Therapeutic Use of LSD in Psychiatry : A Systematic Review of Randomized- Controlled Clinical Trials, Juan Jose Fuentes et al., 2020

Therapeutic Use of LSD in Psychiatry : A Systematic Review of Randomized-Controlled Clinical Trials

Juan José Fuentes, Francina Fonseca, Matilde Elices, Magí Farré and Marta Torrens

Frontiers in Psychiatry, 2020, Vol 10, Article 943.

doi : 10.3389/fpsyt.2019.00943


Lysergic acid diethylamide (LSD) was studied from the 1950s to the 1970s to evaluate behavioral and personality changes, as well as remission of psychiatric symptoms in various disorders. LSD was used in the treatment of anxiety, depression, psychosomatic diseases and addiction. However, most of the studies were not performed under contemporary standards, and it has taken several decades for a resurgence of interest in LSD research and its therapeutic potential for psychiatry. The aim of this review is to identify controlled and randomized clinical trials that assess the potential use of LSD in psychiatry.
PRISMA guidelines for systematic review were followed. A literature search of PubMed and Psychedelic bibliography from Multidisciplinary Association for Psychedelic Studies (MAPS) databases was performed as well as a manual search of references from evaluated studies. Only randomized-controlled clinical trials were included. Study quality was systematically calculated by using the Cochrane Collaboration Tool for assessing risk of bias. A final selection of 11 articles was made after considering inclusion and exclusion criteria. LSD was administered to 567 patients in a dose ranging from 20 to 800 mcg. Despite the design heterogeneity of clinical trials, positive results were observed, thus revealing the therapeutic potential of LSD to reduce psychiatric symptomatology, mainly in alcoholism. The vast majority of authors describe significant and positive short-term changes in patients, despite the fact that in some studies an important homogenization was observed between the LSD treatment group and control group at long-term follow-up.

Multiple variables regarding LSD treatment therapeutic approach and quality of experience were revealed and related to therapeutic outcomes. LSD is revealed as a potential therapeutic agent in psychiatry; the evidence to date is strongest for the use of LSD in the treatment of alcoholism. Despite the difficulty of designing proper double blind clinical trials with this substance, new studies that conform to modern standards are necessary in order to strengthen our knowledge on its use and open new doors in the future.

Keywords : lysergic acid diethylamide (LSD), hallucinogens, therapeutic use, psychiatric disorders, addiction



Since its discovery in 1938 by Swiss chemist Albert Hofmann (1), lysergic acid diethylamide (lysergide, LSD) has maintained an unstable relationship with psychiatry. Hofmann synthesized LSD in an effort to develop ergot derivatives with the goal of reducing postpartum hemorrhage. Some years later, after accidentally getting into contact with a small dose, he was the first subject in history to experience its effects (2). At the end of the 1940s, there was great interest among psychiatrist in the potential use of
LSD as a therapeutic agent (3), which was actually marketed by Sandoz laboratories under the brand name “Delysid” in the 1950s (4) and used in several psychiatric departments in Europe and America. Even the US Army and CIA experimented with this substance as a truth serum, and LSD was further investigated by the US Army as a potential incapacitating agent, however without success (5). After its
prohibition in USA in 1967, due to an increase in popularity and its association with counter-cultural movements, it has taken several decades for a resurgence of interest in its therapeutic potential for psychiatry (6–9).

LSD is part of the pharmacological group known as “classical hallucinogens” or “psychedelics” (term coined by Osmond in 1957) (4), sharing its chemical structure with psilocybin and dimethyltryptamine (DMT) as a variant of indolamine (chemical structure similar to the neurotransmitter serotonin) (10).
The term “classical hallucinogen” is a widely accepted synonym in the literature, with a greater emphasis on the alteration of the perception that these substances cause (11), although its use has been controversial as it does not specify the effect of these agents in consciousness and the self, as indicated by recent psychological and biological studies (12–14). LSD could also be defined, from an anthropological perspective, as an “entheogen”, which implies that users experience (mainly in a religious, shamanic or spiritual context) an altered state of consciousness: “as if the eyes had been cleansed and the person
could see the world as new in all respects” (15).

Classical hallucinogens are psychoactive substances that are believed to mediate their effects mainly through an agonist activity in the serotonin 2A receptor (5-HT2A) (16). Experimental studies have previously shown that the use of 5- HT2A antagonists attenuate the main effects of these substances, both in rats (17, 18) and human subjects (19–22). Other receptors which may contribute to the effects of these agents are the serotonin 2C and 1A receptors, as well as other effects in the dopaminergic and noradrenergic system (16). Likewise, these are potent regulators of transcription factors, which could mediate a potential mechanism of action in the synaptic structure with greater persistence of their effects over time (23, 24).

LSD is one of the most potent classical hallucinogens available, with active doses between 0.5 and 2 mcg/kg (100– 150 mcg per dose). Its half-life is approximately 3 h, varying between 2 and 5 h, and its psychoactive effects are prolonged over time (up to 12 h depending on the dose, tolerance, weight and age of the subject) (25, 26). Recently LSD has been used in microdoses as low as 10 mcg to enhance performance (27).

The usual mental effects of LSD are distortion of sense of time and identity, alteration in depth and time perception, visual hallucinations, sense of euphoria or certainty, distorted perception of the size and shape of objects, movements, color, sounds, touch and body image and delusions (28). Concerning safety, the administration of classical hallucinogens carries some risks. One of them is the so-called
“bad trip” or “challenging experience”, described as an acute state of anxiety, dysphoria and confusion, which can lead to unpredictable behavior in uncontrolled or unsupervised environments (29). Another possible risk is the exacerbation of psychotic disorders or the generation of prolonged psychotic
reactions, which could be related to the subject’s previous predisposition (30). Although no contemporary study has reported psychosis after the administration of classical hallucinogens, an adequate screening of previous psychotic episodes and the patient’s vulnerability is necessary for the use of these substances (31). Another possible adverse effect is a modest increase in blood pressure and heart rate; therefore, patients with severe cardiovascular disease should be excluded from the administration of this agent. Other usual absolute contraindications are pregnancy, epilepsy or paranoid personality traits (32). The remaining adverse effects should not limit its therapeutic use (31, 33).

As a recreational drug, LSD does not entail physical dependence as withdrawal syndrome, as do most of these substances (opioids, cocaine, cannabis and methamphetamine) (34). Its frequent or long-term use can lead to tolerance, and after a single dose, emotional, physical and mental stability is quickly recovered (35, 36). Likewise, classical hallucinogens in general, and LSD in particular, exhibit very low physiological toxicity, even at very high doses, without any evidence of organic damage or neuro-psychological deficits (36, 37) associated with their use. Their safety has recently led to considering LSD as one of the safest psychoactive recreational substances (38–42).