This review (2021; s=9) of ayahuasca for substance use disorders (SUDs; e.g. alcoholism) found improvements in both rodents and humans who were suffering from SUDs (also on scores of anxiety and depression). The human studies were observational (vs RCTs) thus lacking the power to (confidently) infer causality.
Abstract
“Ayahuasca is a hallucinogenic/psychedelic traditionally used for ritual and therapeutic purposes. One such therapeutic use is related to Substance Use Disorders (SUDs). A previous systematic review of preclinical and human studies published until 2016 suggested that ayahuasca and its alkaloids have therapeutic effects in the treatment of SUDs. To conduct an update of this previous review. A systematic review of quantitative studies which analyzed the effects of ayahuasca and its alkaloids on drug use (primary outcome) and other measures (secondary outcomes) related to SUDs was conducted, including articles from 2016 to 2020. Nine studies (four preclinical, five observational) were included in the review. Preclinical studies in rodents reported reductions in amphetamine self-administration and anxiety, and in alcohol- and methylphenidate-induced conditioned place preference. Observational studies among healthy ritual ayahuasca users and patients with SUDs reported reductions in drug use, anxiety, and depression, and increases in quality of life and well-being. We replicated the findings of the previous review suggesting that ayahuasca and its alkaloids have therapeutic effects in the treatment of SUDs. However, translation of preclinical data to humans is limited, observational studies do not allow us to infer causality, and there is a lack of standardization on ayahuasca doses. Although promising, randomized, controlled trials are needed to better elucidate these results.”
Authors: Lucas S. Rodrigues, Giordano N. Rossi, Juliana M. Rocha, Flávia L. Osório, José C. Bouso, Jaime E. C. Hallak & Rafael G. Dos Santos
Notes
This review is a follow-up/update of Nunes et al (2016).
Summary
Ayahuasca is a hallucinogenic/psychedelic traditionally used for ritual and therapeutic purposes. Preclinical studies in rodents showed that ayahuasca and its alkaloids have therapeutic effects in the treatment of Substance Use Disorders, but randomized, controlled trials are needed to better elucidate these results.
Introduction
Substance use disorders are among the most prevalent psychiatric disorders, being associated with individual and public health-related problems. They are often associated with physical and/or other mental health disorders.
SUDs can be caused by the use of alcohol, tobacco, prescription drugs, stimulants, opioids, and cannabinoids, with varying degrees of negative consequences depending on the drug, social and demographic characteristics of the user, and availability.
Current treatments for SUDs include psychotherapy, psychiatric medications, nicotine replacement therapy, methadone and buprenorphine, naltrexone, acamprosate, and disulfiram, and there are no specific drugs to treat cannabis- and cocaine-related disorders.
Classic hallucinogens such as ayahuasca, DMT, psilocybin, and LSD produce alterations in perceptions, mood, and cognition through agonism at cortical serotonin 5-HT2A receptors.
In the 1960s and 1970s, studies with LSD for the treatment of alcoholism showed promising results. Psilocybin treatment was associated with smoking abstinence and a significant reduction in drinking days in two open-label studies. Online surveys among hallucinogens/psychedelics users of the general population also reported reductions in drug use in general and in tobacco use specifically.
Psilocybin has been shown to reduce symptoms of depression and anxiety in patients with cancer and depression, and could also treat these symptoms in SUDs.
Ayahuasca is a hallucinogenic/psychedelic botanical drink prepared by the decoction of Banisteriopsis caapi and Psychotria viridis, which contains the psychedelic tryptamine DMT. It is used for ritual and therapeutic purposes by indigenous tribes in South America.
Ayahuasca use is associated with increased social bonds and enduring participation in communitarian activities, which may be key factors in the therapeutic potential of ayahuasca.
A systematic review analyzed 10 studies on the effects of ayahuasca and its alkaloids on drug use and other measures related to SUDs. The effects were consistent with increased dopamine efflux produced by harmine in the rat nucleus accumbens shell.
Regarding the observational studies previously described, ayahuasca use was associated with reduced lifetime drug use, less last-year and last-month alcohol use, and increased quality of life, spirituality, well-being, and neuropsychological improvements.
Ayahuasca and its alkaloids were associated with reduced drug use in animal models and observational studies, and improved psychological and cognitive measures in people with SUDs.
