This review and hypothesis-building paper (2012) presents where we stand with psychedelic research for the treatment of addiction and provides a rationale for further research.
Abstract
“Alcohol and drug addiction are major public health problems, and existing treatments are only moderately effective. Although there has been interest for over half a century in the therapeutic use of classic hallucinogens to treat addictions, clinical research with these drugs was halted at an early stage in the early 1970s, leaving many fundamental questions unanswered. In the past two decades, clinical research on classic hallucinogens has resumed, although addiction treatment trials are only now beginning. The purpose of this paper is to provide a targeted review of the research most relevant to the therapeutic potential of hallucinogens, and to integrate this information with current thinking about addiction and recovery. On the basis of this information, we present a heuristic model which organizes a number of hypotheses that may be tested in future research. We conclude that existing evidence provides a convincing rationale for further research on the effects of classic hallucinogens in the treatment of addiction.”
Authors: Michael P. Bogenschutz & Jessica M. Pommy
Summary
Introduction
Hallucinogens include several classes of drugs with distinct mechanisms of action, including agonist activity at serotonin (5-HT)2A receptors, antagonism of NMDA receptors, and muscarinic acetylcholine receptor antagonism.
Hallucinogens have been used in religious and medicinal contexts for centuries in a variety of different cultures. In the 1950s through the early 1970s, there was great interest in the use of hallucinogens to facilitate rapid therapeutic effects in alcohol and drug addiction, anxiety, depression, obsessive-compulsive disorder, and other conditions.
Many studies from the 1960s reported psychological changes following hallucinogen administration. Improvements were observed on the clinical scales of the Minnesota Multiphasic Personality Inventory (MMPI) and the Value-Belief Q-Sort in patients who received a single dose of LSD in the context of psychedelic therapy.
In the 1950s through the early 1970s, clinical research on hallucinogenic substances was conducted to treat alcoholism and drug addiction. However, after the Controlled Substances Act was passed, most such studies were discontinued.
A recent meta-analysis of six randomized trials of LSD for alcohol dependence found that 59% of the LSD-treated participants were significantly improved at first post-treatment follow-up, vs 38% of the control participants. These effects decreased with the duration of follow-up, but remained significant at six months.
Although there have been no further addiction treatment trials with classic hallucinogens for over 30 years, early-stage clinical trials with psilocybin for nicotine dependence and alcohol dependence are currently under way.
Acute and persisting brain effects of classic hallucinogens
Hallucinogens include a variety of different compounds with varying pharmacological and behavioural effects, including but not limited to alterations in perception, subjective experiences of reality, and cognitive abilities.
Direct effects on serotonin receptors
Classic hallucinogens stimulate 5HT2A receptors in the cerebral cortex, which causes the psychoactive effects of hallucinogens. Ketanserin, a 5HT2A receptor antagonist, blocks nearly all subjective effects of psilocybin in humans.
Secondary effects on glutamate and dopamine receptors
Some research indicates that classic hallucinogens may have secondary effects on the glutamatergic system. For example, 4-iodo-2,5-dimethoxyphenylisopropylamine (DOI) induces glutamate release from pyramidal cells projecting onto pyramidal cells in cortical layer V, leading to increased activity of the latter through a process that depends on AMPA receptors.
Persisting changes in the brain
Acute drug effects alone cannot account for lasting therapeutic effects; persisting brain changes may also be induced by psychological responses to the experience. DOI and serotonin increase expression of glial cell line-derived neurotrophic factor (GDNF) in glioiblastoma cells and brain-derived neurotrophic factor (BDNF) in rat parietal cortex and other neocortical regions by a 5HT2A-dependent mechanism. These effects could potentially lead to changes in synaptic strength in affected regions.
Acute and persisting psychological effects of classic hallucinogens
Hallucinogenic compounds induce acute psychological effects in addition to their neurobiological effects. These acute psychological effects may contribute to lasting changes in the individual, including changes in addictive behaviour.
A mystical experience is a state of consciousness that can occur under a variety of circumstances and is often understood in religious terms. Hallucinogens can induce mystical experiences within research settings as well as in the context of religion.
Mystical experience and after-effects in research contexts
Hallucinogens have the potential to induce profoundly meaningful experiences that have significant lasting effects. Twenty-two out of 36 participants receiving a single high-dose psilocybin session reported a ‘complete mystical experience’.
