Chapter 13 Neurobiology of Hallucinogens

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Chapter 13. Neurobiology of Hallucinogens

NEUROBIOLOGY OF HALLUCINOGENS: INTRODUCTION

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).

Further obscuring a simple systematic classification of these agents is the emergence of certain

designer drugs (not all of which are hallucinogenic and some of which can produce multiple effects)

and the recent popularization of older substances (mostly natural products or plant-derived

materials) whose human effects have received only limited investigation under controlled clinical

settings. Examples of plant-derived substances with growing popularity include ayahuasca and

Salvia divinorum (with salvinorin A being one of its active constituents). (Examples of

hallucinogen-related designer drugs will be provided later in this chapter, in the section titled

“Hallucinogen-Related and Other Designer Drugs.”) How, then, can these diverse substances be

classified?

Hollister (1968) wrote that “one can scarcely get any agreement upon the term used to describe

this class of drugs” (p. 18) and defined hallucinogenic/psychotomimetic agents on the basis of

their overall pharmacological effects.

In proportion to other effects, changes in thought, perception, and mood should predominate.

Intellectual or memory impairment should be minimal at dosages that produce the effects listed above.

Stupor, narcosis, or excessive stimulation should not be an integral effect.

Autonomic nervous system side effects should be neither disabling nor severely disconcerting.

Addictive craving should be minimal.

Although these criteria are very useful in that they allow the classification of certain agents as

hallucinogenic by a process of elimination, the description still allows inclusion of a rather diverse

variety of pharmacologically distinct agents. Hallucinogenic agents do not represent a behaviorally

homogeneous class of agents. Evidence indicates that agents included in the single, general

category of hallucinogenic/psychotomimetic agents should be further subclassified to create a

clearer picture of the effects that they produce and encourage the development of agents to treat

drug abuse. For example, psychotomimetic PCP-related agents probably produce many of their

actions through interaction at PCP receptors, cannabinoid receptors may account for some of the

actions of various cannabinoids, and hallucinogenic episodes associated with amphetamine

psychosis probably involve a catecholaminergic mechanism (Glennon 2002). Plant products such as

ayahuasca contain a putative hallucinogen and an inhibitor of monoamine oxidase (Riba and

Barbanoj 2005), whereas salvinorin A is thought to be a opioid receptor agonist (Prisinzano 2005;

Yan and Roth 2004). Without subclassification, many agents remain unclassified and none of thePrint: Chapter 13. Neurobiology of Hallucinogens http://www.psychiatryonline.com/popup.aspx?aID=347181&print=yes…

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previously mentioned categories would accommodate hallucinogens such as LSD or mescaline. The

term classical hallucinogen has evolved to account for some of these agents (Glennon 1999; Lin

and Glennon 1994).

CLASSICAL HALLUCINOGENS: CLASSIFICATION

The best functional definition of classical hallucinogen is an agent that meets the Hollister (1968)

criteria, binds at serotonin type 2 (5-HT2) receptors, and is recognized by animals trained to

discriminate 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) from nondrug, or vehicle,

in tests of stimulus generalization (Glennon 1996, 2003). These criteria may comprise many of the

remaining agents.

Although significant amounts of human data on the effects of hallucinogens on animals are

available (Brimblecombe and Pinder 1975; Hoffer and Osmond 1967; Jacob and Shulgin 1994; Lin

and Glennon 1994; Shulgin and Shulgin 1991, 1997; Siva Sankar 1975), many putative

hallucinogens and the effect they have on humans have been poorly investigated, if at all. There

are results from animal studies; however, no reliable animal model of hallucinogenic activity has

been developed (Glennon 1992). As a result, animal data must be interpreted cautiously.

Nevertheless, a procedure that has become widely accepted for classifying centrally acting agents

is the drug discrimination paradigm, usually performed with rats, mice, pigeons, or monkeys as test

subjects (Glennon 1994). Under this paradigm, researchers can use a typical two-lever

operant-behavioral paradigm to train animals to respond in one manner (e.g., to press one of two

levers) under a given set of conditions, and to respond in a different manner (e.g., to press the

second of the two levers) under a different set of conditions. Thus, animals can be reliably trained

to discriminate administration of a centrally acting agent from vehicle. Typically, the drug stimulus

is reliable and robust, and results are replicable from laboratory to laboratory.

