Michael P. Bogenschutz, MD

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This slideshow provides information about the compounds, clinically relevant attributes, approximate dose, and data under study.

5 Classic Hallucinogens Studied in the Treatment of Addictions

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

To become familiar with the scientific evidence relevant to the use of classic hallucinogens in the treatment of substance use disorders.

At the end of this CE activity, participants should be able to:

• Discuss the early-stage trials of psilocybin in the treatment of alcohol and tobacco use disorders as well as its uses for cancer-related anxiety and depression

• Recognize the benefits of classic hallucinogens and their possible clinical value

• Describe the risks associated with the use of these compounds

This continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

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This article summarizes and discusses the scientific evidence relevant to the use of classic hallucinogens in the treatment of substance use disorders. Although none of these compounds is approved for clinical use, interest in the therapeutic potential of these drugs has increased steadily, particularly in the past decade. Recent early-stage trials of psilocybin in the treatment of alcohol and tobacco use disorders, as well as for anxiety and depression in the context of a life-threatening cancer diagnosis, have had very promising results.

The lay press and the Internet have featured many reports of beneficial effects of classic hallucinogens-sometimes exaggerating the possible benefits and minimizing the risks of these drugs. On the other hand, some clinicians and scientists still have an exaggerated view of the risks of classic hallucinogens and reject consideration of their possible clinical value, perhaps because of the reputation of classic hallucinogens as drugs of abuse, or owing to a lack of familiarity with both recent and older literature on their therapeutic use. It is hoped that this article contributes to a more fully evidence-based discussion of the possible clinical value, as well as the risks, of these compounds.

Substance misuse is the leading preventable cause of death and disability in the world.

 The economic costs of substance use disorders-including factors such as health care costs, lost productivity, crime, incarceration, and law enforcement-are estimated at over half a trillion dollars per year in the US alone. Although effective behavioral and pharmacological therapies exist, currently available treatments help only a minority of those who are treated. For example, approximately 1 person achieves abstinence or avoids relapse for every 9 persons treated with the most effective FDA-approved pharmacotherapies for alcohol use disorder.

 With approved medications for smoking cessation, fewer than 35% of those treated remain smoke-free 6 months after treatment.

 Most medications for substance use disorders require adherence to treatment for relatively long periods, which further limits their effectiveness.

The term “hallucinogen” includes a wide variety of drugs with several different mechanisms of action and widely varied effects, of which actual hallucinations are a relatively minor part. Although there is some overlap in the effects of the various classes of hallucinogens, the risks and possible benefits vary greatly among these drugs.

The main focus of this article is classic hallucinogens. This class of drugs is thought to act primarily as agonists or partial agonists at the serotonin 2A (5-HT2A) receptor. There are 2 structural classes of classic hallucinogens: the indoleamines and the phenylalkylamines. The indoleamines share structural similarities to serotonin and include dimethyltryptamine (DMT), psilocin (4-hydroxy-DMT), psilocybin (4-phosphoryloxy-DMT), N,N-dipropyltryptamine (DPT), and lysergic acid diethylamide (LSD). The phenylalkylamines comprise mescaline and synthetic hallucinogens, including substituted amphetamines such as dimethoxymethylamphetamine (DOM). The 

 provides information about the classic hallucinogens that have been studied in relation to substance use disorders.

The acute effects of all the classic hallucinogens are similar but vary in duration and intensity depending on the particular substance, dose, and route of administration. Physiological toxicity is very low with the doses of LSD, psilocybin, mescaline, DPT, and DMT that are typically used in clinical research. Pulse and blood pressure may be moderately elevated. Visual perception is often profoundly altered, and vivid imagery is frequently seen when the eyes are closed. Other sense modalities may be affected as well.

The sense of time is often distorted. Effects on emotion are extremely variable, and emotions can fluctuate rapidly and frequently during a single treatment session. Strong cathartic emotional experiences are common. The psychological content and emotional tone of the experience are unpredictable but are thought to be influenced strongly by the mental state, preparation, and intention of the person taking the drug; the environment in which the effects are experienced; the dose; and the particular drug that is taken. The content of the experience may be dominated by personal experiences and concerns, dream-like symbolic sequences, or religious or spiritual matters.

