Chapter 13. Neurobiology of Hallucinogens

Richard A. Glennon, Ph.D.
DOI: 10.1176/appi.books.9781585623440.347177



Hallucinogenic agents represent an old and very large class of drugs. Nearly every major civilization throughout history has had a preferred drug of abuse or mind-altering substance. In some instances these have been hallucinogens or hallucinogen-related agents or plant products. Various agents can produce hallucinogenic episodes, and terms used to describe such agents include hallucinogens, psychotomimetics, psychedelics, inebriants,and intoxicants. Many agents can be found in this general class of psychoactive agents. More recently, certain hallucinogens have been included in the loose collection of agents termed club drugs, party drugs, or rave drugs. It is clear, however, that membership in these latter categories is not pharmacologically based and that most agents bearing this appellation are not hallucinogens. Do agents as structurally diverse as (+)lysergic acid diethylamide ([+]LSD), phencyclidine (PCP, angel dust), tetrahydrocannabinol (THC; a constituent of marijuana), amphetamine, and mescaline all produce the same (or a common) effect? Do they all work via a common pharmacological mechanism? Studies conducted over the past several decades indicate they do not (see Glennon 2002 for a review).

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FIGURE 13–1. Structures of some of the examples of hallucinogenic agents listed in Table 13–1.DET = N,N-diethyltryptamine; DMT = N,N-dimethyltryptamine; DOB = 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane; DOET = 1-(2,5-dimethoxy-4-ethylphenyl)-2-aminopropane; DOI = 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane; DOM = 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane; (+)LSD = (+)lysergic acid diethylamide; -MeT = 3-(2-aminopropyl)indole; -Methylmescaline = 1-(3,4,5-trimethoxyphenyl)-2-aminopropane; 5-OMe DMT = 5-methoxy-N,N-dimethyltryptamine.

FIGURE 13–2. Structures of some central stimulants, designer drugs, and related substances described in the text.

FIGURE 13–3. Venn diagram representing possible overlapping activities or behavioral similarities among the psychoactive phenylisopropylamines.The agent 1-(3,4-methylenedioxyphenyl)-2-aminopropane [(±)MDA] seems to represent the common (heavily shaded) intersect in that it produces all three actions. See Glennon et al. (1997) and Glennon and Young (2002) for further discussion. A=central stimulant, typified by (+)amphetamine; H=hallucinogenic, typified by 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM); P=other activity, typified by N-methyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA).
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TABLE 13–1. Categories and examples of classical hallucinogens
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Hallucinogens (sometimes referred to as psychotomimetics) represent a very large and (chemically and pharmacologically) heterogeneous class of agents that can produce distinctive, and not necessarily identical, behavioral effects.

No animal assay has yet been identified that reliably identifies hallucinogens as a class, but drug discrimination studies have aided the classification of such substances.

Hallucinogens/psychotomimetics can, depending upon the particular agent, act via one of several different types of brain mechanisms.

One of the largest categories of hallucinogens is the classical hallucinogens.

Classical hallucinogens are made up mainly of indolealkylamines and phenylalkylamines. Indolealkylamine hallucinogens include tryptamine derivatives (e.g., N,N-dimethyltryptamine [DMT]) and lysergamides (e.g., lysergic acid diethylamide [LSD]); phenylalkylamine hallucinogens consist of phenylethylamines (e.g., mescaline) and phenylisopropylamines (e.g., 1-[2,5-dimethoxy-4-methylphenyl]-2-aminopropane [DOM] and 1-[4-bromo-2,5-dimethoxyphenyl]-2-aminopropane [DOB]).

The classical hallucinogens share a common ability to bind at a particular population of serotonin receptors (i.e., serotonin type 2A receptors) and act in an agonist fashion.

Structural modification of indolealkylamines and phenylalkylamines can result in substances (i.e., designer drugs or controlled substance analogues) with hallucinogenic, central stimulant, and/or empathogenic character.

Novel designer drugs include derivatives of indolealkylamines and phenylalkylamines.

Designer drugs can produce one or more of several different (e.g., hallucinogenic, central stimulant, empathogenic) pharmacologically relevant effects, and the effect(s) produced by such drugs is highly dependent upon the particular substitution pattern of the agent. That is, indolealkylamines and phenylalkylamines serve as malleable templates, and specific substituents appended to these structures determine what effect(s) the agent produces.


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Sample questions:
One problem in classifying hallucinogens has been a sufficiently rigorous, specific, and inclusive definition of these chemically heterogeneous substances. An early set of criteria was produced by Hollister (1968). Which of the following is not characteristic of hallucinogens, according to these criteria?
According to the definition of classical hallucinogen, which serotonin receptor is the target of drug binding?
Various chemical compounds meet the criteria for definition as classical hallucinogens. Several of these are classified as indolealkylamines or phenylalklyamines. Which of the following compounds is a phenylalklyamine?
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