108 PSYCHEDELIC DRUGS HENRY DAVID ABRAHAM UNA D. MCCANN GEORGE A. RICAURTE As defined in this chapter, the term psychedelic drugs includes 14.1%, and 7.2% of Danes reported the use of hallucino- both classic hallucinogens [i.e., indolalkylamines and phe- genic mushrooms (3). nylalkylamines, such as lysergic acid diethylamide (LSD) and In the United States, a survey of 633 undergraduates mescaline, respectively], ‘‘dissociative’’ drugs [i.e., arylcyclo- found that 23.8% had experimented with hallucinogenic hexamines, such as phencyclidine (PCP) and ketamine], and mushrooms, and 16.3% had had experience with LSD. substituted amphetamine analogues [i.e., phenylpropano- Among LSD users, 6.6% reported problems associated with lamines, such as 3,4-methylenedioxymethamphetamine LSD (Abraham and Koob, unpublished data). Of this group, (MDMA, ‘‘ecstasy’’)]. The use of psychedelic drugs dates 46.9% reported symptoms of hallucinogen persisting per- from the dawn of recorded history and continues today. ception disorder (HPPD), 37.5% described alcohol depen- Indeed, in Western culture, their use appears to be on the dence, 25% major depression, 18.8% persisting delusions, rise. Despite the longstanding popularity of psychedelic 15.6% panic attacks, and 12.5% auditory hallucinations. drugs, controlled research evaluating their effects in humans LSD use is most likely to occur between the ages of 18 and has been surprisingly scant, and data from preclinical studies 25. Use is more common in male Caucasians and Hispanics. have been largely limited to the last several decades. This Of note is that although the parents of LSD users tend to chapter reviews preclinical and clinical research involving be of a higher socioeconomic status, the users themselves indolalkylamines, arylcyclohexamines, and substituted am- exhibit an inverse relationship between LSD use and educa- phetamines, for which LSD, PCP, and MDMA are used as tional achievement (4). the prototypes, respectively. Significant recent advances are highlighted, and promising areas toward which future re- Early Neurophysiologic Studies search should be directed are identified. Work in the 1950s intimated that hallucinogens simultane- ously activate and depress neural systems in mammals. In INDOLALKYLAMINES 1953, Gaddum (5) reported that LSD antagonizes the ef- fects of serotonin (5-HT). In the visual system, LSD de- Epidemiology creased by 80% the amplitude of the postsynaptic response Surveys in the United States and Western Europe reveal an in the lateral geniculate nucleus of the cat following stimula- increased use of indolalkylamine hallucinogens. For exam- tion of the optic nerve (6). Pentobarbital was found to sensi- ple, trend data in the United States, gathered from 15,000 tize the cells to LSD, and asphyxia transiently overcame high school seniors, showed a rise in prevalence of lifetime the LSD effect. These observations were among the first to hallucinogen use from 6% to 13.7% between 1986 and suggest that in the visual system, LSD is inhibitory, like ␥- 1999 (1,2). Similarly, in Great Britain, the use of LSD rose aminobutyric acid (GABA), and is antagonized by excita- from 7% to 11% between 1989 and 1993. Among German tory amino acids released during hypoxia. drug abusers, the prevalence of LSD use was reported at Neurophysiologic studies in animals and humans indi- cate that hallucinogens produce arousal (7). Multiple EEG studies of LSD in rabbits, cats, and humans have docu- Henry David Abraham: Department of Psychiatry, Harvard Medical mented an increasing shift of alpha frequencies to low volt- School, Cambridge, Massachusetts. age, fast rhythms, and alpha disappearance (8). In studies Una D. McCann: Department of Psychiatry and Behavioral Sciences, of evoked sensory potentials in cats, a low dose of LSD The Johns Hopkins School of Medicine, Baltimore, Maryland. George A. Ricaurte: Department of Neurology, The Johns Hopkins facilitated both auditory and visual primary responses, School of Medicine, Baltimore, Maryland. whereas high doses depressed auditory responses while con- 1546 Neuropsychopharmacology: The Fifth Generation of Progress tinuing to facilitate visual responses (9). Thus, LSD appears in animals was found to correlate with affinity at the 5- to