A Review of Lysergic Acid Diethylamide (LSD) in the Treatment of Addictions: Historical Perspectives and Future Prospects

This review (2014) examines the historic transformation of LSD, from a psychoactive drug that exhibited great promise for the treatment of addiction, to an illicit substance affiliated with counterculture without a medical purpose. This review outlines aspects of its psychopharmacology that are still relevant for the treatment of addiction, which may warrant a renewed interest to continue research in this domain.

Abstract

Review: Lysergic acid diethylamide (LSD) is a semisynthetic compound with strong psychoactive properties. Chemically related to serotonin, LSD was initially hypothesized to produce a psychosis like state. Later, LSD was reported to have benefits in the treatment of addictions. However, widespread indiscriminate use and reports of adverse affects resulted in the classification of LSD as an illicit drug with no accepted medical use. This article reviews LSD’s storied history from its discovery, to its use as a research tool, followed by its widespread association with the counterculture movement of the 1960s, and finally to its rebirth as a medicine with potential benefits in the treatment of addictions. LSD’s pharmacology, phenomenology, effects at neurotransmitter receptors, and effects on patterns of gene expression are reviewed. Based upon a review of the literature, it is concluded that further research into LSD’s potential as a treatment for addictions is warranted.”

Author: Mitchell Liester

Summary

The Discovery of LSD

LSD was first synthesized in 1938 by Hoffman while attempting to synthesize a circulatory and respiratory stimulant derived from ergot. It was found to have strong effects on the uterus.

Hoffman synthesized LSD a second time and in 1943 self-administered 250 micrograms of this medicine to further explore its effects. He experienced confusion, dizziness, perceptual distortion, and a fear of going insane.

Studies were performed on mice, cats, dogs, chimpanzees, fish, and spiders. Low doses of LSD resulted in better proportioned webs.

Pharmacology of LSD

LSD is a semisynthetic compound made from lysergic acid, which is found in ergot alkaloids. Ergot alkaloids have a variety of medicinal effects.

LSD’s psychoactive effects begin within 20-60 minutes of ingesting the drug and typically last 8-12 hours. The effective dose range is 0.0003-0.001 mg/kg, and tolerance develops rapidly if administration is repeated with too short an interval between doses.

Although the lethal dose of LSD in humans is not known, fatalities have resulted from behaviors that occurred while individuals were under the influence of LSD.

LSD’S Effects on Neurotransmitters and their Receptors

LSD is believed to exert its psychedelic properties through its effects on the serotonin system. It binds to 5-HT2A receptors and acts as a partial agonist at 5-HT2A receptors.

5-HT2 receptors activate phospholipase C (PLC), which releases calcium ions and activates calcium/calmodulin kinases, which phosphorylate other proteins involved in the regulation of cellular functions. 5-HT2A receptors also activate phospholipase A2 (PLA2), which releases arachidonic acid, which induces the production of prostaglandins and prostacyclins.

LSD has been found to affect many neurotransmitter systems in addition to the serotonergic system, and the role of glutamate in LSD’s action on the central nervous system has been the focus of increased interest in recent years.

Metabotropic glutamate receptors (mGluRs) have been studied as a mediator of LSD’s actions. It has been demonstrated that mGluRs activate biochemical cascades, which effect neuronal excitability, and that mGluR2s couple with 5-HT2A receptors to form functional complexes in the brain cortex.

LSD’S Affects on Expression Patterns

LSD alters the expression of genes within cells, including genes involved in synaptic plasticity, glutamatergic signaling, cytoskeletal architecture, and communication between the synapse and nucleus.

Somatic Effects

Subjects may experience increased heart rate and blood pressure, sweating, nausea, diarrhea, vomiting, fatigue, muscular tension, tremors, headache, and sexual feelings.

Perceptual Changes

Perceptual changes occur frequently following the ingestion of LSD, including blurring of vision, distortion of three-dimensional space, changes in faces and objects, and color changes.

Cognitive Effects

Cognitive changes include impaired judgment, shortened concentration span, interposed thoughts, mind wandering, wavelike changes in thoughts, inability to control thoughts, and memory changes.

Other Effects

Transcendental or mystical experiences include a sense of unity, insightful knowledge, transcendence of time and space, and positive changes in attitude and/or behavior.

Advarse Effects

Cohen surveyed 62 investigators and found that 0.8 per 1000 normal volunteers and 1.8 per 1000 patients undergoing therapy experienced psychotic breaks, panic attacks, and other psychiatric reactions lasting over 48 hours.

