This systematic review (2020) looked at 10 modern studies (n=188) on psychedelics (psilocybin, ayahuasca, LSD) for the treatment of a variety of mental health disorders. The review found the studies to provide evidence for efficacy (up to months later) and safety.
Abstract
“Objective: To conduct a systematic review of modern-era (post-millennium) clinical studies assessing the therapeutic effects of serotonergic psychedelics drugs for mental health conditions. Although the main focus was on efficacy and safety, study characteristics, duration of antidepressants effects across studies, and the role of the subjective drug experiences were also reviewed and presented.
Method: A systematic literature search (1st Jan 2000 to 1st May 2020) was conducted in Pubmed and Psychinfo for studies of patients undergoing treatment with a serotonergic psychedelic.
Results: Data from 16 papers, representing 10 independent psychedelic-assisted therapy trials (psilocybin=7, ayahuasca = 2, LSD=1) were extracted, presented in figures and tables, and narratively synthesized and discussed. Across these studies, a total of 188 patients suffering either anxiety and/or depressive symptoms associated with cancer (C-RPD), major depressive disorder (MDD), obsessive compulsive disorder (OCD) or substance use disorder (SUD) were included. The reviewed studies established feasibility and evidence of safety, alongside promising early data of efficacy in the treatment of depression, anxiety, OCD, and tobacco and alcohol use disorders. For a majority of patients, the therapeutic effects appeared to be long-lasting (weeks-months) after only 1 to 3 treatment session(s). All studies were conducted in line with guidelines for the safe conduct of psychedelic therapy and no severe adverse events were reported.
Conclusion: The resurrection of clinical psychedelic research provides early evidence for treatment efficacy and safety for a range of psychiatric conditions, and constitutes an exciting new treatment avenue in a health area with major unmet needs.”
Authors: Kristoffer A. A. Andersen, Robin L. Carhart-Harris, David J. Nutt & David Erritzoe
Summary
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A systematic review of modern-era psychedelic therapy trials was conducted. The authors found that psychedelics have therapeutic effects on the serotonergic system.
A systematic review of 16 studies on 188 patients undergoing treatment with a serotonergic psychedelic was conducted. The studies established feasibility and evidence of safety, alongside promising early data of efficacy in the treatment of depression, anxiety, OCD, and tobacco and alcohol use disorders. Early evidence suggests that psychedelic compounds may have therapeutic effects for a range of psychiatric conditions, including mood disorders and addictions.
This article is protected by copyright. All rights reserved for psychedelic therapy is to be considered preliminary at this stage.
Psychedelic compounds were first tested in the late 1940s – early 1950s for their acute effects on schizophrenia symptoms, but were later used for their therapeutic potential in patients suffering from chronic alcoholism, obsessive neurosis, chronic pain, opioid dependence, and anxiety associated with cancer.
Most studies of psychedelic therapy for unipolar mood disorders carried out between 1949 and 1973 showed clinician-judged improvement on depressive symptoms, but most did not live up to today’s standards in psychological and pharmacological research. Popular and countercultural movements increasingly embraced psychedelics during this period, but legislations put an end to this period of early psychedelic research. It has also been suggested that novel conventions about how to conduct state of the art randomized clinical trials might have played a role in the field’s downfall. In the last couple of decades, scientists have renewed their interest in serotonergic psychedelic compounds. They have applied modern brain imaging techniques to study these drugs in the lab, and have found that past use is associated with reduced psychological distress and suicidality.
Psychedelic use has been associated with improvements in mental health outcomes, including minor psychiatric distress, reduced personality measures of harm avoidance and reward dependence, and increased openness to experience. However, serious adverse events have been documented in some ceremonial users of ayahuasca. Researchers have re-targeted intervention with psychedelics towards clinical populations, mainly for treatment of depression, anxiety and addiction. This systematic review will provide an overview of the new wave of clinical studies on the therapeutic effects of serotonergic hallucinogenic drugs in treatment of psychiatric disorders.
A systematic review was conducted using PubMed and PsychINFO databases to identify clinical research trials published between 2000 and 2020 that used psilocybin, DMT, LSD, Mescaline, or Ayahuasca as treatment for schizophrenia.
In this systematic review, single-blind and double-blind placebo-controlled randomized trials, open label trials, and proof of concept trials in mental health patient populations were included. Additional follow-up papers providing long-term data of the clinical trials were also included.