Once animals have been trained to discriminate a given training drug from vehicle, several types of

studies can be conducted. Two of the most useful and widely employed studies are tests of stimulus

generalization and tests of stimulus antagonism. In the former, challenge drugs are administered

intermittently to the trained animals to determine whether the agents produce stimulus effects

similar to (i.e., whether they substitute for, or generalize to) those of the training drug. Results are

both qualitative and quantitative; that is, the method allows classification of the type of action

produced and also provides information about the potency of a challenge drug relative to the

training drug. In tests of stimulus antagonism, the training drug’s mechanism of action can be

explored by attempting to antagonize the stimulus effects of the drug with various

neurotransmitter antagonists. Although such studies are not limited to the investigation of

hallucinogenic agents and have been used more for the investigation of nonhallucinogens, they

have provided a wealth of information regarding the classification and mechanism of action of

hallucinogens. Furthermore, results obtained from such studies can be compared with results of

human studies, where such data are available, to corroborate the findings.

The strength of the drug discrimination paradigm is that stimulus generalization does not occur

between agents that do not produce common stimulus effects. For example, animals trained to

discriminate (+)LSD do not recognize PCP or THC, animals trained to discriminate (+)amphetamine

do not recognize mescaline, and so on. Using this procedure, several classical hallucinogens,

including (+)LSD, DOM, mescaline, and 5-methoxy-N,N-dimethyltryptamine, have been used as

training drugs (Glennon 1996). Moreover, animals trained to one of these agents recognize each of

the other agents, further attesting to the similarity of their stimulus effects. Several hundred

agents have now been examined in rats trained to discriminate DOM from vehicle, and this research

has aided the classification of the agents. Table 13–1 shows categories and examples of classical

hallucinogens, and Figure 13–1 shows chemical structures of selected examples. The agents in

Table 13–1 seem to share a common component of action in that they are recognized by

DOM-trained animals.

TABLE 13–1. Categories and examples of classical hallucinogensPrint: Chapter 13. Neurobiology of Hallucinogens http://www.psychiatryonline.com/popup.aspx?aID=347181&print=yes…

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Category Subcategory Examples

Indolealkylamines Tryptamines

N,N-Dimethyltryptamine (DMT)

N,N-Diethyltryptamine (DET)

4-Hydroxy DMT (psilocin)

5-Methoxy DMT

-Alkyltryptamines

-Methyltryptamine ( -MeT)

5-Methoxy- -MeT

Lysergamides Lysergic acid diethylamide (LSD)

-Carbolinesa

Harmaline

Phenylalkylamines Phenylethylamines Mescaline

Phenylisopropylamines

-Methylmescaline (3,4,5-TMA)

1-(2,5-Dimethoxy-4-methylphenyl)-2-aminopropane (DOM)

1-(4-Bromo-2,5-dimethoxyphenyl)-2-aminopropane (DOB)

1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI)

1-(3,4-Methylenedioxyphenyl)-2-aminopropane (MDA; “love

drug”)

Note. Although certain -carbolines bind at 5-HT2A serotonin receptors and are recognized by DOM-trained

animals, none has been shown to produce a 5-HT2A-mediated agonist effect (e.g., phosphatidylinositol [PI]

hydrolysis).

aCategorization as a classical hallucinogen is tentative.

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 = Print: Chapter 13. Neurobiology of Hallucinogens http://www.psychiatryonline.com/popup.aspx?aID=347181&print=yes…

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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.

Because animals trained to discriminate DOM from saline do not recognize (i.e., because

substitution does not occur upon administration of), for example, PCP, THC, and amphetamine, it

can be assumed that the discriminative stimulus (i.e., cueing) effects produced by these agents are

different. Furthermore, drug discrimination studies (i.e., stimulus antagonism studies) with, for

example, PCP, THC, and amphetamine, indicate that these agents act via a PCP receptor,

cannabinoid receptor, and cholinergic receptor mechanism, respectively (Glennon 2002).