In 1962, Cohen and Ditman described an increasing number of adverse effects associated with LSD-25 administration. These effects included prolonged psychotic decompensation, depressive reactions, release of preexisting psychopathic antisocial trends, and paranoid reactions.

Set and Setting

LSD’s effects are strongly influenced by the set and setting in which the drug is utilized. Social learning plays an important role in determining the subjective experience with LSD.

Uses of LSD

Stoll’s paper raised the topic of LSD being used in psychiatry. Low doses of LSD appeared to facilitate psychotherapy.

Sandoz provided LSD at no charge to physicians and research institutes around the world as an experimental drug for research.

LSD was initially used by researchers to study mental illnesses such as schizophrenia, and it was also believed that administering LSD to non-psychotic subjects would cause them to experience a schizophrenia-like state, providing a model for studying this disease and potentially discovering new and improved treatments.

Based upon the observed effects of LSD in experimental sessions, psychedelics were referred to as “hallucinogens”. Osmond offered “psychedelic” as a replacement term, contending these medicines did much more than “mimic psychosis”.

Researchers began to recognize that psychedelic drugs did more than produce hallucinations, and renounced the model psychosis theory.

In the 1950s, researchers began exploring LSD’s therapeutic potential, especially in treating patients who were considered poor candidates for psychotherapy.

LSD as a Treatment for Alcoholism

Among the physicians who initially focused on LSD’s “psychomimetic properties” was Osmond and Smythies. Their theory suggested that the body might produce an endogenous hallucinogen during times of stress.

Osmond and Hoffer studied the possibility that LSD might produce a controlled experience similar to delirium tremens, and found that two subjects who were administered LSD remained sober for several months after discharge.

Based upon the results of this preliminary investigation, a larger study was designed. Twenty-four inpatients were selected, and were administered a single dose of 200 to 400 micrograms of LSD in a hospital setting.

In this study, 12 out of 24 alcoholics were unchanged, 6 were improved, and 6 were much improved after treatment with LSD.

Based upon this early research, Hoffer and Osmond developed a treatment model for patients suffering from addictions that involved administering 300 to 1500 micrograms of LSD each session.

Ecstatic states are characterized by the loss of boundaries between the subject and the objective world, and by visions of brilliant white or golden light, rainbow spectra or elaborate designs.

According to Grinspoon and Grof, psychedelic therapy was used to induce a mystical experience or to facilitate the transcendence into the psychedelic peak experience.

O’Reilly et al. administered 200 micrograms of LSD to 68 chronic alcoholic patients who had not responded to other forms of treatment. Of the 26 patients who had been abstinent from alcohol during the two months prior to follow-up, 38 had been abstinent for 34 months.

Jensen published the first controlled trial of LSD as a treatment for alcoholism in 1962. Of the 145 subjects, 65 received LSD, 35 received the same therapy without LSD, and 45 received one-on-one psychotherapy and milieu therapy in an inpatient setting.

Jensen and Ramsay modified their study design and included 125 patients. Of the remaining subjects, 46 (74%) of the treatment group and 12 (41%) of the control group were improved at six to 18 months post-discharge.

LSD and Peak Expariences

In 1970, Pahnke et al. published a study that found that alcoholic patients who reported a psychedelic-peak experience showed greater improvement than patients who did not experience a psychedelic-peak experience.

In 1967, Hoffer and Osmond reported that LSD improved the recovery rate of alcohol addicts when used in combination with other forms of treatment and supportive measures. Later studies showed that nearly fifty percent of severe chronic alcoholics treated with a single dose of LSD remained sober 1-2 years after treatment.

Reviews of Research Using LSD as a Treatment for Alcoholism

Several reviews have examined the effectiveness of LSD in the treatment of alcohol dependence. The reviews have found that the studies are inconclusive.

Abuzzahab and Anderson reviewed 31 studies involving 1105 alcoholics and concluded that meaningful generalizations could not be reached.

Krebs and Johansen performed a meta-analysis of six randomized controlled trials on LSD and alcoholism. They concluded that a single dose of LSD is as effective as daily naltrexone, acamprosate, or disulfiram.

LSD as a Treatment of Narcotic Addictions

Ludwig and Levine administered moderate doses of LSD to 70 subjects following detoxification and found that the subjects’ self-concept and coping attitudes improved, but drug abstinence and behavioral changes were not assessed.

Seventy-four subjects were randomly assigned to a treatment group that received LSD and psychotherapy. After one year, 25% of the treatment group remained abstinent, whereas only 5% of the control group remained abstinent.

