This paper (2021) reviews the current literature regarding LSD, psilocybin, ketamine, ibogaine, and ayahuasca as potential treatments for addiction. The authors conclude that the available evidence is promising, but that more robust research is needed.
Abstract
“The utility of hallucinogenic drugs within psychiatry is an emerging topic, although not entirely a novel idea. After their introduction to western society in the mid-twentieth century, psychologists and psychiatrists studied their properties for use as adjunctive therapy in the treatment of psychiatric illness. Unfortunately, their classification as Schedule 1 drugs by the Drug Enforcement Administration in the 1970s put an end to this research. In the past decade, however, interest in hallucinogens has been reignited. The psychiatric community has begun to reinvestigate their role in mental health treatment, with addiction being one focus. Though there is a growing pool of research surrounding the use of hallucinogens in addiction treatment, there have been few reviews focusing on this topic. This paper will serve to summarize this data, focusing specifically on the following hallucinogenic agents: lysergic acid diethylamide, psilocybin, ketamine, ibogaine, and ayahuasca. It will review both the basic pharmacology of each of these chemicals and studies assessing their use in treating various addictions including alcoholism, nicotine addiction, opioid use disorder, and cocaine use disorder. Though more robust research is needed before use of these drugs can be effectively adopted into clinical practice, the current data is promising and suggests the potential for a new and unique avenue for the treatment of addiction.“
Authors: Kabir B. Nigam & Ananda K. Pandurangi
Summary
The use of hallucinogenic drugs in psychiatry is an emerging topic, although not entirely a novel idea. This paper will review the basic pharmacology of several hallucinogenic drugs and their use in treating various addictions, including alcoholism, nicotine addiction, opioid use disorder, and cocaine use disorder.
Introduction
Global statistics estimate that 18.4% of the population is affected by heavy episodic alcohol use and 15.2% by daily tobacco use. Alcohol and tobacco use represent the top three most common preventable causes of death, and opioid use has begun to trend upward.
Pathophysiology of Addictions
Drugs of abuse hijack the brain’s biological reward system to induce hedonistic emotions that reinforce the activating behavior. This mechanism is shared by many different illicit drugs, and is what drives addiction to illicit substances.
Current Therapies
Numerous meta-analyses have shown that psychological and psychosocial interventions like cognitive-behavioral therapy, contingency management, and motivational interviewing are effective in treating alcoholism. However, there is room for improvement with current pharmacological and behavioral interventions. Treatment for opioid use disorder involves replacing one opioid with another, albeit less addictive or safer. Advances in the treatment of nicotine addiction have shown that pharmacological drugs like varenicline can be effective, but relapse rates remain the same.
Hallucinogens
The use of hallucinogens in psychiatry in conjunction with other therapies has become of recent interest in the treatment of psychiatric disorders where current treatment is not satisfactory, such as acute suicidality, treatment-resistant depression, and post-traumatic stress disorder.
Recent trials with psychedelic-assisted therapy have shown promising results, and the use of these substances in treatment of addiction has been reinvestigated. Hallucinogens treat addiction from a new standpoint, and their effects are likely key in reducing repetitive behaviors characteristic of addictive disorders.
Methods
PubMed and Google Scholar were used to search for studies on psychedelics and addiction. MDMA was excluded from this paper due to lack of research investigating its utility in treatment of addictive disorders.
A total of 392 articles were screened for studies directly addressing the utility of hallucinogens in addiction. Of these, 25 studies were identified for use in this review, which included clinical trials, meta-analyses, and retrospective studies assessing addiction severity among individuals who use hallucinogens therapeutically.
Lysergic Acid Diethylamide
LSD was synthesized by Swiss chemist Albert Hofmann in 1938 and was used by psychologists as tool for psychotherapy. It was declared a Schedule I drug by the DEA in the 1960s.
LSD’s hallucinogenic properties can be attributed to its effects on the serotonergic system, and its affinity for D2 dopamine receptors likely plays a role in the drug’s behavioral effects.
Many studies on LSD in the mid-twentieth century focused on its use in treating alcoholism. The earliest studies date back to the 1950s and showed a 50% response rate.
Hollister et al. sought to further explore the therapeutic relationship between LSD and alcohol use in men by adding a control group. They noted significant improvements in scoring on a drinking behavior scale at the 2-month mark for the experimental group as compared to the control group.
Researchers conducted a controlled study on male veterans with a mean age in the mid-forties that used LSD in combination with an alcohol treatment program based on the Human Relations Training Laboratory (HRTL) program. The results showed that the group receiving LSD had similar results to the group receiving therapy alone.
A meta-analysis of six trials investigating the use of LSD in the treatment of alcoholism was conducted in 2012. The results showed that LSD had a significant effect on alcohol misuse and abstinence at short-term and medium-term follow-ups, but not at long-term follow-up.