From all non-duplicated studies, the following data was extracted: year of publication, names of authors, psychiatric exclusion criteria, participant characteristics, type of study design, type of pharmacological intervention, type of non-drug intervention, type of clinical outcome measure, and type of side-effect measure/collection method.
Study selection
The systematic search identified 671 references, 16 potential research papers were assessed according to eligibility criteria, and ten unique clinical trials with oral administration of serotonergic psychedelics were included in this systematic review. The data were synthesized narratively and grouped into three broad diagnostic categories.
Five different diagnostic groups were included in this review, including cancer related anxiety and depression disorders, illness related anxiety and depression disorders, depressive disorders, obsessive compulsive disorder, and substance use disorders. Four trials used a randomized, placebo (including active placebo) controlled, crossover design. Six trials were conducted in USA, two trials were conducted in Brazil, one in the UK and one in Switzerland on 201 patients with depression, anxiety, substance use disorder and OCD.
Non-drug psychotherapy interventions
In two trials, psilocybin and LSD were used to treat RADD, but the psychotherapeutic interventions varied in quantity and type.
In the smoking cessation trial, cognitive behavioral therapy (CBT) was delivered, and in the alcohol dependence trial, both CBT and motivational enhancement therapy were employed. Three trials provided structured sessions prior to and following the psychedelic experience, while three trials did not provide any sort of psychotherapy or psychosocial interventions.
Measures of anxiety, substance use and biological markers of nicotine dependence were collected using Spielberger’s State-trait Anxiety Index, Hospital Anxiety Depression Scale, Hamilton Anxiety Rating Scale and Time-Line Follow back.
Symptoms of OCD were measured using a visual analogue scale, the Yale-Brown obsessive compulsive scale, the Mystical Experience Questionnaire, the 11-Dimensional altered states of consciousness questionnaire, the 5-Dimentional altered states of consciousness questionnaire, and the State of consciousness questionnaire. Ayahuasca has been tested for the treatment of depression and anxiety in several studies. In one study, 17 patients with recurrent major depressive disorder received one oral dose of ayahuasca, and in another study, 29 patients with treatment-resistant unipolar depression received one dose of freeze-dried ayahuasca brew.
Ayahuasca was used in the treatment of patients with chronic depression. A significant difference in response rate was seen between the ayahuasca group and the placebo group at day seven. In a London-based open-label, uncontrolled study, 20 patients with moderate or severe unipolar major treatment-resistant depression received two doses of psilocybin 97. Psilocybin was administered at a moderate dose (10mg) and a high dose (25mg) and showed significant short- to mid-term reductions in Quick Inventory of Depressive Symptoms. Moreno and colleagues recruited 9 TR-OCD patients for a modified double-blind study on psilocybin’s treatment efficacy, tolerability and safety. The participants received psilocybin in escalating dosages, and one subject qualitatively reported having achieved a sustained long-term remission at 6- month follow-up. Grob and colleagues 61 recruited 12 subjects for a double blind, placebo-controlled study on psilocybin’s anxiolytic effects. The results showed that both groups experienced significant reduction in trait anxiety at 1 and 3-months, and in depression at 6-month follow-up. Peter Gasser and colleagues 69 evaluated the safety and efficacy of LSD-assisted psychotherapy in patients with anxiety related to chronic life-threatening illness. They found that patients who received the full dose condition had significant improvement in state anxiety.
Psilocybin was effective in treating depressed mood and anxiety in psychologically distressed cancer patients, including those with chronic adjustment disorder with anxiety and mixed anxiety and depression. Participants were randomly assigned to either a placebo-like low dose first (1 or 3 mg/70kg) or a high dose first (22 or 30mg/70kg) group, and received two psilocybin sessions. The high dose group experienced significantly more pronounced decreases in measures of depressed mood and anxiety than the low dose group. In a similar study, 29 cancer patients participated in a randomized, double-blind, placebo controlled trial assessing the symptom reduction of psilocybin assisted psychotherapy on anxiety and depression associated with life-threatening cancer.
After their psilocybin dose, all patients showed significant within-group reductions on anxiety and depression, and these reductions were acute (one day after), and significantly maintained at all points of assessment. The psilocybin first group also demonstrated significant within-group reductions on all clinical outcome measure assessments.
Bogenschutz and colleagues 63 administered psilocybin to 10 patients with DSM-IV-established diagnosis alcohol dependence. The change in drinking behavior from baseline to 1 to 8 weeks after the first psilocybin treatment served as the primary study outcome.