Possible mechanisms of action for LSD as a treatment for addictions include biochemical, psychological, and transcendent mechanisms of action.

Biochemical Hypothesis Regarding LSD’s Anti-Addictive Properties

Addiction has been linked to alterations in the mesolimbic dopamine pathway of the brain, which is associated with motivation, pleasure, and reward. This decreased level of dopaminergic tone has been proposed to produce anhedonia and drug craving.

One proposed treatment model involves utilizing dopamine agonists to reduce craving and withdrawal symptoms associated with discontinuation of DOA’s, but dopamine agonists can themselves become DOA’s if they release too much dopamine.

LSD is proposed to modulate dopamine release in the MDP via D1 and D2 receptors, as well as 5-HT2C receptors, thus alleviating allostasis and restoring homeostasis, thus decreasing the reinforcing properties of drugs of abuse.

The psychological hypothesis regarding LSD’s antiaddictive properties is based upon the benefits derived from using LSD in conjunction with psychotherapy. This form of therapy was termed “psycholytic therapy” and involved low doses of LSD integrated with psychotherapy.

Transcendent Hypothesis Regarding LSD’s AntiAddictive Properties

A third hypothesis regarding LSD’s potential mechanism of action as an anti-addiction medicine stems from its reported ability to produce transcendent, mystical, or peak experiences.

Recreational Use of LSD

The use of LSD spread from research laboratories and psychiatric hospitals to the streets of America in the 1960’s, creating a “psychedelic movement” in which people began using LSD for recreational or spiritual purposes. Unsupervised use by individuals who lacked medical supervision resulted in widespread abuse and “bad trips”.

Timothy Leary and Richard Alpert were strong proponents of LSD use in non-medical settings, but abandoned the scientific method.

Even within the psychiatric community, the use of LSD provoked controversy. Grinker chastised psychiatrists who administered the drug to themselves and claimed their conclusions were biased.

Numerous social and political issues fueled the controversy surrounding LSD. The Baby Boomer generation rebelled against their parents’ values, and the media and politicians failed to distinguish monitored, therapeutic use of LSD from unmonitored, recreational use.

Legal Status of LSD

The burgeoning recreational use of hallucinogens and other drugs in the 1960’s created escalating social and political pressures to control the use of these drugs. In 1965, the U.S. Congress passed the Drug Abuse Control Amendments.

Senator Robert Kennedy called for congressional hearings on LSD, but Sandoz halted production and distribution, resulting in a reduction in the number of research studies investigating LSD’s potential therapeutic effects.

In 1968, President Lyndon Johnson created the Bureau of Narcotics and Dangerous Drugs (BNDD), which was responsible for enforcing the Drug Abuse Control Amendments of 1965. In 1973, the Drug Enforcement Agency (DEA) was established and assumed responsibility for enforcing the Drug Abuse Control Amendments of 1965.

The increasing legal restrictions placed on LSD and the social stigmatization of psychedelics led to a precipitous drop in the number of research studies involving LSD in the 1970’s.

Resurgence of Research

A group of Swiss psychiatrists studied the effects of LSD on anxiety in patients with life-threatening illnesses. All 12 subjects reported benefits from the treatment.

Other Uses of LSD

LSD was utilized as an adjunct to various forms of psychotherapy, including individual psychotherapy, psychoanalysis, and Jungian psychotherapy. It was found to produce unexpected effects, such as increased insight into the emotional meaning of symptoms, and decreased anxiety.

LSD has been investigated as a treatment for nonpsychiatric disorders as well. It has been found to exhibit potent analgesic properties and has provided longer lasting reductions in pain.

LSD has also been used to treat cluster headaches. 7 out of 8 LSD users reported remission period extension following self-administration of LSD.

Conclusion

Addictions constitute a global health crisis. Prescription drug abuse and dependency are growing at alarming rates, and excessive consumption of alcohol is now the third leading cause of death in the US.

Early optimism regarding LSD’s potential as a treatment for addictions was later replaced by skepticism. However, a reevaluation of the historical context indicates that such skepticism may have been premature.

If historical prejudices can be overcome, opportunities exist for research into the potential therapeutic benefits of LSD and other consciousness-altering medicines. Collaboration with healers from other cultures may also help avoid future pitfalls.

An improved understanding of the biochemical basis for addictions supports the possibility that LSD may be an effective pharmacological treatment for addictions.

Study details

Topics studied
Addiction

Study characteristics
Literature Review

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