Serotonergic Hallucinogens

Introduction

This chapter focuses on hallucinogens with psychoactive properties mediated through the serotonin system. Although commonly referred to as “hallucinogens,” a lexigraphic disclaimer is warranted, as the experience elicited by these drugs commonly centers on distortion of perception, not true hallucinations. The most apt term is probably “psychedelic” from the Greek psukhē , meaning “mind” and dēloun, meaning “reveal” or “make visible.” Although the enlightenment sought by recreational users may be an artifact of the psychoactive experience, researchers study these compounds hoping to gain insight into how the brain produces the mind. Nonetheless, in conforming to common usage, in this chapter these drugs will be referred to as hallucinogens.

History

Perceptions provide reassurance into our existence and the existence of the world around us. Thus it is not surprising that compounds capable of producing altered states of perception are regarded with mystical fascination and trepidation. The ritualistic consumption of plants, many of which derive their psychoactive properties through the serotonin system, has been an important part of religious and social ceremonies throughout human history.

Conceivably the oldest known ritualistic use of hallucinogens was in the Indus Valley during the second millennium BCE. A group of people known as Aryans worshiped a deity they named “Soma,” which recent evidence suggests is the mushroom Amanita muscaria or Fly agaric. These served as an inspiration to several later cultural sources: Aldous Huxley refers to soma as the “ideal pleasure drug” in his novel Brave New World, and the red and white spotted mushroom that is A. muscaria incidentally bears resemblance to the mushroom featured in the Mario Brothers video game worshipped by many adolescents in the second millennium CE.

Spiritual use of hallucinogens has been a part of various cultures throughout the world. In the 14th century CE, Aztecs and other Indians of Central America ingested psilocybin-containing mushrooms to bestow powers of clairvoyance during religious ceremonies. Contemporary South American and Caribbean peoples snorted a narcotic powder (Cohoba), which, reminiscent of modern club drugs, was used to promote friendliness during convulsive dance ceremonies. In Western cultures, hallucinogens may underlie mythos of witchcraft and sorcery. In his book Hallucinogens and Shamanism , Michael Harner relates the symbol of a witch riding on a broomstick to the practice of medieval women achieving magical powers by anointing their mucous membranes with hallucinogenic substances. Linnda Caporael hypothesized that that the affliction of the girls sparking the Salem witch trials resulted from ergot (the natural substance from which lysergic acid diethylamine [LSD] is derived) poisoning caused by ingestion of rye grains contaminated with the fungus Claviceps purpurea . More recently, a study conducted by Griffiths et al. found that when administered under supportive conditions psilocybin occasioned experiences similar to spontaneously occurring mystical experiences.

The modern synthetic drug era began in the late 1960s with the legendary synthesis of LSD by the Swiss chemist, Albert Hoffman. While working at Sandoz Laboratories, Hoffman synthesized LSD as part of an effort to develop ergot derivatives capable of reducing postpartum bleeding. Not useful in this regard, the compound was shelved. Five years later, according to psychedelic lore, Hoffman was haunted by a “peculiar presentment” and repeated its synthesis. After accidentally absorbing a small amount he experienced its psychoactive effects while bicycling home. Psychedelic enthusiasts refer to this fateful day, April 16, 1943, as “Bicycle Day.”

In the 1960s and 1970s, Timothy Leary brought LSD and other psychedelics to the forefront of pop culture. His introduction of psychedelic drugs to academic and therapeutic settings led to the research responsible for most of what is currently known about these drugs. However, his temerarious promotion of these drugs for individual enlightenment and the ensuing underground abuse precipitated strict government regulation, which for several decades halted substantial scientific research. In the 1980s, attention to hallucinogen use reemerged with the trend of all night dance parties known to as raves. These large gatherings featured electronic dance music and laser light shows. Attendees often used psychedelic drugs (most commonly 3,4-methylenedioxymethamphetamine—also known as MDMA or Ecstasy) to promote sociality and heighten the sensory stimuli of the music and lights. Despite the emergence of new hallucinogens, the use of LSD and the traditional psychedelics continued throughout recent decades.