CLASSICAL HALLUCINOGENS: MECHANISM OF ACTION

The actions of hallucinogens such as (+)LSD, DOM, mescaline, and many (perhaps hundreds) of

other related agents cannot be simply accounted for on the basis of the mechanisms described

above. The vast majority of hallucinogenic substances seem to act via a mechanism unique among

those already mentioned. Tests of stimulus antagonism have been conducted, using agents such as

(+)LSD and DOM as training drugs, with various neurotransmitter antagonists, and serotonin

(5-HT) receptor antagonists were found to antagonize their effects. Early on, it was thought to be a

curiosity that certain 5-HT receptor antagonists but not others were effective in blocking the

discriminative stimulus effects of these hallucinogens in tests of stimulus antagonism. However, in

retrospect, it is now apparent that there are seven families of 5-HT receptors (5-HT1–5-HT7) and

that these receptor types can be further subdivided into more than a dozen different subfamilies

(Glennon and Dukat 2002). Initially, ketanserin and pirenperone, and later M 100,907 (formerly

MDL 100,907) and other antagonists with an affinity and reasonable selectivity for a particular

population of serotonin receptors (i.e., 5-HT2 receptors), were found to be most effective in

blocking the stimulus effects of the classical hallucinogens, leading to the concept that certain

hallucinogens act as 5-HT2 receptor agonists. Subsequently, the 5-HT2 receptor affinities of various

hallucinogens were measured, and a significant correlation was found between any two of the

following parameters: 1) drug discrimination–derived potencies using DOM-trained rats, 2) human

hallucinogenic potencies, and 3) 5-HT2 receptor affinities. Hallucinogens that bind at 5-HT2

receptors have been termed classical hallucinogens. This theory has become known as the

5-HT2hypothesis of classical hallucinogen action (Glennon 1994), and this class of agents has been

alternatively referred to as serotonergic hallucinogens (Glennon 2003). This hypothesis does not

preclude a role for other populations of 5-HT (or nonserotonin) receptors in the actions of

hallucinogens. Indeed, individual hallucinogens can display widely varying binding profiles.

Nevertheless, 5-HT2 receptor affinity is the one feature that all classical hallucinogens have in

common. In the first clinical study of its kind, the actions of the indolealkylamine hallucinogen

psilocybin, the phosphate ester of psilocin, was shown to be antagonized in humans by the 5-HT2

antagonist ketanserin (Vollenweider et al. 1998).

Three populations of 5-HT2 receptors (5-HT2A, 5-HT2B, and 5-HT2C) have been identified since the

5-HT2 hypothesis was originally proposed. Although classical hallucinogens typically bind at all

three subpopulations (Nelson et al. 1999), work from several laboratories indicates that classical

hallucinogens act primarily via a 5-HT2A receptor agonist mechanism (Fiorella et al. 1995; Ismaiel

et al. 1993; Schreiber et al. 1994). Hence, it might be more appropriate to refer to the classical

hallucinogens as those agents that specifically activate brain 5-HT2A serotonin receptors.

Most of the classical hallucinogens are indolealkylamines or phenylalkylamines (see Table 13–1).

This is not to imply that all indolealkylamines and phenylalkylamines are hallucinogenic.

Nevertheless, a very large number of agents have been described as such. Furthermore,

structure-activity relationships have been formulated, and today there is a fairly good

understanding of what structural features are necessary for an agent to produce DOM-like effects.

Perhaps the best compilations of the pharmacological effects produced by indolealkylamines andPrint: Chapter 13. Neurobiology of Hallucinogens http://www.psychiatryonline.com/popup.aspx?aID=347181&print=yes…

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phenylalkylamines in human subjects are those by Shulgin and Shulgin (1991), (1997). In many

instances, the particular agents were evaluated only in limited subject populations.