Selection criteria and study selection
The review included randomized and open-label clinical studies, observational studies, quantitative studies, and preclinical studies using ayahuasca or any of its alkaloids in the treatment of SUDs.
Recorded variables, data extraction, and analysis
Preclinical studies were reviewed for ayahuasca use in humans and animals. Data were extracted on the type of animal used, sample characteristics, substances used, and administration routes.
Evaluation of selected studies
To assess the quality of preclinical studies, the Systematic Review Center for Laboratory animal Experimentation (SYRCLES) guidelines and checklist were used, and the National Institutes of Health (NIH) study quality assessment tools were used to assess the quality of human studies.
Identification of studies
A bibliographic search was performed in four databases, and 9 studies were included in the systematic review. Five were human observational studies and four were preclinical studies.
Human studies
A study was conducted to evaluate the psychological, neuropsychological functions, and substance use of 30 adult UDV members in the United States compared to 27 non-ayahuasca adults from the same region. Researchers used the Medical Outcome Study Short Form (SF-36), the Big Five Inventory (BFI), Barratt Impulsiveness Scale (BIS-11), Profile of Mood States (POMS), and the Addiction Severity Index (ASI) to analyze the consumption of substances and psychological functions. They found that volunteers in the UDV group showed lower depression and confusion.
In a sample of 96,901 volunteers over 16 years old from different countries, ayahuasca users presented higher well-being compared to classic psychedelics users and non-users, and scored lower on the AUDIT for problematic alcohol consumption when compared to classic psychedelics users and non-users.
A cross-sectional observational study was conducted to assess the impact of ayahuasca use on alcohol and tobacco consumption among UDV Brazilian members. The results showed that the UDV group had a lower prevalence of disorders related to alcohol and tobacco consumption.
Berlowitz et al. [50] conducted a study with a prospective observational cohort design on 36 males recently admitted to the Takiwasi therapeutic center in Peru for a 3-12 month treatment for SUDs. Researchers used the Mini International Neuropsychiatric Interview (MINI), the Hospital Anxiety and Depression Scale (HADS), the Addiction Severity Index (ASI-5) and the Craving Experience Questionnaire (CEQ) to assess the severity of dependence symptoms in volunteers. There was a significant decrease in dependence severity, emotional distress and substance craving.
A study was conducted by Giovannetti et al. with a prospective observational cohort design that assessed the effectiveness of ayahuasca on symptoms of depression and anxiety related to SUDs. The study found that volunteers with opioid dependence showed a greater decrease in the scores of the Beck Depression Inventory and Beck Anxiety Inventory.
The quality of the included human studies was medium to high, with the most common biases being related to the size and power of the sample, blinding of the researchers during the analysis of results, and data collection at only one point.
Preclinical studies
Ayahuasca (2 mL/kg) was used to treat rats that self-injected amphetamine for 13 days. The animals were evaluated for locomotion and anxiety behaviors. Rats that received amphetamine consumed more water, showed more locomotor activity, and spent more time in the closed arms of the elevated plus-maze than rats that received ayahuasca only.
Cata-Preta et al. tested the effects of ayahuasca, B. caapi extract and P. viridis extract on mice in a Conditioned Place Preference (CPP) paradigm promoted by alcohol. The results showed that ayahuasca induced CPP, while EBc and EPv blocked the development of CPP.
In another preclinical study in rats, the researchers administered naltrexone, alcohol, and ayahuasca intraperitoneally and administered ayahuasca by gavage to assess voluntary alcohol consumption and the expression of cFos protein expression in brain areas related to substance consumption. The cFos expression analysis showed that alcohol increased the expression of cFos in the medial orbital cortex (MO), lateral orbital cortex (LO), ventral orbital cortex (VO), nucleus accumbens (NAc), and caudal putamen (CPu) of the animals exposed to alcohol, naltrexone, and ayahuasca.
Ayahuasca and methylphenidate both increased the expression of Fos protein in the limbic regions associated with the behavioral effects of drugs of abuse, but methylphenidate increased the expression of Fos protein in the cingulate cortex area-1 (Cg1), prelimbic cortex (PrL), and frontal orbital cortex-orbito lateral area (OFC-LO) more than ayahuasca. Ayahuasca treatment reduced the CPP behavior in the Cg1, PrL, and OFC-LO regions of the brain when compared with the non-treated group, and prevented an increase of Fos levels in the NAc shell and core.