Many other serotonergic drugs are often classified as hallucinogens, but either do not have significant 5-HT2A agonist activity or have other effects that are important. The best-known example is MDMA (methylenedioxymethamphetamine), a drug that has only weak 5-HT2A activity but is a potent releaser of serotonin. It has few typical hallucinogenic effects and is more accurately classified as an empathogen or entactogen. Although this drug can cause significant harm when used illicitly, it has produced very promising results and has shown an excellent safety profile in a series of trials that investigated its effects in the treatment of PTSD.

Another important group is the NMDA receptor antagonist hallucinogens, including ketamine and phencyclidine (PCP). Ketamine is a Schedule III drug used widely as a dissociative anesthetic. In sub-anesthetic doses, it is a powerful hallucinogen. The discovery of its short-term antidepressant effects has generated much excitement, and it is now seeing significant off-label use for treatment-resistant depression. More limited research has investigated ketamine as a possible treatment for opioid use disorder, alcohol use disorder, and cocaine use disorder. Although their primary molecular target is different, classic hallucinogens stimulate some of the same signaling pathways as the NMDA receptor antagonists, which suggests that there could be some overlap in mechanisms of action.

Two other classes of hallucinogen with possible relevant effects in substance use disorders are the iboga alkaloids and the kappa opioid agonists. Ibogaine and related alkaloids occur naturally in the African shrub 

. These alkaloids bind to a broad range of receptors. Although ibogaine is a Schedule I substance in the US, it is used clinically in some addiction treatment centers in other countries, and underground in the US. Although anti-addictive effects of ibogaine have been demonstrated in preclinical studies, drug development has been stalled by toxicity concerns. The analog 18-methoxycoronaridine (18-MC) is currently under study as an anti-addictive agent and is thought to lack the psychoactive properties of ibogaine.

The kappa opioid agonist salvinorin A is found in a species of sage called 

. It causes profound but brief alterations in consciousness when inhaled in quantities under 1 mg. Although there is preclinical evidence for anti-addictive effects of salvinorin A and related compounds, no clinical trials of these drugs for the treatment of substance use disorders have been conducted.

Classic hallucinogens in the treatment of substance use disorders

Following Albert Hoffman’s accidental discovery of the psychoactive effects of LSD in 1943, the 1950s through the early 1970s saw an explosion of research on classic hallucinogens. LSD, psilocybin, and other hallucinogens were legally available for clinical use as an experimental treatment until the mid to late 1960s. Over 1000 articles published during this period documented the treatment of more than 40,000 people with classic hallucinogens. In reaction to concerns about increasing misuse of psychedelics in the context of the cultural upheaval of this period, clinical research on hallucinogens was halted in the early 1970s. The Controlled Substances Act, passed in 1970, placed all the major classic hallucinogens into Schedule I, and clinical research with classic hallucinogens became essentially impossible.

Although there were no further clinical trials with classic hallucinogens for more than 30 years, interest in the therapeutic potential of these drugs has steadily increased in the past decade or so. Extensive evidence supports the relative safety of classic hallucinogens (particularly psilocybin and LSD) in clinical research settings. Early-stage clinical trials of psilocybin or LSD for obsessive-compulsive disorder, anxiety and depression associated with a life-threatening cancer diagnosis, major depression, tobacco use disorder, and alcohol use disorder have recently been published.

In the 1950s through the early 1970s, there was extensive research on the effects of LSD in the treatment of alcoholism. At least a dozen trials with some form of control group were conducted, but these studies were under-powered, and results were mixed. A 2012 meta-analysis of the 6 randomized trials of LSD for alcoholism included 325 participants who received LSD and 211 who received control treatment.