Psilocybin
Psilocybin is an active ingredient in naturally occurring mushrooms around the world that has been consumed by humans for centuries. Its hallucinogenic effects are mediated by its actions on the serotonergic system.
Research into the use of psilocybin for the treatment of addiction has shown promising results, with the drug being granted breakthrough therapy status by the FDA.
A group at Johns Hopkins examined the feasibility and potential efficacy of psilocybin as an adjunct in the treatment of nicotine dependence. After 15 weeks of treatment, 12 of 15 participants exhibited sustained abstinence, with 8 of these participants reporting continuous abstinence since their initial quit date.
A follow-up study by the same group examined the long-term effects of psilocybin on smoking habits. Nine out of 15 original participants were biologically confirmed as smoking abstinent at long-term follow-up.
Bogenschutz et al. found that participants with alcohol dependence who received psilocybin-assisted therapy had decreased heavy drinking days and total drinking days at all follow-up points, except for heavy drinking days during weeks 9 – 12 (p =0.059).
Ketamine
Ketamine was introduced into clinical practice in the 1960s as an anesthetic capable of preserving cardiorespiratory support mechanisms. It has since been repurposed as a potent antidepressant capable of reducing the risk of suicide.
Ketamine acts as an antagonist at the NMDA receptor in the brain, and inhibits L-type voltage-dependent calcium channels, monoamine transport, and opioid receptor potentiation.
Ketamine’s potent psychoactive and antidepressant effects led researchers to investigate its potential in treating addiction. A controlled clinical trial demonstrated superior efficacy of supplementing the standard alcoholism treatment with ketamine therapy, and the authors postulated that it is the psychological rather than biochemical effects of the drug that facilitate recovery.
A study looked at the use of ketamine in patients with cocaine use disorder, and found that those who received ketamine were less likely to relapse and had lower craving scores throughout the trial.
KPT has been studied in the treatment of heroin addiction. A double-blind randomized controlled trial found that addicts who received ketamine therapy had higher rates of abstinence and a longer lasting reduction in craving than addicts who received a non-hallucinogenic dose of ketamine.
Ibogaine
Ibogaine is an indole alkaloid derived from the roots of a West African plant known as Tabernanthe iboga that has been used by native populations for centuries due to its unique properties. It is also used in ceremonies celebrating the transition from adolescence to manhood as a rite of passage.
Malcolm et al. enrolled 50 participants with opioid dependence in a week-long ibogaine-assisted opioid detoxification program. The participants were converted to short-acting opioids four weeks prior to treatment and maintenance therapy with either methadone or buprenorphine was discontinued. The authors reported significant decreases in opioid withdrawal symptoms based on the COWS and SOWS. These results were confirmed by one of the largest open-label studies to date.
A study treated 30 patients with diagnosed opioid dependence with ibogaine and found that the short-term benefits of ibogaine treatment would be sustained over time. At 1 month, 50% of patients were opioid free and at 3 months, 33% were opioid free.
Ayahuasca
Ayahuasca is a natural plant derivative that has been used by native communities for centuries. It is made from the Banisteriopsis caapi vine and the Psychotria viridis shrub and contains DMT, a serotonin-like compound with agonist activity at multiple 5-HT1 and 5-HT2 receptor subtypes.
Ayahuasca has been studied in the treatment of addiction, but the data is much sparser compared to the other chemicals discussed in this review. One observational study found statistically significant improvements in many behavioral well-being measures, but no reduction in self-reported alcohol, tobacco, or cocaine use.
Another group reported two experiments looking at the Addiction Severity Index (ASI) over 1 year in ayahuasca users. They found that ayahuasca users scored significantly lower on ASI alcohol use and psychiatric status subscales than rural controls.
A retrospective analysis of 41 adolescents who consumed ayahuasca in Brazil compared to 43 adolescents who never consumed the substance found no significant differences in lifetime consumption of drugs between the two groups.
Discussion
Addictions are notoriously difficult to treat due to the complex interplay between neurobiology and psychology. Pharmacology alone cannot treat addiction, but therapy can help.
The US government’s hypothesis that hallucinogens can be used for mind control was not far off, because they allow people to access insights and replace ingrained habits, patterns, behaviors, and beliefs with healthier ones.
Pharmacologically, LSD and psilocybin share strong agonist activity at the 5-HT2A receptor, and ayahuasca and ketamine have antagonistic properties at the NMDA receptor. Ibogaine has complex pharmacodynamics that have been shown to directly interfere with the physiological effects of heroin addiction.
Though the data assessing the utility of hallucinogens in addiction is promising, more systematic, double-blind, randomized controlled trials with large number of subjects are needed in order for this to be adopted safely in clinical practice.
The preliminary data supports the necessity for further investigation into the use of hallucinogens in the treatment of addiction, and future studies investigating repeated use at scheduled intervals over the long term are needed to show greater efficacy and/or sustainability.