Studying the Effects of Classic Hallucinogens in the Treatment of Alcoholism: Rationale, Methodology, and Current Research with Psilocybin

This review (2013) summarizes preclinical evidence to support the therapeutic efficacy of psychedelics in the treatment of alcoholism and makes suggestions for future paradigms to assess their clinical efficacy, bearing in mind the issues of blinding and expectancies that are addressed within double-blind placebo-controlled study designs.

Abstract

“Recent developments in the study of classic hallucinogens, combined with a re-appraisal of the older literature, have led to a renewal of interest in possible therapeutic applications for these drugs, notably their application in the treatment of addictions. This article will first provide a brief review of the research literature providing direct and indirect support for the possible therapeutic effects of classic hallucinogens such as psilocybin and lysergic acid diethylamide (LSD) in the treatment of addictions. Having provided a rationale for clinical investigation in this area, we discuss design issues in clinical trials using classic hallucinogens, some of which are unique to this class of drug. We then discuss the current status of this field of research and design considerations in future randomized trials.”

Author: Michael P. Bogenschutz

Summary

1. Rationale for the studying the use of classic haallucinogens to treat alcohol dependence

A number of articles have reviewed the literature on the use of hallucinogens in the treatment of addictions, including a recent addition of two reviews that incorporate current research on the effects of classic hallucinogens more generally.

1.1. Relevant Preclinical Research

Classic hallucinogens bind to many serotonin receptor subtypes and other receptors, but their psychoactive effects depend primarily on their actions at 5HT2A receptors. The effects of hallucinogenic 5HT2A agonists are mediated by different intracellular signaling cascades from those activated by serotonin and non-hallucinogenic 5HT2A agonists.

Classic hallucinogens induce down-regulation of 5HT2A receptors, increases expression of glial cell line-derived neurotrophic factor (GDNF) in glioblastoma cells, and increases the size of dendritic spines on cortical neurons in rat models. These changes may contribute to the antiaddictive effects of classic hallucinogens.

1.2. Neuroimaging Studies of Acute Effects of Classic Hallucinogens on Functioning of the Human Brain

PET, SPECT, and fMRI technologies have been applied to studies of the acute effects of classic hallucinogens, including psilocybin and ayahuasca. These studies have demonstrated that psilocybin increases cerebral glucose metabolism and increases activation in multiple brain regions in response to recollection of autobiographical events. Acute effects of classic hallucinogens on brain function are only beginning to be understood, but persisting effects are more directly relevant to therapeutic benefit.

1.3. Can Administration of Classic Hallucinogens Precipitate or Facilitate Lasting Psychological Change?

Hallucinogens were studied extensively in the 1950s through the early 1970s for the treatment of alcohol and drug addiction as well as anxiety, depression, obsessive-compulsive disorder, and other conditions. Two contrasting models of treatment were developed: the psycholytic and psychedelic models.

Psilocybin can occasion profoundly meaningful experiences in normal volunteers, and the effects last for months. In one study, 22 out of 36 participants met a priori criteria for a “complete mystical experience”, and 67% rated the experience as one of the 5 most significant spiritual experiences of their lives.

1.4. Relationship of Sacramental Hallucinogen Use to Use of Other Substances

Cross-sectional studies have consistently shown that members of religions that use serotonergic hallucinogens as a regular part of their practice use less alcohol than non-members.

1.5. Past Research on Classic Hallucinogens for Alcohol and Drug Dependence

In the 1950s and early 1970s, there was extensive research on the use of LSD in the treatment of alcoholism. The studies were heterogeneous, with sample sizes ranging from 20 to 176, LSD doses ranging from about 210 to 800 mcg, and control conditions including placebo, low dose LSD, and amphetamine.

59% of LSD-treated participants were significantly improved, compared to 38% of the control participants, after 6 months of follow-up. These effects were highly consistent across 6 studies.

