Psychedelic drugs in the treatment of anxiety, depression and addiction, Tor-Morten Kvam et al., 2018

Psychedelic drugs in the treatment of anxiety, depression and addiction

Tor-Morten Kvam, Lowan H. Stewart & Ole A. Andreassen

Tidsskriftet, Den Norske Legeforening, November 2018


There is growing interest in the use of psychedelic drugs for the treatment of mental disorders. The drugs are considered safe when administered within a clinical framework. Older studies performed prior to 1970 had methodological shortcomings, but studies in recent years have shown promising results regarding the use of psychedelic drugs in unipolar depression, depression in life-threatening illness, anxiety and addiction. The aim of this literature review is to provide an overview of recent results and the limitations of these studies.

We searched the PubMed database for clinical studies from the period 1990–2017 with the keywords anxiety, depression, addiction and psychedelic drugs. The quality of the studies was then assessed on the basis of their methods and statistical power.

The search yielded 424 articles, of which nine were included (four on anxiety and depression in life-threatening illness, two on depression, two on addiction disorders and one on obsessive-compulsive disorder). Two double-blind, randomised, controlled phase II trials with moderate sample sizes reported immediate, marked and sustained efficacy of a single dose of psilocybin against anxiety and depression in life-threatening illness. The results of the other studies were less clear. There were no serious adverse effects or reports of addiction.

Psychedelic drugs have shown promising results in the treatment of several mental disorders, but the studies are small and have methodological shortcomings. There is a need for systematic clinical trials to obtain robust evidence of efficacy and to establish routines for the monitoring of potential adverse effects.


In the 1950s and 60s, the classic psychedelic drugs lysergic acid diethylamide (LSD) and psilocybin were tested in numerous clinical trials. The results suggested efficacy against anxiety and depression in cases of life-threatening illness, unipolar depression and addiction (1–3). An open study of LSD in cancer patients demonstrated improvement in symptoms such as pain, anxiety and depression and a greater acceptance of death in approximately 70 % of the sample (1). A review of open studies examining the efficacy of psychedelic drugs in unipolar depression showed an improvement in approximately 80 % of patients (2). A meta-analysis of randomised studies of LSD in cases of alcohol misuse demonstrated significant efficacy of LSD relative to the control group, with an odds ratio of 1.96 (3). The use of psychedelic drugs in treatment and research ended around 1970 as a result of international legislation (4). Psychedelic drugs are classified by the United Nations as substances with potential for abuse, with serious adverse effects on public health and no therapeutic potential, but this classification has been criticised (5).

Classic psychedelic drugs may be synthetic (such as LSD) or naturally occurring, such as psilocybin from psilocybin (‘magic’) mushrooms, N,N-dimethyltryptamine (DMT) from the herbal drink ayahuasca, and mescaline from the Peyote cactus. All are serotonin receptor agonists and primarily stimulate the 5-hydroxytryptamine (HT)2A receptor (4, 6). Classic psychedelic drugs give rise to altered perception, especially visual perception, changes in affect in the direction of both ecstasy and anxiety, altered time perception, audiovisual synaesthesia, derealisation and depersonalisation, as well as pseudo-hallucinations (i.e. hallucinations with preserved awareness of reality) (7). The effects of the most studied psychedelic drugs, psilocybin and LSD, last for approximately 6 and 12 hours, respectively (4). Repeated use leads to tolerance owing to 5-HT2A receptor downregulation (4).

It has been argued that classic psychedelic drugs can have dangerous adverse effects, but these claims are based on studies with questionable methodology (4). Systematic studies to date show the drugs to have low toxicity and a high therapeutic index (4). Classic psychedelic drugs pose minimal risk of addiction (4). In a ranking of 20 legal and illegal substances on the basis of harmful effects for the individual user and society, alcohol was ranked bottom, whereas psilocybin and LSD were among the least harmful (5). The latter have little impact on the dopaminergic system, which may explain the low risk for development of dependence (4). However, there are also case reports describing serious but rare and mainly transient adverse effects, such as rhabdomyolysis, lower extremity ischaemia and cortical blindness following recreational use (4). The use of psychedelic drugs of uncontrolled strength and purity, and the tendency for multiple psychoactive drugs to be used simultaneously, complicates the interpretation of such case reports (4). Further, the risk of these complications in a controlled clinical environment appears to be low. These adverse effects have not been observed in modern clinical trials of classic psychedelic drugs in selected patient populations (8–16).

Hallucinogen Persisting Perception Disorder (HPPD) is a condition that has primarily been associated with recreational use of LSD (17). The condition is characterised by recurring perceptual symptoms long after the acute effects of the drug have worn off. Its incidence is unknown, but it is considered rare. Studies of the condition have methodological weaknesses and are based largely on case reports (17), and the condition has not been observed in modern studies in the field (8–16). An American study with 130 000 participants, of whom 13.4 % reported current and/or previous use of psychedelics (LSD, psilocybin or mescaline), showed no association between usage and mental health problems (18). A larger and more recent population study found that the risk of mental disorders including suicidal thoughts was reduced among users of classic psychedelic drugs, whereas it was increased among users of other illegal substances (19).