Notwithstanding this shortcoming, these works are some of the best descriptions of the human

actions produced by, literally, hundreds of indolealkylamines and phenylalkylamines. It is also clear

from the above-mentioned structure-activity studies that other, previously unreported, substances

remain to be synthesized and evaluated. Hence, it is likely that newer agents will continue to

appear on the clandestine market in the future.

HALLUCINOGEN-RELATED AND OTHER DESIGNER DRUGS

Designer drugs, or controlled-substance analogues, are structural variants of known drugs of

abuse. Because they are “new” and are thought to promise a seemingly novel effect, they appear to

have appeal to individuals interested in exploring the effects of novel substances. Initially, the term

designer drug was reserved for new substances being introduced to the clandestine market to

circumvent legal constraints. Today, the term is applied to nearly any substance making an

appearance on the street, regardless of whether it is new or was previously reported in the

scientific literature. There is no specific type of pharmacological action associated with agents

termed designer drugs. For example, the designer drug Nexus (2-CB) is a phenylethylamine or

mescaline-like analogue of the phenylisopropylamine (PIA) hallucinogen

1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane (DOB) and is a hallucinogen. The PIAs

represent one of the largest categories of hallucinogens. Not all PIA designer drugs are

hallucinogenic. Amphetamine (Figure 13–2), a nonhallucinogen central stimulant that can produce

hallucinations (called amphetamine psychosis) upon chronic administration of high dosages, is also

a PIA. Amphetamine and some related PIAs are amphetamine-like central stimulants rather than

hallucinogens. Cathinone (Figure 13–2), a constituent of the shrub khat, is also a central stimulant;

it is similar in structure to amphetamine and has been shown to produce amphetamine-like

pharmacological effects. Methcathinone (“cat”) (Figure 13–2), the N-monomethyl analogue of

cathinone, shares structural similarity with methamphetamine and is an example of a designer drug

with stimulant activity. Other PIAs produce empathogenic effects (i.e., increased empathy,

talkativeness, openness, and feelings of well-being). The 3,4-methylenedioxy analogue of

amphetamine, 1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDA; “love drug”) (Figure 13–2) is

known to possess hallucinogenic and central stimulant character. MDA is a mixture of optical

isomers, and it has been demonstrated that its hallucinogenic properties are associated primarily

with its R(–)isomer whereas its stimulant character is attributable to its S(+)isomer. A prototypical

example of an empathogenic agent is the N-monomethyl analogue of MDA:

3,4-methylenedioxy-N-methylamphetamine (MDMA; “XTC,” “ecstasy,” “X,” “E”) (Nichols and

Oberlender 1989). MDMA also produces some amphetamine-like stimulant actions. Although not a

new substance, the N-ethyl homologue of MDMA, MDE (or MDEA; “Eve”) (Figure 13–2), is gaining in

popularity. N-Methyl-1-(3,4-methylenedioxyphenyl)-2-aminobutane (MBDB; “Eden,” “methyl-J”),

the -ethyl homologue of MDMA, is an MDMA-like agent that seems to lack central stimulant

character (Nichols and Oberlender 1989). Yet another type of PIA is represented by the designer

drug N-methyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA), a nonhallucinogenic nonstimulant

N-methyl analogue of 4-methoxyamphetamine (PMA; “white death,” “chicken powder”) (Figure

13–2). Thus, minor structural alterations of a PIA can result in agents with central stimulant,

hallucinogenic, or other actions (see Figure 13–3). In fact, stimulus generalization occurs in the

optical isomers of 3,4-DMA among animals trained to discriminate either MDMA or PMMA from

saline vehicle, but does not occur in animals trained to discriminate (+)amphetamine or DOM from

vehicle. As such, 3,4-DMA might be considered the common denominator for MDMA-like and

PMMA-like stimulus actions. A PIA might have more than one such action, depending on its specific

chemical structure. Unlike stimulant PIAs, hallucinogenic PIAs are not typically self-administered

by animals; however, the multiplicity of effect of certain PIAs might explain why some PIA

hallucinogens are self-administered, whereas most are not.