In a recent human administration study, psilocybin induced significant elevations on the Hood Mysticism Scale, which was correlated with ratings by community observers who reported similar positive changes in participants.
Hallucinogen use in formal religious contexts
Classic hallucinogens have been used ceremonially and religiously for centuries. Studies have consistently shown decreased rates of alcohol dependence among members of religions that use classic hallucinogens as a regular part of their practice.
Ayahuasca is a hallucinogenic tea made from plants containing DMT and beta carboline alkaloids. A study found that ayahuasca users had lower scores on the Addiction Severity Index (ASI) alcohol use and psychiatric subscales compared to a control group, and that church participation played a pivotal role in their recovery.
The peyote cactus, which contains psychoactive quantities of the classic hallucinogen mescaline, has been used ceremonially by native North Americans for at least 5500 years. Some have suggested that taking peyote in a religious context helps alcoholics achieve sobriety.
Halpern et al. assessed the cognitive and psychological effects of long-term peyote use by members of the NAC, and found that the peyote group scored significantly higher on the Rand Mental Health Inventory than the non-substance using comparison group.
Relationship of mystical experience to addiction and recovery
William James described the phenomenon of sudden change in the form of religious conversion, and more recently, ‘quantum change’ has been elucidated as overlapping considerably with mystical experience.
A recent spiritual awakening was associated with increased rates of 12-month continuous abstinence in a large sample of alcoholism treatment participants. A change in religiosity/ spirituality partially mediates the effects of AA involvement on abstinence.
Mood and anxiety
Mood and anxiety disorders often co-occur with substance use disorders. Psilocybin, ketamine, and MDMA may improve symptoms of depression and PTSD.
Effects of psilocybin on mood and anxiety
Griffiths et al. found that participants taking psilocybin reported persistent enhancement of mood two months after the drug session, as well as increased sense of well-being and positive attitudes about one’s life and oneself.
Two published studies have explored the effects of psilocybin in anxiety disorders. The effects were not demonstrated in a double-blind, cross-over design, but statistical trends suggested a positive effect on mood.
Effects of non-classic hallucinogens on mood and anxiety
Ketamine produces rapid and robust antidepressant effects in patients with treatment-resistant major depression and bipolar depression.
MDMA is not a classic hallucinogen, but causes presynaptic release of serotonin and dopamine and has strong stimulant effects. It has less prominent effects on perception and cognition than classic hallucinogens, and may have ’empathogen’ effects.
Relevance of mood and anxiety to addiction
Mood and anxiety disorders increase the risk of substance use disorders. The temporal sequencing of these disorders is variable, making it difficult to generalize about the direction of causal relationships.
Negative affective states are established as a risk factor for relapse. Treatment of anxious alcoholics with buspirone may improve drinking behaviour. Although animal studies have supported the use of antidepressants to decrease ethanol consumption, studies of antidepressant treatment in depressed alcoholics and drug addicts have yielded mixed results, possibly due to the limited effectiveness of antidepressants in these populations.
Effects of classic hallucinogens on personality
There has been minimal research in the past 20 years investigating the mechanisms of hallucinogen effects on personality. However, Maclean et al. recently reported that psilocybin administration can produce positive changes in personality.
Relevance of personality to addiction
Several studies have shown that personality traits associated with substance use disorders include decreased conscientiousness, increased extraversion, increased neuroticism, and decreased openness. These personality traits may be induced by substance use and improve due to abstinence.
Established change mechanisms in addiction
Three mechanisms have been proposed to mediate recovery from addictions: reduced craving, enhanced self-efficacy, and increased motivation. Social support for abstinence vs. drinking is another well-established change mechanism, particularly in the context of AA.
Craving and its brain correlates
Craving is a multi-dimensional construct that includes motivational, affective and cognitive components. Neuroimaging studies have demonstrated a positive relationship between craving intensity and relapse.
Brain regions associated with the reward system, including the ventral striatum and nucleus accumbens, have been assessed through animal research and neuroimaging techniques in humans. The mesolimbic dopamine system is believed to be responsible for the ‘wanting’ process associated with the reward system. Serotonin plays an important role in motivational and appetitive behaviours, reward processing, impulse control and inhibitory processes that are impaired in addiction. Medications that increase central serotonergic activity could theoretically reduce craving and relapse.
Serotonergic drugs have been studied extensively in the treatment of alcoholism. SSRI antidepressants appear to decrease craving for alcohol under some circumstances, but longer term studies have not demonstrated such effects.