 At the first post-treatment follow-up, 59% of the LSD-treated group were significantly improved compared with 38% of the control participants (odds ratio, 1.96; 

 = .0003). Moreover, the beneficial effect of LSD remained significant after 6 months. Although these findings are not conclusive evidence of efficacy, they provide a strong argument for renewed clinical investigation of classic hallucinogens for the treatment of alcoholism.

Limited research was also conducted on the use of DPT in the treatment of alcoholism. In a single-group pilot study involving 51 participants who received between 1 and 6 (mean, 1.9) DPT sessions, Grof and colleagues

 reported highly significant improvement in clinical outcomes including abstinence at 6 months. A subsequent randomized trial conducted by the same group did not detect any clinical benefits with DPT treatment.

 This study suffered from methodological limitations including very high rates of dropout during treatment and in the follow-up period.

Psilocybin has been studied extensively since its isolation in the late 1950s, and it was used to some extent in the treatment of alcoholism, although much less than LSD. My colleagues and I undertook a proof-of-concept study in which 10 volunteers with alcohol dependence received oral psilocybin as well as Motivational Enhancement Therapy.

 Drinking did not decrease significantly in the first 4 weeks of therapy but declined significantly after psilocybin administration. Effect sizes were large, and gains were largely maintained during 36 weeks of follow-up. The intensity of self-reported effects during the first psilocybin session at week 4 strongly predicted improvement in drinking during weeks 5 to 8 (r = 0.76 to r = 0.89). Based on these promising initial results, we are conducting a larger double-blind trial to investigate efficacy and mechanisms of action (NCT02061293).

Although alcoholism has been the main focus of substance abuse treatment using classic hallucinogens, at least 2 studies have been conducted with LSD in the treatment of drug addiction. In a trial at the US Public Health Service Hospital in Lexington, Kentucky, 70 “post-narcotic drug addicts” were randomly assigned to receive a single session that included 1 of 5 treatments, 3 of which included LSD.

 The group that received both LSD (2 µg/kg) and hypnosis had more self-reported improvement in psychopathology than the other 4 groups for up to 2 months following the session. However, drug use behavior after discharge from the hospital was not evaluated in this trial.

 conducted a controlled trial of LSD-assisted treatment of heroin addiction. Incarcerated males (N = 78) with heroin addiction were randomly assigned to usual care in an outpatient, abstinence-based program, including daily urine drug monitoring and weekly group therapy, or to 4 to 6 weeks of residential treatment, including a single high-dose LSD session, followed by usual outpatient care. Results showed that 25% in the psychedelic therapy group were continuously abstinent during the 12-month follow-up compared with 5% in the control group. While the design of this study does not separate the effects of LSD from other aspects of residential treatment, the outcomes in the LSD-treated group are impressive for drug-free treatment of severe heroin use disorder.

Although there have been no further published trials on classic hallucinogens in the treatment of illicit drug use disorders, a pilot study is currently investigating the effects of psilocybin-assisted treatment of cocaine use disorder (NCT02037126).

A manualized 15-week program of cognitive-behavioral therapy that incorporated 2 or 3 psilocybin sessions demonstrated excellent smoking cessation outcomes: 12 of the 15 participants (80%) were biologically confirmed as smoke-free at 6-month follow-up.9 Smoking outcomes were significantly correlated with measures of mystical experience during sessions and retrospective ratings of personal meaning and spiritual significance of psilocybin sessions.

 These findings were consistent with earlier findings that suggested an important role of the nature of subjective experience occasioned by psilocybin. A larger, open-label randomized trial is now being conducted contrasting the effects of psilocybin-assisted treatment with those of the standard-of-care treatment with nicotine replacement therapy (NCT01943994).

Ayahuasca is a tea that contains the classic hallucinogen DMT and beta-carbolines (monoamine oxidase inhibitors that render DMT orally active). Ayahuasca has been used by indigenous peoples of the Amazon basin for centuries and is used sacramentally by a number of organized religions. Observational studies have consistently shown decreased rates of alcohol misuse among members of religious sects that use ayahuasca.