1.6. Recent Studies of Psilocybin as Treatment for Various Conditions

In the past decade, interest in potential clinical applications of classic hallucinogens, particularly psilocybin, has resurged. Currently, psilocybin is being investigated as an adjunct in smoking cessation treatment at Johns Hopkins University and for alcohol dependence at the University of New Mexico.

2. METHODOLOGICAL ISSUES IN CLINICAL TRIALS USING HALLUCINOGENS

Hallucinogens have several features that make them unique in clinical trials. These features include acute psychoactive effects, persisting effects that outlast the acute pharmacologic effects, and subjective experiences that may be mediated by the acute psychological effects.

2.1. Choice of Drug

Although there is a good case for studying the use of ibogaine derivates and NMDA antagonists to treat addiction, the focus of the current review is on classic hallucinogens. LSD and psilocybin are the two leading candidates for application in the treatment of addiction.

2.2. Number of Sessions and Dose

The dose used and the number of sessions depend on the intended effect and the model of treatment being used. The most important predictor of positive effect is having a “peak-psychedelic” or mystical experience. Fisher reported that a standard psychedelic dose of LSD was 300-500 mcg, and for psilocybin 20-40 mg. The Johns Hopkins group reported that a dose of psilocybin of up to 30 mg/70 kg (0.43 mg/kg) was effective for addiction treatment.

Although the randomized trials of LSD for alcohol dependence used a single high-dose session, other variations of the psychedelic model were also used, including multiple sessions, booster doses, and combining classic hallucinogens with psychostimulants.

Based on existing data, the high-dose, single-session model is the most effective approach for treating addictions, but a model that includes a few (2-4) sessions with the dose escalating until an optimal effect is achieved and/or dose-limiting side effects are experienced is also possible.

2.3. Psychosocial Treatment

In psychopharmacotherapy trials, it is desirable to standardize psychosocial treatment, even if this treatment consists only of “pharmacologic management” by the treating clinician. The psychosocial treatment might also help establish the purpose of the session, provide a conceptual framework for the experience, or promote particular kinds of drug experiences.

Different models of treatment with hallucinogens have differed in their hypotheses for the mechanism of action, and have employed differing therapeutic approaches. Psycholytic therapy is based primarily in the psychoanalytic model, while psychedelic therapy is based on maximizing the probability of having a peak-psychedelic experience.

Regardless of the model, it is prudent to recommend that the psychosocial treatment provide sufficient support to minimize the probability of traumatic drug experiences, and include sufficient monitoring and evaluation to identify any significant adverse events and intervene as needed.

Providing psychosocial treatment in the context of treatment with classic hallucinogens requires training and supervision, and the therapist should have sufficient knowledge and experience of the possible range of responses to the drug and be equipped to handle any situations that may arise.

It is generally believed that the mental state of the participant and the setting of the session will affect both the acute and the post-session effects of the session. Although there are no data to support this supposition directly, positive expectancies and positive intentions may be important predictors of outcome.

2.4. Patient Characteristics, Potential Moderators and Sample Size

To minimize the probability of adverse events in studies involving administration of hallucinogens, participants should not have a personal or family history of psychosis, have no past exposure to psychedelics, and have a reasonable likelihood of completing the treatment and follow-ups.

Patients should be assessed for characteristics that may affect response to psychedelic drug treatment, including alcoholism typology, age of onset, severity, craving, and other comorbid substance use. Personality and psychopathology may also affect treatment effect.

A phase 3 trial of a drug for alcohol dependence should include enough participants to detect clinically meaningful effects with adequate power. The history of LSD treatment for alcoholism amply demonstrates the risks of inadequate size.

2.5. Outcome Measures and Mediators

There are no generally accepted criteria for success in addiction treatment research. Self-report measures are generally reliable and valid, but objective biological measures such as urine drug screens are often used as primary outcomes or combined with self-report to form composite measures that perform better under some circumstances than either considered separately.