In a substance use disorder study, psilocybin treatment reduced drinking days and heavy drinking days, and improved urine cotinine and breath carbon monoxide levels. Seven out of nine participants reported continuous abstinence since first psilocybin session. In all other reviewed trials, participant’s subjective psychedelic experience was collected and analyzed. The magnitude of the mystical/peak experience during the psychedelic treatment session was found to be a significant predictor of short and mid/long term clinical benefits.
In all studies included in this review, the active drug was administered in quite similar controlled settings, with five factors being common: 1) individual treatment in an isolated environment/specific room 2) treatment personnel present at all times 3) standardized set of music 4) dimmed lights 5) non-directive psychosocial support if needed. All studies monitored blood pressure and heart rate, and reported that increases were transient and dose-dependent, and typically peaked about 2-3 hours post-dose. There were no reports of any serious cardiovascular adverse events in any of the studies.
In the psilocybin trials, most patients reported mild and transient anxiety/fear, headache, nausea or purging side-effects, while in the LSD trial, most patients reported illusions, feeling cold, and a feeling of abnormality side-effects. We systematically reviewed 10 post-millennium psychedelic-assisted therapy studies for mental health indications, and found that all were conducted in line with guidelines for the safe conduct of psychedelic therapy. No severe adverse events were reported. The larger-scale multicentre COMPASSPathways and Usona Institute studies may provide conclusive evidence for an antidepressant effect of psilocybin, with the lowest dose of 1mg being ineffective.
A modern-era study of psychedelic-assisted therapy for alcohol use disorder shows significant long-lasting reductions in drinking days following psilocybin administration, and a recent meta-analysis of clinical studies in alcohol dependence from The 1950-70s concluded significantly improved odds ratio for abstinence after single high-dose of LSD. In the reviewed study of tobacco dependence, 2-3 psilocybin doses in combination with cognitive behavioural therapy resulted in substantially higher 6 months smoking abstinence rates than typically observed with other medications or CBT alone. Psychedelic therapies show promise for a range of conditions, including depression, anxiety, addictions and binge eating/food addiction. These conditions are characterized by a narrowed, internalized mental state.
Psychedelics produce acute alterations in perception, a sense of meaningfulness, insightfulness and unity, and a more malleable, flexible and open to change state. Psychedelic therapy is a novel treatment paradigm that relies on subjective peak experiences. These experiences are significantly more predictive of positive clinical outcomes than altered visual and auditory perception, and thus emphasize the “psychedelic” rather than the “hallucinogen” effect of these substances. Microdosing psychedelic compounds in repeated small doses (typically 2-3 doses per week of 5-10% of full tripping doses) may improve mood, wellbeing, cognition and creativity, but there have been no trials of microdosing for any psychiatric disorder.
Psychedelic therapy has long-lasting therapeutic effects, whereas conventional pharmacotherapy uses repeated (daily) dosing. A comparison of ketamine versus psilocybin should be carried out in a randomised design using a psychedelic setting and post trip psychotherapy or both drugs, to see whether the context could affect the effects. Standard antidepressants do not directly affect the underlying cause of depression. In contrast, psychedelic therapy harnesses a therapeutic window opened up by the brain effects of the drugs to facilitate insight and emotional release and a subsequent healthy revision of outlook and lifestyle.
Patients who are relapsing receive a booster intervention session, and could sessions be shortened by administering shorter acting psychedelics, such as DMT or 5Meo-DMT, or by using intravenous rather than oral administration of psilocybin. Evidence suggests that 5-HT2A receptors are centrally involved in affect regulation. Elevated 5-HT2A receptor expression has been observed in depressed suicide victims, un-medicated remitted depressed patients with high traits “pessimism” and “dysfunctional attitudes”, and recreational use of psychedelics is associated with reduced cortical 5-HT2A receptor binding.
Studies have shown that 5-HT2A receptor agonism induces increased cognitive flexibility, which might be a central component of the therapeutic action of 5-HT2A receptor stimulation. Psychedelics may also cause lasting, beneficial and corrective change to the individual’s psyche. Psychedelic therapy increases functional connectivity within the default mode network (DMN) and decreases cerebral blood flow in the amygdala, and positively correlates with improvement in depression scores. ECT treatment leads to a normalization of DMN functional connectivity.
The resurrection of research into the therapeutic application of psychedelics provides promising pilot data on efficacy and safety in the treatment of a range of mental health conditions. Furthermore, brain imaging work applied to the study of these 5-HT2A agonists is delivering remarkable insights into brain function.