The included preclinical studies had an average score of 39%, considered low to moderate quality. The most prevalent biases were absent randomization, lack of data collection randomization, and researchers’ blinding.
Discussion
All preclinical studies reported mostly positive results, with ayahuasca reducing amphetamine self-administration and anxiety, and inhibiting alcohol- and methylphenidate-induced modifications of cFos/Fos protein expression. Observational studies reported mixed results, with greater lifetime substance use and mental health disorders in ayahuasca users compared to controls.
In our previous systematic review by Nunes et al. [32], we found that isolated -carbolines were effective in reducing self-administration of cocaine and morphine, opioid withdrawal, alcohol-induced behavior, and C-shape responses to psychostimulants in planarians.
Two observational studies showed that UDV members consumed alcohol and tobacco throughout their lives at a higher rate than controls, but had lower consumption in the last 30 days and 12 months. An open-label study with 10 volunteers carried out with psilocybin showed remission in heavy and daily alcohol consumption after the administration of the drug during an eight-month follow-up. However, the study has its limitations and needs to be observed with caution.
Lawn et al. reported that ayahuasca users showed less problematic alcohol consumption in the previous year compared to other serotoninergic psychedelics users, and greater alcohol intake when compared to the group of volunteers who did not consume any psychedelics.
Despite the promising data observed by these researchers, it is important to note that these studies are observational, retrospective, and that the samples were self-selected. Moreover, it is important to notice that the lifetime substance use of the volunteers from some studies was greater than that of controls.
Two studies in the present review described patients with SUDs who were treated at the Takiwasi center in Peru, where ayahuasca and other Amazonian plants and healing methods were used in a prolonged treatment program. The results showed a significant reduction of drug use by these patients.
UDV members scored higher on the agreeableness and openness traits of the BFI, but the role of ayahuasca in the modulation of personality traits is still poorly investigated.
Two rodent models showed that ayahuasca reduced the preference of the animals to areas associated with alcohol and methylphenidate consumption. These results suggest that ayahuasca and its alkaloids could have beneficial effects in alcohol- and psychostimulant-related disorders.
Ayahuasca and harmine decreased the reinforcement effects caused by morphine, cocaine, methamphetamine, mephedrone, and nicotine in rats and planarians.
Ayahuasca blocks the modifications of cFos/Fos protein expression produced by alcohol and psychostimulants, and reduces amphetamine self-administration, anxiety and locomotor activity in animals. Moreover, ayahuasca increases cFos expression in brain regions related to SUDs in animals, but reduces cFos expression in animals exposed to alcohol and treated with ayahuasca.
SUDs are complex and multifactorial disorders that need a treatment model that targets the individual at a bio-psychological level, as well as his/her social network, attitudes/behaviors, and family. Ayahuasca may help with these disorders through increased neuroplasticity and agonism at cortical 5-HT2A expressed in brain areas related to emotional processing, introspection, and social cognition.
LSD reduced alcohol consumption and preference in rats, but failed to have a long-lasting effect on alcohol relapse. However, other 5-HT2A agonists have also been shown to reduce drug preference and self-administration in rats.
Psychological effects of psilocybin include increased esthetic appreciation, altruism, and pro-social behavior, as well as improved emotional regulation and changed priorities/values. These effects persist 30 months after psilocybin sessions.
Observational studies suggest that ayahuasca usage is associated with a reduction in drug misuse and related problems. Social bonds and spirituality may be important mediators of the therapeutic effects of ayahuasca.
This review found nine studies on ayahuasca and its effects, but most were pre-clinical trials with low to moderate quality. The remaining five studies were observational studies with medium to high quality, but causality cannot be established.
Conclusions
Preclinical and observational studies suggest that ayahuasca may have therapeutic effects in the treatment of SUDs, including decreased consumption of substances, increased quality of life and reduction of depressive and anxiety symptoms.
Despite the promising effects reported in this systematic review, the studies have limitations, including preclinical studies, observational designs, and small sample sizes. Further randomized, placebo-controlled clinical trials are needed to replicate the data found in this systematic review.