Addiction affects many life domains, and treatment can affect outcomes in these areas. The character of the drug experience is an important proximal outcome, and can be measured using instruments such as the 5D-ASC and the Hallucinogen Rating Scale HRS.

Prior studies of treatment of addictions with classic hallucinogens have not assessed neurobiological changes in the brain beyond the period of intoxication. These studies are valuable for providing information about the brain activity associated with altered states of consciousness. PET and SPECT can be used to study receptor density and occupancy, as well as direct assessment of metabolism, which can only be inferred using fMRI. Magnetoencephalography can be used to measure brain activity directly on a shorter time scale than fMRI.

2.6. Design

2.6.1. Dealing with Interactions Between Pharmacotherapy and Psychosocial Treatment

In a clinical trial of a classic hallucinogen, the therapeutic intervention consists of drug and psychosocial treatment. It is expected that there will be an interaction between the psychosocial treatment and the drug effect, but factoral designs involving multiple psychosocial treatment conditions greatly increase the cost of a study. The psychosocial treatment must be designed to be credible and potentially effective for patients who do not receive active medication, and minimize demoralization in patients who do not have a strong experience from the medication.

To compare the effects of a hallucinogen with a psychosocial treatment that works with the drug, compare the drug-therapy package to a different psychosocial treatment and/or medication of known efficacy.

2.6.2. Control Conditions and the Issues of Blinding

Double-blind conditions are challenging in studies involving psychoactive doses of hallucinogens, because participants may expect the drug to have powerful effects, and therapist behavior may be affected by observation of a participant having a strong emotional reaction or other pronounced effects during a session.

Use of active controls in studies with hallucinogenic drugs is an alternative to placebo control, but has the drawback that patients will in most cases know whether they received active medication or not. A low dose of the drug under investigation could be used in controlled trials to determine whether it has therapeutic effects. However, it is difficult to exclude the possibility that a low psychoactive dose could have therapeutic effects.

In some studies, participants and therapists are blinded to aspects of study design. This is done by not giving complete information about the treatments included in the study, the relative probabilities, or the possible orders of treatments.

2.6.3. Possible Study Designs for Clinical Trials

Four basic trial designs are discussed in this section. A simple two-group design may work well if the study treatment involves a single drug administration session, but expectancy can be compounded for multiple-session treatments if patients and therapists can predict the experience of later sessions based on earlier sessions.

Cross-over designs are ideal for studying treatments for conditions in which clinical status tends to be stable over time, but are problematic in addiction treatment because clinical status can change markedly over relatively short periods of time, independent of treatment.

Some participants would be sober after the first course of treatment, some would be drinking more heavily, some would have been hospitalized, some would be using other drugs, some would be unchanged, and some would have dropped out or been lost to follow-up.

A double-blind trial with 2-4 groups followed by administration of open-label active drug (perhaps one additional session) for all participants is another possible design variation. The disadvantage is that the between-group comparison would only be valid until the open-label session was conducted.

3. DISCUSSION

Existing data justify renewed clinical investigation into the effects of classic hallucinogens in the treatment of alcoholism and other addictions. Psilocybin has been shown to have positive effects on attitude, mood, and behavior, and is strongly associated with decreased alcohol and drug use.

Clinical trials using hallucinogens involve a number of unusual design issues, including the difficulty of blinding to the subjective effects of the drugs, and the possibility complex interactions between psychological factors and the biological effects of the drug.

There are many clinical populations that could be studied and many approaches that could be justified, but it is not certain at this point how to optimize the therapeutic effects of these drugs in the treatment of addictions. Double-blind controlled trials should be designed bearing in mind the issues of blinding and expectancies.

Authors

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Michael Bogenschutz
Dr. Michael P. Bogenschutz is a Professor in the Department of Psychiatry at NYU Grossman School of Medicine who specializes in treating addiction and anxiety disorders.

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NYU Langone Health
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