Despite many different kinds of substances available for depression treatment, depression itself still appears to be a clinical challenge. Recently, formerly illicit substances came to scientists’ attention, including lysergic acid diethylamide (LSD), psilocybin and dimethyltryptamine (DMT). Some studies suggest that these substances might be effective in depression treatment.
Recently, ketamine has emerged as a new therapeutic option for drug-resistant depression, which until recently was associated by psychiatrists primarily as an anesthetic or as a component of the patient’s polytoxicomania. At the same time, research is being conducted into the use of another substance that is illegal in most countries, 3,4-methylenedioxymethamphetamine (MDMA), popularly known as ecstasy, in the treatment of drug-resistant post-traumatic stress disorder (PTSD). Research is well advanced, and it is possible that MDMA will be approved as a drug by the FDA by 2022 . For these reasons, scientists worldwide are exploring other, previously known as illicit, drug substances. According to the Global Drug Survey 2020 report by an independent UK scientific organization that studies the impact of psychoactive substance use on mental health, 8 of the 20 most commonly used psychoactive substances in 2020 are in the psychedelics and dissociatives group: in the past 12 months, 21.0% of respondents have used LSD, psilocybin mushrooms were used by 16.1% of respondents and DMT by 4.8% of respondents. These data come from over 110,000 individuals from over 25 countries, mostly in Europe . By comparison, the 2019 Global Drug Survey reports that in the past 12 months, 17.5% of respondents have used LSD, 14.8% of respondents have used psilocybin mushrooms, and 4.2% of respondents have used DMT . Equally popular is the interest in treating depression with psychedelics. On 23 June 2021, the Google search engine returned 2,310,000 results for the query “psychedelic treatment for depression”, and the topic is covered by well-known media outlets such as the BBC and Daily Mail . Due to the increasing popularity of psychedelics in society, it is important to conduct further multidirectional research on them, including not only their use in therapy but also broadly understood public health issues, which is why the authors decided to conduct a systematic review of these substances in depression treatment.
We did not find any studies on LSD use in depression treatment even though the three substances share very similar mechanisms of action, which justifies conducting such studies.
Six studies were included in the analysis. The total number of participants included in the psilocybin studies ranged from 12 to 51, both male and female. Subjects were adults. In three studies the sample was composed of subjects with major depressive disorder , and in the other three studies the sample was composed of subjects with depression and anxiety in the course of life-threatening cancer . Three out of six of the psilocybin studies were rated strong. Psilocybin is the best documented substance in depression treatment from the three substances, which makes psilocybin in a medical setting a very promising treatment option for patients with depression.
Only one out of four DMT studies was rated high. Three out of four of the DMT studies included were non-RCT studies, which do not allow to draw final conclusions on efficiency in depression treatment. No clinical studies of DMT use alone in depression treatment were found, as all of the included studies dosed ayahuasca, and it should be remembered that ayahuasca is administered with monoamine oxidase inhibitors, which may have an effect on mood themselves. It should also be remembered that ayahuasca contains other alkaloids, such as harmine or harmaline, and since it is a decoction of the plants themselves, it is difficult to estimate the dose of alkaloids consumed .
The use of psychedelic substances is not without risks. The pharmacology and mechanism of action of each substance is fairly well understood, and while LSD, psilocybin and DMT have relatively low health and life risks somatically, the risk of psychiatric complications must be considered. In addition to psychosis, another clinically significant complication that can occur after even a single ingestion of a psychedelic substance is Hallucinogen Persisting Perception Disorder or HPPD for short, classified as F16 in ICD-10 and 292.89 in DSM-V. This disorder manifests as chronic perceptual changes that can interfere with daily functioning and reduce quality of life and satisfaction. Duration is an individual matter, usually transient symptoms lasting from a few minutes to several months, although in extreme cases symptoms can last throughout life . There are two types of HPPD: type 1, in which there is a brief recurrence of psychedelic effects in the form of a “flashback”, occurs in 1:20 people, and type 2, which occurs less frequently, in 1:50,000 and in which symptoms are chronic. Since the etiology and scientifically proven treatments remain unknown, HPPD should be considered a significant risk for patients undergoing treatment with psychedelics .