Classic hallucinogens have not been shown to affect alcohol or drug craving, but it is possible that persistent brain changes induced by acute brain stimulation during intoxication could modify established patterns of response in brain networks underlying craving.
Self-efficacy
Bandura suggested that self-efficacy beliefs determine how people feel, think, motivate themselves, and behave. Self-efficacy beliefs can be addressed in alcohol treatment by addressing clients’ sense of efficacy to control drinking.
Research has shown that self-efficacy is a significant predictor of treatment outcome in addiction. Self-efficacy has been found to be a partial mediator in the effect of AA attendance and consequently, abstinence.
Motivational Interviewing supports self-efficacy by identifying four ways in which self-efficacy affects motivation, including the amount of energy expended on achieving a goal.
How hallucinogen treatment could work to enhance self-efficacy
Hallucinogenic drug administration may lead to enhanced self-efficacy by encouraging acceptance of the possibility of change, improving mood, and by increasing self-efficacy associated with specific personality dimensions.
Motivation to change
According to the Transtheoretical Stages-of-Change Model, motivation influences patients to seek, complete and comply with treatment and to make successful long term changes in drinking. Motivation involves several processes, including consciousness raising, self-reevaluation, self-liberation, dramatic relief, and environmental reevaluation.
MI and MET are empirically based interventions used in substance abuse treatment that rely on increasing the individual’s motivation to change their behaviours and become sober. The techniques involve exploring and resolving ambivalence regarding the behaviour to be changed.
How hallucinogen treatment might work to increase motivation
Hallucinogen treatment could enhance motivation through several processes, including mystical experience, personality change, and enhanced self-efficacy. This could lead to increased desire to change and increased belief in the possibility of change.
Ibogaine
Ibogaine is an hallucinogenic alkaloid found in several plants, used for medicinal and spiritual purposes by the indigenous people of Western Africa. It was used to treat opioid withdrawal, but was eventually discontinued due to toxicity concerns.
Preclinical work suggests that ibogaine may have anti-addictive effects across several classes of drugs, including morphine, cocaine, and alcohol. Ibogaine may also increase GDNF, a potential target for future pharmacological interventions for addiction.
Ketamine
Ketamine, an NMDA receptor antagonist, has been investigated in Russia as a potential treatment for both alcohol dependence and heroin dependence. In a controlled but non-randomized study, alcohol-dependent subjects who volunteered to receive ketamine-assisted psychotherapy showed significantly higher rates of abstinence at one year. Ketamine treatment for heroin dependence has been shown to have positive effects. Patients who received 2 or 3 ketamine sessions had greater and more enduring reductions in heroin craving than those who received one session.
Discussion
Recent research has demonstrated that hallucinogens can mobilize biological and psychological processes that are relevant to addictions, and that these drugs may promote recovery when administered in an environment and therapeutic context designed to maximize the therapeutic effects of the experience.
The current generation of research on classic hallucinogens does not yet include clinical studies in addiction populations. Pilot studies are currently underway in nicotine dependence and alcohol dependence.
Conceptual model for research on addiction treatment using classic hallucinogens
We have developed a model to explain how administration of a hallucinogen might lead to reduced substance use. The model includes four levels: the treatment situation, the acute effects of the treatment, persisting general effects of the treatment, and specific end effects.
The dose, mode of administration, and patient characteristics of the participant can all influence the experience induced by hallucinogens. Lastly, the setting in which the hallucinogen is administered can affect the treatment outcome.
The hallucinogen-assisted treatment induces acute effects on the brain and the mind, which can be measured and described by different methodologies. The psychological effects are often held as highly meaningful by those who experience them.
Administration of hallucinogens can result in persisting improvements in mood and reduction in anxiety, changes in beliefs and values, and even personality changes.
The proposed model of reduced substance use includes decreased craving, enhanced self-efficacy, and increased motivation. However, no one has yet studied the effects of hallucinogen treatment on these mechanisms.
Conclusions
Evidence suggests that hallucinogenic drug experiences can be safely facilitated in a relatively structured supportive setting, and that these experiences may produce persisting beneficial change. Hallucinogens may have clinically relevant effects on depression and anxiety, and non-classic hallucinogens have shown promise in early phase trials in drug and alcohol dependence.
This question contains many questions, and the evidence reviewed in this paper may be of use to those formulating more specific hypotheses regarding therapeutic effects of classic hallucinogens on substance use disorders.