Introduction

Since its discovery in 1938 by Swiss chemist Albert Hofmann , 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 . At the end of the 1940s, there was great interest among psychiatrist in the potential use of LSD as a therapeutic agent , which was actually marketed by Sandoz laboratories under the brand name “Delysid” in the 1950s 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 . 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 .

LSD is part of the pharmacological group known as “classical hallucinogens” or “psychedelics” (term coined by Osmond in 1957) , sharing its chemical structure with psilocybin and dimethyltryptamine (DMT) as a variant of indolamine (chemical structure similar to the neurotransmitter serotonin) .

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 , 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 . 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” .

Classical hallucinogens are psychoactive substances that are believed to mediate their effects mainly through an agonist activity in the serotonin 2A receptor (5-HT2A) . Experimental studies have previously shown that the use of 5-HT2A antagonists attenuate the main effects of these substances, both in rats and human subjects .

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 . 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.

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). Recently LSD has been used in microdoses as low as 10 mcg to enhance performance.

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.

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. 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. 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. 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. The remaining adverse effects should not limit its therapeutic use.

As a recreational drug, LSD does not entail physical dependence as withdrawal syndrome, as do most of these substances (opioids, cocaine, cannabis and methamphetamine). Its frequent or long-term use can lead to tolerance, and after a single dose, emotional, physical and mental stability is quickly recovered. 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 neuropsychological deficits associated with their use. Their safety has recently led to considering LSD as one of the safest psychoactive recreational substances.

However, LSD remains one of the most stigmatized and legally restricted agents among psychoactive substances. It is still included in Schedule I of the United Nations classification of drugs, restricting its use in research and making it difficult to potentially use it as a therapeutic tool in medicine. This classification has recently been questioned by various authors. A few decades ago, anecdotal reports of suicidal acts in recreational users were published, and intensely emphasized by the media. These attempts are in contrast with some recent population studies, which show significant associations between the use of a single dose of classical hallucinogens and a decrease in the likelihood of psychological distress and suicide. Other recent studies also established a clear link between life-time use of classical hallucinogens and a lower probability of developing mental problems, as well as a positive association, although non-significant, regarding several variables related to mental health. Nevertheless, the unpredictability of subject behavior makes it necessary to adequately control the environment and monitor the reaction of each individual.

Regarding its therapeutic potential, LSD was used from the 1950s to the 1970s to achieve 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. During that time, it was also observed that LSD together with suitable accompaniment during its administration, could reduce pain, anxiety and depression in patients with advanced cancer Other studies involving larger patient samples also established its safety and promising results in patients with terminal cancer. Studies in schizophrenic patients, however, reached less response to the same dose and worse clinical outcomes compared with non-schizophrenics patients, and negative effects on these patients have been described, both in LSD experience itself and later benefits. The data indicate that the responsivity of schizophrenic patients to the administration of lysergic acid is less than that of normal subjects.

Prediction of individual responses to LSD depends on several variables, some of which were already discussed at the international LSD therapy conference in 1965 . LSD reaction involves a series of complex interactions between doses, “set” (thoughts, mood and expectations of the subject prior to treatment) and “setting” (the physical and interpersonal environment in which the subject undergoes treatment). Three different major approaches to LSD use as a treatment were then applied to clinical research: “psycholytic therapy”, “psychedelic-chemotherapy” and “psychedelic-peak therapy” . In psycholytic therapy, mainly practiced in Europe, low-moderate doses (25-200 mcg) of this drug were used in more than one therapeutic session of psychodynamic orientation. In psychedelic-chemotherapy, drug use itself was emphasized at relatively high doses (200 mcg or more), with a very limited or absent psychotherapeutic approach. As for psychedelic-peak therapy (or “psychedelic therapy”), it involves administering a single and relatively high dose with the aim of triggering a mystical-type experience (“peak experience” or “ego dissolution” as synonyms). This approach should include the proper prior preparation of the patient (set) and a comfortable environment during the session (setting), as well as a discussion on it during subsequent follow-up sessions with the subject (after-care related to LSD session). Mystical experiences are referred to as those in which a sense of unity with the environment is experienced achieving a vivid transcendental experience at an emotional, cognitive and ego-structural level, after a previous and personal therapeutic preparation. The aim is to catalyze rapid and fundamental changes in the value system and self-image of the subject.

