This expert review (2018) of systematic reviews concludes that the research into psychedelics is promising but needs bigger samples and longer duration studies.
Abstract
“Introduction: Mood, anxiety, and substance-use disorders are among the most prevalent psychiatric disorders in the population. Although several pharmacological treatments are available, they are not effective for a significant proportion of patients and are associated with several adverse reactions. Therefore, new treatments should be explored. Recent studies suggest that serotonergic hallucinogens/psychedelics including ayahuasca, psilocybin, and lysergic acid diethylamide (LSD) have anxiolytic, antidepressive, and antiaddictive effects. Areas Covered: A systematic review of systematic reviews assessing the efficacy, safety, and tolerability of serotonergic hallucinogens/psychedelic was performed using the PubMed data base until 11 April 2018. Systematic reviews with or without meta-analysis were analyzed, but only reviews that described at least one randomized controlled trial (RCT) were included. Expert Commentary: Psilocybin and LSD reduced anxiety and depression in cancer patients and symptoms of alcohol and tobacco dependence, and ayahuasca reduced depression symptoms in treatment-resistant depression. Although the results are promising, several studies were open-label, and only few were RCTs, and most had small sample sizes and short duration. Single or few doses of these drugs seem to be well-tolerated, but long-term studies are lacking. New RCTs with bigger samples and longer duration are needed to replicate these findings.”
Authors: Rafael G. dos Santos, José Carlos Bouso, Miguel Ángel Alcázar-Córcoles & Jaime E. C. Hallak
Notes
This paper is included in our ‘Top 10 Articles on Psychedelics in the Treatment of Depression‘
Summary
Efficacy, tolerability, and safety of serotonergic psychedelics for the management of mood, anxiety, and substance-use disorders: a systematic review of systematic reviews
Mood, anxiety, and substance-use disorders are among the most prevalent psychiatric disorders. Recent studies suggest that serotonergic hallucinogens may have anxiolytic, antidepressive, and antiaddictive effects.
- Introduction
Mental and substance-use disorders are the fifth cause of global disability-adjusted life years, and the leading cause of Years Lived with Disability worldwide. However, traditional medications are not effective for a significant proportion of patients. Researchers argue that psychedelics, or serotoninergic hallucinogens, could be new psychopharmacological therapies for psychiatric and mental health disorders, and that they might have a beneficial effect on memory and cognitive deficits, which could open new avenues for the treatment of neurodegenerative diseases.
Psychedelics are serotoninergic hallucinogens that interact with 5-HT2A receptors to increase glutamate release, increasing electrical activity at the cortex and thus increasing information processing. This increases neuroplasticity by disrupting neural hierarchies and increasing bottom-up information transfer.
Psychedelics improve emotion processing, improve positive mood and emotional empathy, and induce mystical type experiences. These effects may be mediated by ‘ego dissolutive’ experiences.
Psychedelics have been shown to modulate psychological and affective states in experimental research, and preliminary results from clinical trials are consistent with these findings.
2.1. Search strategy
A systematic review was performed using the PubMed database. All studies published until 11 April 2018 were included, without any language restriction.
2.2. Selection criteria and study selection
Systematic reviews of randomized controlled trials and observational studies assessing adverse reactions related to psychedelic drug use were included in this review.
After inspection for duplicates, titles and abstracts of all records were reviewed. Two independent reviewers made the final decision on inclusion or exclusion of studies.
2.3. Recorded variables, data extraction, and analysis
The systematic review included studies on mood, anxiety, or substance-use disorders, hallucinogenic/psychedelic drugs, and risk of bias found. The main findings were presented in odds ratios, heterogeneity, and statistical significance.
3.1. Study selection
The search of the literature yielded 531 separate references, 14 of which were potentially relevant. Full-text reports of these citations were obtained for more detailed evaluation, and 10 were included in the systematic review.
The studies included one meta-analysis, nine descriptive systematic reviews, and two adverse effects reviews. The studies assessed therapeutic effects, acute physiological, psychological, neurophysiological, and long-term safety effects of ayahuasca and its alkaloids.
3.2. Overview of the results
Although most of the included reviews are descriptive systematic reviews including few RCTs with small sample sizes, the results suggest that serotonergic hallucinogens/psychedelics are safe and are associated with antidepressive and anxiolytic effects, with less consistent results regarding substance-use disorders.
Observational studies suggest that recreational use of hallucinogens/psychedelics is associated with anxiety- and psychotic-like features, but these reactions are less common in experimental and clinical settings.
3.3. Therapeutic effects
Ayahuasca and its alkaloids have anxiolytic properties, and ritual ayahuasca intake is associated with remission of anxiety disorders.
Preclinical evidence suggests that ayahuasca and its alkaloids have antidepressive properties, and observational studies of ritual ayahuasca intake report remission of mood disorders.
3.4.1. Ritual context
Long-term ritual ayahuasca use is not associated with increased psychiatric symptoms or disorders, or deficits in neuropsychological functioning. The most common adverse reactions are nausea, gastrointestinal discomfort, vomiting, diarrhea, and transient dysphoric reactions with anxiety- and psychotic-like features.