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

described in the text.Print: Chapter 13. Neurobiology of Hallucinogens http://www.psychiatryonline.com/popup.aspx?aID=347181&print=yes…

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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).

Hallucinogenic, central stimulant, and empathogenic phenylalkylamines share a common basic

chemical structure and their specific action is determined by the particular substituents appended

to the molecule. The structurally simplest phenylalkylamine is phenylethylamine; this compound

lacks significant central actions because it does not readily penetrate the blood-brain barrier, and

what little does get into the brain is rapidly metabolized. In contrast, the addition of one more

carbon unit, resulting in the simplest phenylisopropylamine or PIA, amphetamine, affords an agent

that readily enters the brain and produces central effects (i.e., central stimulation). Further

structural changes of this template molecule, depending upon the particular change, can result in

retention of central stimulant effects (e.g., methamphetamine) or can shift its actions to those of a

hallucinogen (e.g., DOM) or an empathogen (e.g., MBDB). The PIA moiety serves as a malleable

skeleton whose pharmacological properties can be altered by the introduction of various otherPrint: Chapter 13. Neurobiology of Hallucinogens http://www.psychiatryonline.com/popup.aspx?aID=347181&print=yes…

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structural features. In general, homologation of the -methyl group of the PIAs to an -ethyl group

diminishes their central stimulant or hallucinogenic potency but seems to have little effect on their

empathogenic character. As such, it is not uncommon to find an -ethyl group present in the

structures of phenylalkylamines (e.g., MDDB) and indolealkylamines (e.g., -ET) that retain

empathogenic or MDMA-like qualities. Further homologation of this -ethyl group to a longer

homologue (e.g., -n-propyl or -n-butyl homologue) results in a further decrease in either

hallucinogenic, central stimulant, or empathogenic potency, depending on the action of the parent

agent; hence, it is fairly uncommon to find the longer-chain functionalities in potent psychoactive

agents.

Using the PIA template, other designer drugs have appeared that generally conform to established

structure-activity considerations. For example, 1-(4-methylthiophenyl)-2-aminopropane (4-MTA;

“flatliner”) (Figure 13–2) has been shown to produce MDMA-like and PMMA-like, but not

amphetamine-like or DOM-like, stimulus effects in animals (Khorana et al. 2004). On the other

hand, 2C-T-7 (“blue mystic”) (Figure 13–2) has been shown to be a hallucinogenic agent that lacks

MDMA-like or amphetamine-like stimulus properties (Fantegrossi et al. 2005; Khorana et al. 2004).

Using the PIA—more specifically, 1-phenyl-2-aminopropiophenone—cathinone as a new structural

template, researchers have identified several novel agents. For example, the N-monomethyl

analogue of MDC (i.e., 3,4-methylenedioxycathinone), 3,4-methylenedioxymethcathinone (i.e.,

1-[3,4-methylenedioxyphenyl]-2-aminopropiophenone, MDMC), has been shown to be an

MDMA-like agent with amphetamine-like character (Dal Cason et al. 1997). MDMC, more recently

termed methylone, is known on the street as “explosion” (Bossong et al. 2005; Cozzi et al. 1999).

The parent indolealkylamine, tryptamine, has also been used as a template for agents that are

receiving some notoriety. Of recent interest is the hallucinogen

5-methoxy-N,N-diisopropyltryptamine (5-OMe DIPT; “foxy methoxy”) (Fantegrossi et al. 2006;

Glennon et al. 1983; Shulgin and Carter 1980) (Figure 13–2). The -ethyl homologue of -MeT,

-ethyltryptamine ( -ET; AET, ET) (Figure 13–2), has been shown to produce a combination of

effects (Glennon et al. 2006) (see below).