Despite the foregoing, most clinical studies involving the use of LSD were published between the 1960s and 1970s, up to the strict prohibition of its use in research. Obviously, most of these studies were not performed under contemporary standards. The purpose of this systematic review is to identify controlled and randomized clinical trials that assess the potential use of LSD in psychiatry and identify variables controlled by the researcher as potentially related to therapeutic outcomes. This is with the aim of informing a discussion on the benefits and challenges of integrating contemporary classic hallucinogens research into modern clinical trial designs and providing a guide for further research involving LSD as a therapeutic agent.

Methods

Data Acquisition and Search Strategy

This study was conducted according to the requirements established in the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) protocols.

Pubmed database was searched for the following terms: [“lysergic acid diethylamide” OR “LSD” OR “lysergic acid diethylamide” (MeSH Terms)] OR “lysergic acid”) AND [“therapeutics”(MeSH Terms) OR “mental disorder” (MeSH Terms) OR “therapy” OR “psychotherapy” OR “treatment”]. In addition, the Multidisciplinary Association for Psychedelic Studies (MAPS) Psychedelic Bibliography was also consulted. To ensure literature saturation, the electronic search was supplemented by a manual review of the reference lists from eligible publications. Two authors independently screened the titles and abstracts yielded by the search against the inclusion criteria. Full reports for all titles that appear to meet the inclusion criteria were obtained. Reviewers resolved disagreements by discussion. The search was limited to the time period compressed between 01-01-1950 and 05-05-2019, based on the results obtained in the reference search.

Search results were examined by two authors (JJF and FF) reading the titles and abstracts. Each potentially relevant publication found during the search was retrieved and assessed for its use in this review after inclusion and exclusion criteria were specified.

Data Items

Dosage, frequency and duration of the treatment, for both experimental and control interventions were extracted. Patient’s characteristics (including age, gender and diagnosis) and inclusion/exclusion criteria were extracted together with country, trial design, trial size, and length of follow up. For non-pharmacological comparators, type, frequency and duration of the intervention were extracted, if appropriate.

As studies with different diagnostic groups were included, outcomes varied depending on the psychiatric condition under study. In any case, change scores from baseline or endpoint were extracted. Side effects and overall tolerability were also studied.

Eligibility Criteria

Randomized controlled trials of LSD as a therapeutic tool for psychiatry were included. This review included only randomized controlled clinical trials involving patients with a diagnosis of mental illness. Experimental studies in healthy volunteers were excluded. Trials with no control group or not randomized, animal studies, observational studies, review papers, qualitative studies, case reports, opinion pieces or comments, letters or editorials, conference abstract, posters and books chapters were excluded. Of interest were interventions using LSD, as a stand-alone treatment or as an adjunctive treatment. Only studies comparing LSD with other interventions were included. Active and non-active comparators were included.

Quality Assessment

The Cochrane Collaboration risk of bias assessment tool was used to determine the quality of the studies. This tool involves an assessment of six specific domains: 1) sequence generation, 2) allocation concealment, 3) blinding of participants, 4) personnel and outcome assessors, 5) incomplete outcome data, and 6) selective outcome reporting and other sources of bias. The tool was applied to each RCT independently by two authors. Discrepancies were resolved through discussion with a third author.

Results

A total of 3,668 papers were identified through the search in Pubmed, and 12 additional records were found through other sources (manual search based on review papers and meta-analysis). After the removal of duplicates and exclusion based on titles or abstracts, 43 papers were screened in more detail for eligibility. Subsequently, another 32 were excluded, which resulted in the 11 papers used in this systematic review. This process is described in the PRISMA flowchart. The quality of the great majority of the clinical trials found did not conform to modern standards, with a non-randomized control group or without control group itself. The highest quality of trials was observed in studies on the therapeutic use of LSD in alcoholism.