 Ayahuasca is currently being used in treatment centers and in shamanic or “neo-shamanic” contexts for the treatment of substance use disorders and other conditions, as well as for purposes of personal or spiritual growth. Although many individuals have reported that ayahuasca has facilitated their recovery from substance use disorders, no controlled trials have been published to date.

Among treatments currently under development, the classic hallucinogens are unusual in that persistent therapeutic effects result from no more than a few discrete exposures to the medication. Plausible biological mechanisms have been proposed, including modulation of 5-HT2A receptors and induction of neuroplastic processes. However, at this point the strongest evidence is for the role of drug-occasioned experiences as mediators of therapeutic effects.

The pathogenesis of PTSD bears some resemblance to this process. In PTSD, an overwhelming psychological trauma can cause persistent harmful changes in brain structure and function, as well as subjective experience and behavior. Extremely intense and personally meaningful experiences occasioned by classic hallucinogens may produce persistent therapeutic changes through mechanisms that are not currently understood. This mechanism is unique among pharmacotherapies and provides a fascinating model of the interaction between subjective experience and neurobiology.

As with all drugs, there are risks associated with administration of classic hallucinogens. Nonmedical use of classic hallucinogens can precipitate prolonged psychiatric reactions (eg, psychosis). Although rare, prolonged psychiatric reactions have also been observed when the hallucinogens were administered under controlled conditions in medical settings.

Physiological toxicity of the classic hallucinogens is remarkably low, even at very high doses. Rarely, nonmedical use of classic hallucinogens can result in clinically distressing persistent perceptual abnormalities (eg, hallucinogen persisting perception disorder). However, such cases have not been observed in clinical research. Although classic hallucinogens can be misused in dangerous ways in nonclinical settings, they do not normally engender compulsive drug-seeking (addiction) as with most drugs of abuse (eg, opioids, cocaine, methamphetamine, cannabis, NMDA antagonist hallucinogens). Because of the intense subjective experiences possible with classic hallucinogens-including fear, anxiety, and occasionally paranoia-dangerous and erratic behavior during intoxication is possible, so patients must be carefully monitored.

 Screening for severe psychiatric disorders and/or a predisposition to these disorders

Preparatory meetings with research therapists to develop rapport and to prepare the volunteer for dealing with potentially powerful drug effects

Availability of rescue medication (eg, antihypertensives, benzodiazepines, antipsychotics), although such medications are rarely needed

Monitoring by multiple individuals who have developed rapport with the patient during drug administration sessions

 Follow-up contact with treatment staff to discuss and process such experiences, and to monitor for any emerging psychopathology or treatment needs

Taken as a whole, the evidence suggests that classic hallucinogens may hold considerable promise in the treatment of substance use disorders, particularly given the unique mechanisms of these drugs, their low toxicity, the potential to induce lasting change after a few administrations (or even one) of the drug, and the limited efficacy of existing treatments. Although the preliminary efficacy data are suggestive, it must be underscored that they are very limited except in the case of LSD treatment of alcoholism.

Based on existing evidence, none of the classic hallucinogens meets medical standards for safety and efficacy. Large rigorous trials will need to be completed to determine whether classic hallucinogens have a place in the treatment of addiction or other psychiatric disorders. On the other hand, considerable data support the safety of these drugs when patients are carefully screened and prepared, and appropriate safeguards are employed. Thus, there do not appear to be valid scientific or ethical barriers to energetically addressing questions of efficacy, which were prematurely dropped over 40 years ago.

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Dr. Bogenschutz is Professor of Psychiatry, New York University School of Medicine, New York.

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 Cahill K, Stevens S, Lancaster T. Pharmacological treatments for smoking cessation. 

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 Grob CS, Danforth AL, Chopra GS, et al. Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. 

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 Johnson MW, Garcia-Romeu A, Cosimano MP, et al. Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction. 

 Bogenschutz MP, Forcehimes AA, Pommy JA, et al. Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. 

 Carhart-Harris RL, Bolstridge M, Rucker J, et al. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. 

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Here: a review of the scientific evidence relevant to the use of classic hallucinogens in the treatment of substance use disorders. 

Michael P. Bogenschutz, MD

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