To better characterize the stimulus effects produced by various phenylalkylamine-related designer

drugs, such agents were examined in rats trained to discriminate one of three agents from vehicle

in tests of stimulus generalization: DOM, (+)amphetamine, and PMMA. Substitution does not occur

among these three agents regardless of which is used as a training drug, indicating that their

stimulus actions are distinct. Tests of stimulus generalization with other phenylalkylamines showed

that they substitute in one or more of these three training groups. The concept is summarized in

Figure 13–3. For example, methamphetamine substituted only in the (+)amphetamine-trained

animals and can be considered an A-type agent, whereas DOB substituted only in the DOM-trained

animals and can be considered an H-like agent.

By use of this classification scheme (Figure 13–3), Nexus now can be classified as a DOM-like

hallucinogen, and methcathinone as an amphetamine-like stimulant. MDMA is best characterized as

an A/P-type agent, in that it produces both amphetamine-like and PMMA-like effects. On the other

hand, MBDB, a homologue of MDMA that lacks stimulant character (Nichols and Oberlender 1989),

is defined as a PMMA-like agent (Rangisetty et al. 2001). Racemic MDA represents the common

intersect because it produces all three actions; however, its individual optical isomers, R(–)MDA

and S(+)MDA, are classified as H/P- and A/P-type agents, respectively (Glennon and Young 2002).

PMMA and 1-(4-methoxyphenyl)-2-aminopropane (PMA) have been used to adulterate MDMA or

have been represented on the street as MDMA-like substances; PMA produces PMMA-like effects. An

example of a newer PMMA-like agent is 4-MTA. MDMC (methylone) is an A/P-type agent because it

substituted both in (+)amphetamine- and PMMA-trained animals. Such a classification scheme also

has been extended to indolealkylamine hallucinogens such as -ET. S(–) -ET substituted in

(+)amphetamine- and PMMA-trained animals but not in DOM-trained animals, whereas R(+) -ET

substituted in DOM- and PMMA-trained animals but not in (+)amphetamine-trained animals

(Glennon et al. 2006). The specific mix of actions of certain agents may contribute to their

attractiveness as drugs of abuse and may also explain the difficulty of classifying various PIAs andPrint: Chapter 13. Neurobiology of Hallucinogens http://www.psychiatryonline.com/popup.aspx?aID=347181&print=yes…

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indolealkylamines with respect to their observed clinical effects (Glennon et al. 1997). Various new

agents are appearing on the street; little is known about their actions and mechanisms of action.

These agents (including their metabolites and synthetic by-products) require further investigation.

But a classification of drug action and recognition that certain agents can produce multiple effects

could impact treatment modalities for drug overdose.

One last and important note regarding designer drugs is that the identity of clandestine substances

is not always as advertised. For example, tablets sold as MDMA have been found to include other

agents (including MDA, PMA, MBDB, DOB, MDE, methamphetamine, and 5-OMe DIPT) in addition to

MDMA, or instead of MDMA (Cheng et al. 2006; Tanner-Smith 2006). When the identity of an

ingested substance is unknown, this creates a significant problem not only from a toxicity and

treatment standpoint, but it also confounds self-reports of the pharmacological effects and

effective dosages of street drugs.

CONCLUSION

Hallucinogens/psychotomimetics represent a diverse group of agents that are perhaps best

understood by subdividing them into several categories (e.g., PCP-like psychotomimetics,

cannabinoids, cholinergic hallucinogens, classical or serotonergic hallucinogens). The agents that

generally come to mind when one hears the term hallucinogen, such as LSD and mescaline, are

categorized as classical hallucinogens. Even though the agents in this latter class do not necessarily

produce identical effects, they do seem to produce a common effect that represents the activation

of 5-HT2A receptors in the brain. Structural modification of these agents modulates their potency

and action. That is, certain structurally related designer drugs produce hallucinogenic, central

stimulant, and/or other actions, depending upon their pendant substituents, and the effects of

these phenylalkylamines and indolealkyamines should be considered when addressing or treating

hallucinogen abuse.

KEY POINTS

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 structuresPrint: Chapter 13. Neurobiology of Hallucinogens http://www.psychiatryonline.com/popup.aspx?aID=347181&print=yes…

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determine what effect(s) the agent produces.

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