3.4.2. Experimental/clinical context
Experimental and clinical studies suggest that serotonergic hallucinogens/psychedelics have a good safety and tolerability profile, with the most common adverse reactions being transient dysphoric reactions with anxiety- and psychotic-like features.
3.5. Risk of bias and methodological quality assessment
The risk of bias and methodological quality assessment of 10 systematic reviews was moderate to high, with eight reviews scoring >4. The most common reason for reduced scores was lack of quality assessment.
One of the reviews was available only as an unedited manuscript, and a clear declaration of conflicts of interest was not present.
- Discussion
In the present systematic review, we analyzed 10 systematic reviews on the efficacy, safety, and tolerability of classical or serotonergic hallucinogens/psychedelics in the treatment of anxiety, mood, and substance-use disorders. The studies included were observational studies or open-label studies with few volunteers.
Although a meta-analysis showed promising results for the antiaddictive effects of LSD in patients with alcohol dependence and the anxiolytic and antidepressive effects of psilocybin in patients with advanced-stage cancer and nonmalignant life-threatening diseases, more RCTs are needed to replicate these findings.
Psilocybin can be an effective treatment for patients with existential anxiety and depression. It has been shown to induce rapid and sustained antidepressive and anxiolytic effects in 12 patients with unipolar treatment-resistant depression.
Future studies should investigate the role of different psychotherapeutic techniques and music in the therapeutic effects of serotonergic hallucinogens/psychedelics, especially in the case of ayahuasca, since no psychotherapeutic intervention was used in an open-label study with 17 patients with treatment-resistant MDD.
The lowest level of evidence of efficacy was found for the antiaddictive properties of ayahuasca and psilocybin, where observational (ayahuasca) and open-label studies were described. However, new RCTs are being planned or are already being conducted.
Observational studies of ritual ayahuasca use and experimental studies with psilocybin and LSD with healthy volunteers showed positive and significant changes in personality measures. These results may be replicated in RCTs.
Three descriptive systematic reviews showed observational, experimental, or clinical evidence of good safety and tolerability when used in controlled settings (ritual, experimental, or clinical). However, several reports described subjects with a personal and possibly a family history of psychotic disorders. We are not aware of any controlled study of ayahuasca with healthy volunteers or patients in which a prolonged psychotic reaction happened. However, patients with these characteristics are common in psychiatric clinics.
Most studies reported good safety and tolerability of LSD and psilocybin, with transient anxiety- and psychotic-like reactions, moderate increases in blood pressure, headaches, nausea, or vomiting.
- Conclusion
Classic or serotonergic hallucinogens such as ayahuasca/DMT, psilocybin, and LSD showed anxiolytic, antidepressive, and antiaddictive potentials in experimental, open-label, and (less frequently) in RCTs. However, the clinical evidence for using these compounds is still far from being conclusive.
Serotonergic hallucinogens/psychedelics showed a good safety and tolerability profile in controlled settings, with few transient and moderate adverse reactions. However, prolonged psychotic symptoms may occur, and this must be taken into consideration when using these compounds.
Long-term ritual ayahuasca use was not associated with increased psychopathology or cognitive deficits. However, rare cases of prolonged psychotic episodes were observed, even in the recreational context.
Serotonergic hallucinogens/psychedelics, especially ayahuasca for MDD and psilocybin and LSD for existential anxiety and depression, seem to be promising treatments, but more studies are needed.
- Expert commentary
Anxiety, mood, and substance-use disorders are prevalent psychiatric disorders, but many patients do not respond to traditional drugs. New pharmacological treatments with better efficacy and less adverse reactions are needed.
Traditional anxiolytic, antidepressive, and antiaddictive drugs are mostly based on agonist/antagonist actions on monoaminergic neurotransmission, but their efficacy is still limited, and their adverse reactions are still significant.
Serotonergic hallucinogens/psychedelics such as DMT, ayahuasca, LSD, and psilocybin stimulate cortical 5-HT2A serotonergic receptors, stimulating neuroplasticity and reducing anxiety and rumination. When used in controlled settings, these drugs have a good safety and tolerability profile.
Phase II/III RCTs on serotonergic hallucinogens/psychedelics will need to be performed in the following years to take these drugs into mainstream psychiatry as new treatments.
Natural substances with significant ethnobotanical and religious/ritual importance must be respected, such as ayahuasca, which has been used therapeutically by Northwestern Amazonian indigenous groups for centuries.
Future studies should explore the effects of these drugs on other disorders, such as creative enhancement and religious or meditative practices.
- Five-year view
In the next 5 years, new clinical trials will be performed with serotonergic hallucinogens/psychedelics, especially with psilocybin, LSD, and ayahuasca. Psilocybin may be the first of these compounds to be regulated for clinical use.
Serotonergic hallucinogens/psychedelics like ayahuasca, psilocybin, and LSD have anxiolytic, antidepressive, and antiaddictive effects. They can be safely administered in controlled settings.
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https://doi.org/10.1080/17512433.2018.1511424
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