Today, restrictions on research have loosened and there is a gradual increase in obtaining approval and carrying out research on psychedelic drugs. In recent years, emerging evidence is accumulating, indicating that serotonergic hallucinogens may be useful in a variety of clinical situations, such as treating cluster headaches, anxiety associated with life-threatening diseases, and substance use disorders. Alongside the increased prevalence of hallucinogen use for individual enlightenment and therapeutic potential, concerns regarding potential adverse effects of these drugs increased as well. These include both physiological effects, which in some cases led to severe adverse effects (e.g., cases of seizures, cardiac arrhythmia, and death following ibogaine use ), as well as psychiatric adverse effects (e.g., include anxiety, flashbacks, psychosis following LSD use ). Accordingly, the use of hallucinogens for personal and spiritual growth was gradually met with concerns surrounding abuse of these substances, and particular concerns regarding their potential adverse effects.

Epidemiology

Hallucinogen use has declined since the 1970s, with the annual prevalence remaining below 10%. The types of hallucinogens used have also changed. LSD, which was the most widely used hallucinogen, has been surpassed by newer synthetic club drugs. In 2014, the Substance Abuse and Mental Health Services Administration (SAMHSA) reported findings from the National Survey on Drug Use and Health (NSDUH), indicating that use of hallucinogens has remained relatively steady since 2002. In 2014, 1.2 million people in the United States (0.4% of the population) reported using hallucinogens in the past month (use was higher among males compared to females: 748,000 vs. 426,000). In the same year, there were 936,000 people 12 years of age or older in the United States who had used hallucinogens for the first time within the past 12 months. According to the same report, the most common hallucinogen used was MDMA, with 609,000 people 12 years or older reporting use in the past month.

Classification

Serotonergic hallucinogens can be divided by chemical structure ( Fig. 31.1 ). Indolealkylamines, which have more than one carbon ring and are structurally similar to serotonin, include LSD, ibogaine, psilocin, psilocybin, and N,N -dimethyltryptamine. The phenethylamines, that have only one carbon ring, more closely resemble amphetamine and the catecholamine neurotransmitters (dopamine, epinephrine, and norepinephrine). This class comprises mescaline, MDMA, 3,4-methylenedioxyamphetamine, and dimethoxymethylamphetamine. The psychopharmacology of all of the serotonergic hallucinogens (except for MDMA) is similar.

To avoid redundancy, this chapter begins with a general discussion of mechanism of action and then concentrates on representative indolealkylamines (LSD, psilocybin, and ibogaine) and phenethylamines (mescaline and MDMA), with LSD serving as a prototype for comparison.

Mechanism of Action

After nearly a half a century of research, it is currently understood that the psychoactive effects of both indolealkylamine and phenethylamine hallucinogens are mediated primarily through agonist activity at the 2A subtype of serotonergic receptors (as serotonin is also known as “5-hydroxytryptamine” [5HT], these are known as 5HT2A receptors). The structural resemblance of indolealkylamines to the serotonin neurotransmitter led researchers to suspect that their psychoactive effects were serotonergically mediated. Furthermore, the reported similarity of psychic experiences elicited by the phenethylamines and the indolealkylamines, as well as cross-tolerance between the two classes, suggest a shared mechanism of action, although distinct effects via distinct psychodynamic activity are yet to be understood.

Serotonin Receptor

The monoamine family of neurotransmitters comprises serotonin, epinephrine, norepinephrine, and dopamine. The serotonin receptor system is particularly complicated, with 14 distinct receptors belonging to 7 families (5HT1R–5HT7R) having been discovered so far. The system is made more complex by posttranslational receptor modifications, multiple G proteins, phenotypic switching, and crosstalk within and probably between receptor families. All but one of the serotonin receptors are coupled to G proteins. The 5HT2A and 5HT2C receptors are similar and often referred to as the 5HT2A/2C receptor. There is a paucity of ligands with selectivity between these two subtypes, making it difficult to rule out an ancillary role of 5HT2C receptors in the psychoactive effects of hallucinogens.

Indolealkylamine Hallucinogens