, with a third species as Cannabis ruderalis. The human organism has two cannabinoid receptors (CB1 and CB2) and two endogenous cannabinoids Narachidonoylethanolamin (anandamide) and 2-arachidonoylglycerol (2AG).

Cannabis use has demonstrated some significant sex differences in preclinical and human research, with women reporting greater abuse-related drug effects such as “good” and “take again” compared to men.

Cannabis has been used to treat a variety of medical conditions, including nausea and vomiting due to chemotherapy, chronic neuropathic or cancer pain, spasticity due to multiple sclerosis, and weight gain in HIV patients, Tourette syndrome, and treatment of sleep disorders.

Several other therapeutic applications of cannabinoids have garnered interest, including an anticancer agent, for epilepsy, mood disorders, and PTSD, as well as a potential role for cannabis in reducing opioid abuse.

Cannabinoids, and particularly CBD, may be useful in reducing seizures in epilepsy with limited adverse effects, though well controlled trials are still forthcoming.

Cannabis and the endocannabinoid system have been implicated in the neurobiology of anxiety and depression, and several studies have suggested that smoked cannabis may be useful for the management of depressive symptoms in cancer patients.

Individuals with PTSD often self-medicate with cannabis, and have reported decreased PTSD symptoms as a result. Recent human neuroimaging studies have shown pronounced differences in CB1 receptor densities and anandamide signaling in sufferers of PTSD as compared to healthy controls and traumatized individuals without PTSD.

Discussion

The data presented here provide a review of potential therapeutic applications of hallucinogenic drugs, including LSD, psilocybin, mescaline, DMT and ayahuasca, for a range of psychological disorders for which currently available treatments are often insufficient.

While some concerns remain about possible neurotoxicity or adverse cognitive effects associated with chronic abuse of ‘Ecstasy’, limited exposure to pure MDMA in controlled settings has not been observed. Classic psychedelics such as LSD or psilocybin may serve as reasonable alternatives to MDMA.

The dissociatives have been studied more thoroughly over the past several decades, and ketamine has shown promise as an antidepressant and anti-addictive agent in conjunction with psychotherapy. However, translation to clinical practice has not been widely adopted.

Atypical hallucinogens such as ibogaine and Salvinorin A have shown varying degrees of clinical potential, including as an aid in opioid detoxification and substance use disorder treatment. However, concerns remain about safety and toxicity, tempering the widespread implementation of ibogaine research and treatment for the time being.

The medical cannabis movement has become increasingly widespread over the past two decades, and recreational cannabis use has been legalized in Colorado, Oregon, Alaska, and Washington state. However, cannabis remains a Schedule I substance at the federal level.

The convergence of historic events has brought us to the verge of a new scientific framework for considering all drugs, both scheduled and unscheduled. This new framework should take into account not only the adverse effects of various drugs, but also their possible beneficial uses.

Population data from 2010 indicate that 32 million individuals in the US have used a psychedelic in their lifetime, and epidemiological studies have found no significant association between lifetime psychedelic use and mental health problems of any kind.

A related study using pooled NSDUH data from 2008 – 2012 found that lifetime psychedelic use was associated with significantly lower rates of past month psychological distress, and past year suicidality, while illicit use of other drug classes such as sedatives was generally associated with increased risk of psychological distress and suicidality.

Scientists are hesitating to investigate the uses of these drugs because of the unfavorable publicity and the threat of condemnation if they are identified with irresponsible researchers.

In the popular press and media, sensational reports can abound on the “miraculous” healing qualities of certain compounds, but a judicious assessment paints a much more nuanced and complex picture. Hallucinogens exhibit a collection of remarkable properties, some of which can elicit harm, and others which can promote healing or wellbeing.

While individuals continue to suffer the burden of illnesses such as addiction and post-traumatic stress disorder, biomedical researchers and clinicians should explore every available treatment option, and public policy should beholden to the scientific data on these substances, not vice versa.

Public Health Significance

Although most hallucinogens are currently highly restricted, some may have therapeutic applications for a variety of difficult to treat conditions.