Key messages
- In people with life-threatening diseases (e.g. cancer), we found that psychedelic-assisted therapy with “classical” psychedelics (i.e. psilocybin ('magic mushrooms'), LSD), may result in a reduction of anxiety and depression symptoms.
- We also found that existential distress (such as feeling that life has no meaning) and quality of life may be improved by classical psychedelics, but the evidence is mixed and very uncertain.
- Data regarding these outcomes is minimal for psychedelic-assisted therapy with MDMA ('Ecstasy'), and we are very uncertain about the results.
- No severe negative side effects of psychedelic-assisted therapy were reported in the studies we identified, but the evidence is very uncertain. Moderate side effects subsided after the drug effects wore off or within the following week.
What is the significance of anxiety, depression, and existential distress in people with life-threatening diseases?
Anxiety, depression and existential distress are frequently experienced by people facing a life-threatening disease and negatively impact their quality of life as well as the quality of life of their caregivers.
How are anxiety, depression, and existential distress treated?
Treatment of these symptoms is challenging, especially in end-of-life care, because well-established antidepressant or anti-anxiety medication may not work and psychotherapy may take a long time or be difficult to access.
What is psychedelic-assisted therapy?
Psychedelics are illegal in most countries, but a few places have allowed restricted access, and research into the potential use of these drugs is increasing. Psychedelic-assisted therapy involves the intake of a psychedelic drug (e.g. LSD, psilocybin ('magic mushrooms'), MDMA ('Ecstasy')) under close supervision by a therapist (physicians, psychologists, and others). Psychedelic-assisted therapy includes three treatment phases: preparation sessions take place first, then the drug dosing (intake) session, and afterwards, integration sessions are conducted to reflect on the experience.
What did we want to find out?
We wanted to find out whether psychedelic-assisted therapy was better than active-placebo-assisted therapy to improve anxiety, depression, and existential distress. We also wanted to find out whether psychedelic-assisted therapy was linked with any unwanted effects or risk of harm.
What did we do?
Our aim was to systematically collect and evaluate available evidence for psychedelic-assisted therapy to treat anxiety, depression, and existential distress. We searched for high quality clinical studies. We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods.
What did we find?
We found six studies testing psychedelic-assisted therapy using psilocybin (3 studies), LSD (2 studies), and MDMA (1 study). The studies involved 149 adults with anxiety, depression, or existential distress. The largest study tested psilocybin in 56 people and the two smallest studies tested psilocybin or LSD in 12 people. The studies took place in the USA and Switzerland. Most studies had a follow-up of 6 to 12 months. Drug companies were not involved in study funding, but funding was provided by organisations that promote psychedelic-assisted therapy.
Psychedelic-assisted therapy with classical psychedelics (psilocybin, LSD) compared to an active placebo (e.g. a very low dose of the same drug) may reduce anxiety and depression. However, our confidence in the effect estimate is limited; we may find that the true effect is substantially different when more studies are conducted. Psychedelic-assisted therapy with classical psychedelics may reduce existential distress, but the evidence is mixed and very uncertain. For psychedelic-assisted therapy with MDMA, the data on anxiety or depression is inconclusive, and existential distress was not investigated.
Psychedelic-assisted therapy with classical psychedelics (psilocybin, LSD) compared to an active placebo may improve quality of life and induce spiritually significant experiences, but the evidence is very uncertain. For MDMA-assisted therapy, quality of life did not improve, but the evidence is very uncertain. Spirituality outcomes were not assessed for MDMA.
Psychedelic-assisted therapy seems to be well tolerated, but evidence about side effects is very uncertain. The studies reported no serious side effects. The classical psychedelic studies reported mild to moderate side effects such as nausea, anxiety, dry mouth, psychotic-like symptoms (e.g. pseudo-hallucination, where people know that they are hallucinating), and high blood pressure, which subsided when the drug effects wore off or the following day. The MDMA study reported anxiety, dry mouth, jaw clenching, and headaches, which subsided when the drug effects wore off or within the following week.
What are the limitations of the evidence?
There were several limitations to the evidence. Importantly, participants were often aware of the treatment they were receiving, which may influence their results. In addition, the studies were small. It is important to note that future studies might change the conclusions of this review. As the US Drug Enforcement Administration (DEA) currently classifies psychedelics as Schedule I substances (i.e. having no accepted medical use and a high potential for abuse), research involving these drugs is restricted, but is steadily increasing.
How up to date is this evidence?
This review is based on a search for evidence up to March 2024.
Implications for practice
Psychedelic-assisted therapy with classical psychedelics (psilocybin, LSD) may be effective for treating anxiety, depression, and possibly existential distress, in people facing a life-threatening disease. Psychedelic-assisted therapy seemed to be well tolerated, with no treatment-emergent serious adverse events reported in the studies included in this review. However, the certainty of evidence is low to very low, which means that we cannot be sure about these results, and they might be changed by future research. At the time of this review (2024), psychedelic drugs are illegal in many countries.
