This review (2016) provides a chronologic history of LSD and examines its safety profile, the potential for abuse, its therapeutic potential to treat alcoholism or terminally ill patients. It also summarizes insights about its receptor pharmacology, mechanism of action, and (adverse) effects, while highlighting some of its potential clinical applications such as an antianxiety agent, a creativity enhancer, a suggestibility enhancer, or a performance enhancer.

Abstract

“Lysergic acid diethylamide (LSD), described as a classical hallucinogen, began its journey from the middle of the last century following an accidental discovery. Since then, it was used as a popular and notorious substance of abuse in various parts of the world. Its beneficial role as an adjunct to psychotherapy was much unknown, until some ‘benevolent’ experiments were carried out over time to explore some of its potential uses. But, many of its effects were unclear and seemed to be a psychedelic enigma. In this review article, we have described the receptor pharmacology, mechanism of action, effects and adverse effects of LSD on the normal body system. We have also highlighted its addictive potentials and the chances of developing tolerance. We have assimilated some of the interesting therapeutic uses of this drug, such as an antianxiety agent, a creativity enhancer, a suggestibility enhancer, and a performance enhancer. We have also described LSD to be successfully used in drug and alcohol dependence, and as a part of psychedelic peak therapy in terminally ill patients. The relevant chronological history and literature in the light of present knowledge and scenarios have been discussed. Based on available evidence, LSD could be tried therapeutically in certain specific conditions under controlled settings. But as we mention, due to all the safety concerns, the use of this nonaddictive ‘entheogen’ in actual practice warrants a lot of expertise, caution, cooperation and ethical considerations.”

Authors: Saibal Das, Preeti Barnwal, Anand Ramasamy, Sumalya Sen & Somnath Mondal

Summary

Effects of LSD on the normal system

LSD is known as a remarkable hallucinogenic agent, and is said to enhance the user’s appreciation of the environment, increase creativity, and open the gates of awareness to mind-bending mystical or religious experiences.

LSD is one of the most potent, mood-changing, semi-synthetic psychedelic agents, and can cause numerous side effects, including increased activity of monosynaptic reflexes, increased muscle tension, tremors, and muscular incoordination.

LSD users may develop tolerance to the drug, which increases the risk of experiencing bad trips. Schizophrenia and severe depression may also occur with chronic use.

Mechanism of action of LSD

LSD influences diverse neurotransmitter systems, but its psychosensory effects are mainly mediated by activation of the 5HT2A receptors. No neuroimaging studies have been conducted with LSD, but studies with psilocybin and dimethyltryptamine have yielded inconclusive results.

LSD abuse is difficult and does not lead to physical dependence. However, psychological dependence does develop after a few days of abstinence.

Is LSD only ‘bad’? A brief passage through time

Classic hallucinogens have been used over the past 5000 years, but LSD was first synthesized in 1938 by Albert Hofmann. It caused restlessness and had effects on the uterus.

Hofmann again synthesized LSD in 1943 and deliberately self-administered 250 g of this compound to explore its effects further. The median lethal dose (LD50) varied widely between animal species.

Following Hofmann’s discovery of LSD, there was a surge of scientific work on the classic hallucinogens. LSD was introduced to the medical community as an experimental tool to induce temporary psychotic-like states in ‘normals’.

LSD was found to reduce anxiety, depression, and pain in patients with advanced cancer in the early 1960s. However, there were many adverse effects with LSD administration, and the unsupervised use of this euphoric drug might increase its potential for antisocial behavior and abuse.

The Hallucinogenic Drug Regulations (1967) were introduced to restrict the use of these drugs only by qualified practitioners. However, some LSD-assisted psychotherapy continued in Czechoslovakia, the Netherlands, and Germany during the 1970s, and in Switzerland from 1988 to 1993.

One study reviewed the use of LSD, peyote, ibogaine, and ayahuasca in the treatment of drug dependencies. The study found that these substances help through serotonin-based dynamics.

Effects on prepulse inhibition

In a double-blind, randomized, placebo-controlled, crossover study, 16 healthy subjects were administered LSD and placebo. LSD produced pronounced alterations in waking consciousness, increased subjective happiness, closeness to others, wellbeing, openness, and trust, and decreased prepulse inhibition (PPI) of the acoustic startle response.

Harman and colleagues suggested that using a psychedelic drug under appropriately controlled test conditions enhances the creative process. Dobkin de Rios and Janiger gave LSD to a mixed group of 60 visual artists over a 7-year period and found that the artists’ work was improved by LSD.

Five studies on the influence of LSD on human creativity were published in 1972. These studies demonstrated that LSD improved creativity in graphic arts, engineers, theoretical mathematicians, physicists, architects, and designers.

To enhance suggestibility

In a within-subject, placebo-controlled design, intravenous LSD enhanced suggestibility but not MIT in 10 healthy volunteers. This enhanced suggestibility was positively correlated with trait conscientiousness, which is again related to ego control. In a study involving 24 healthy participants, suggestibility was significantly enhanced by LSD and mescaline. 5HT2A signaling was also linked to increased cognitive flexibility, associative learning, and neural plasticity, which may be prerequisites for improvement in suggestibility.

Krebs and Johansen (2012) found that 59% of subjects receiving LSD reported lower levels of alcohol misuse compared to 38% of subjects receiving placebo.

Psychedelic trip in the terminally ill

End-of-life issues, including pain management and palliative care, are increasingly recognized as significant public health concerns. High doses of LSD have been used as psychedelic therapy, and as ‘psychedelic peak therapy’ in terminally ill patients to improve psychological aspects of attitudes, emotions, and sleep patterns.

Current research is being targeted at patients who have developed secondary anxiety-related disorders associated with end-stage disease (cancer), and are refractory to conventional anxiolytic therapy. The effects of psilocybin include decrease in craving, increase in self-efficacy, and positive behavioral changes and improvements in the feeling of wellbeing and satisfaction with life.

Classic hallucinogens can be used in dangerous ways in nonclinical settings, but do not normally engender compulsive drug-seeking behavior (addiction) as with most other abused drugs. They also have very low physiological toxicities, with no evidence of resulting organ damage or neuropsychological deficits even at very high doses.

LSD-assisted psychotherapy may be used to treat psychoneurosis, conversion phobic depressive disorders, neurotic depressive reaction, reactive depression, other personality disorders, cyclothymic and passive-aggressive compulsive sexual deviation addiction, transient situational personality disorders, and manic-depressive reaction in remission.