Implications for research
The risk of bias due to 'unblinding' (participants being aware of which intervention they are receiving) could be reduced by measuring expectation bias, checking blinding has been maintained before cross-over, and using active placebos. More studies with larger sample sizes are needed to reduce imprecision. As the US Drug Enforcement Administration (DEA) currently classifies psychedelics as Schedule I substances (i.e. having no accepted medical use and a high potential for abuse), research involving these drugs is restricted, but is steadily increasing.
Psychedelic-assisted therapy refers to a group of therapeutic practices involving psychedelics taken under therapeutic supervision from physicians, psychologists, and others. It has been hypothesised that psychedelic-assisted therapy may reduce symptoms of anxiety, depression, and existential distress in patients facing life-threatening diseases (e.g. cancer). However, these substances are illegal in most countries and have been associated with potential risks.
To assess the benefits and harms of psychedelic-assisted therapy compared to placebo or active comparators (e.g. antidepressants) for treatment of anxiety, depression, and existential distress in people with life-threatening diseases.
We searched CENTRAL, MEDLINE, Embase, and two trial registers on 30 March 2024. In addition, we undertook reference checking, citation searching, and contact with study authors to identify additional studies. We used no language or date restrictions.
We included randomised controlled trials (RCTs), with no restrictions regarding comorbidity, sex, or ethnicity. Interventions comprised a substance-induced psychedelic experience preceded by preparatory therapeutic sessions and followed by integrative therapeutic sessions.
We used the standard methodological procedures expected by Cochrane.
We included six studies in the review, which evaluated two different interventions: psychedelic-assisted therapy with classical psychedelics (psilocybin ('magic mushrooms') and lysergic acid diethylamide (LSD)), and psychedelic-assisted therapy with 3,4-methylenedioxymethamphetamine (MDMA or 'Ecstasy'). The studies randomised 149 participants with life-threatening diseases and analysed data for 140 of them. The age range of participants was 36 to 64 years. The studies lasted between 6 and 12 months, and were conducted in outpatient settings in the USA and in Switzerland. Drug companies were not involved in study funding, but funding was provided by organisations that promote psychedelic-assisted therapy.
Primary outcomes (at 1 to 12 weeks)
Anxiety
Psychedelic-assisted therapy using classical psychedelics (psilocybin, LSD) may result in a reduction in anxiety when compared to active placebo (or low-dose psychedelic): State Trait Anxiety Inventory (STAI-Trait, scale 20 to 80) mean difference (MD) −8.41, 95% CI −12.92 to −3.89; STAI-State (scale 20 to 80) MD −9.04, 95% CI −13.87 to −4.21; 5 studies, 122 participants; low-certainty evidence. The effect of psychedelic-assisted therapy using MDMA on anxiety, compared to placebo, is very uncertain: STAI-T MD −14.70, 95% CI −29.45 to 0.05; STAI-S MD −16.10, 95% CI −33.03 to 0.83; 1 study, 18 participants; very low certainty evidence.
Depression
Psychedelic-assisted therapy using classical psychedelics (psilocybin, LSD) may result in a reduction in depression when compared to active placebo (or low-dose psychedelic): Beck Depression Inventory (BDI, scale 0 to 63) MD −4.92, 95% CI −8.97 to −0.87; 4 studies, 112 participants; standardised mean difference (SMD) −0.43, 95% CI −0.79 to −0.06; 5 studies, 122 participants; low-certainty evidence. The effect of psychedelic-assisted therapy using MDMA on depression, compared to placebo, is very uncertain: BDI-II (scale: 0 to 63) MD −6.30, 95% CI −16.93 to 4.33; 1 study, 18 participants; very low certainty evidence.
Existential distress
Psychedelic-assisted therapy using classical psychedelics (psilocybin, LSD) compared to active placebo (or low-dose psychedelic) may result in a reduction in demoralisation, one of the most common measures of existential distress, but the evidence is very uncertain (Demoralisation Scale, 1 study, 28 participants): post treatment scores, placebo group 39.6 (SEM 3.4), psilocybin group 18.8 (3.6), P ≤ 0.01). Evidence from other measures of existential distress was mixed. Existential distress was not measured in people receiving psychedelic-assisted therapy with MDMA.
Secondary outcomes (at 1 to 12 weeks)
Quality of life
When classical psychedelics were used, one study had inconclusive results and two reported improved quality of life, but the evidence is very uncertain. MDMA did not improve quality of life measures, but the evidence is also very uncertain.
Spirituality
Participants receiving psychedelic-assisted therapy with classical psychedelics rated their experience as being spiritually significant (2 studies), but the evidence is very uncertain. Spirituality was not assessed in participants receiving MDMA.
Adverse events
No treatment-related serious adverse events or adverse events grade 3/4 were reported. Common minor to moderate adverse events for classical psychedelics were elevated blood pressure, nausea, anxiety, emotional distress, and psychotic-like symptoms (e.g. pseudo-hallucination where the participant is aware they are hallucinating); for MDMA, common minor to moderate adverse events were anxiety, dry mouth, jaw clenching, and headaches. Symptoms subsided when drug effects wore off or up to one week later.
Certainty of the evidence
Although all six studies had intended to blind participants, personnel, and assessors, blinding could not be achieved as this is very difficult in studies investigating psychedelics. Using GRADE criteria, we judged the certainty of evidence to be low to very low, mainly due to high risk of bias and imprecision (small sample size).