affect the midbrain and cerebral cortex, particularly the HT2 receptor (19). visual cortex, and its effects both stimulate and inhibit, de- pending on the system studied. Chemistry Considerable work has been directed at structure–activity Behavioral Studies relationships of the ergoline hallucinogens (20,21). Substi- A variety of behavioral models in animals have been em- tution at the N(1) position of LSD abolishes activity, as ployed to study psychedelics. The strength of such models does substitution at the C(2) position with a halogen. (R)- over human studies is that ethical concerns are mitigated, stereochemistries are essential at both C(5) and C(8) for experimental controls are more comprehensive, tissue is activity. Reduction of the double bond at the 9,10 position available for in vitro assessment, and genetic studies are pos- abolishes hallucinogenic activity. Hydroxylation of C(13), sible with the use of knockout, mutagenesis, and antisense which may occur in vivo, confers a high level of dopami- nucleotide strategies. The weakness of animal models is that nergic potency on ergolines (21). Most interesting is that they cannot provide a direct, reliable method to determine ethylation of LSD at N(6) enhances potency, as determined if or when an animal is hallucinating. Despite this limita- in both animal and human studies. A monoalkyl amide, a tion, drug discrimination paradigms have been useful in diastereomer of chlorobutyl LSD, is at least 50% more po- establishing comparative benchmarks between LSD, mesca- tent than LSD. In ligand binding at 5-HT2, 5-HT1A, D1, line, and other hallucinogens, associating potency data with and D2 receptors, the (R)-2-butylamide substituent is like- binding at specific receptor types, correlating animal poten- wise more potent. Cloning of the 5-HT-2 receptor permit- cies with human data, and describing structure–activity re- ted replacement of aspartate 120 in second transmembrane lationships (10). Sophisticated behavioral studies by Geyer domain with asparagine. This resulted in a significant de- et al. (11) suggest that LSD disrupts two fundamental mech- crease in affinity for LSD and abolished phosphatidylinosi- anisms of filtering of sensory information, habituation and tol turnover. Additionally, aspartate 155 is required for ago- prepulse inhibition. nist and antagonist binding (22). Second messenger systems in hallucinogen-responsive receptors represent another promising avenue to unraveling the mechanism of halluci- Neuropharmacology nogens. 5-HT2 receptors are coupled to at least three trans- The mechanism of action of the hallucinogens is one of the duction systems: potassium channels, cationic Ih channels, compelling questions in pharmacology, the answer to which and phosphoinositide hydrolysis. The close correlation be- promises insights into the mechanisms of perception, mood, tween hallucinogen affinities for the 5-HT2 and 5-HT1C and psychosis. Early studies of LSD in peripheral tissue receptors raises the possibility that the latter may play an implicated serotoninergic receptors in the mechanism of independent or complementary role in hallucinogenic activ- hallucinogenic activity. Freedman (12) found that LSD de- ity. This is supported by the fact that LSD is an agonist creases brain 5-HT turnover. This effect correlated with at 5-HT1C receptors, as determined by phosphoinositide behavioral changes and the plasma half-life of LSD, was hydrolysis (23). limited to hallucinogens, and was replicated in several spe- cies. Hirschhorn and Winter (13) showed that rats can dis- Recent Neurophysiologic Studies criminate LSD and mescaline from saline solution. Discrim- ination fell in the presence of serotonin antagonists, More recent electrophysiologic studies of hallucinogens in supporting a 5-HT-agonist mechanism for the action of animal models support the involvement of postsynaptic 5- hallucinogens. HT2 and 5-HT1C receptors in hallucinogen activity. The In intracellular recordings from serotoninergic dorsal locus ceruleus, considered a sensory novelty detector in the raphe neurons of the rat brain in vivo, LSD directly inhib- pons, projects widely throughout the brain. Hallucinogens ited firing, but other hallucinogens did not (14). In 1979, indirectly decrease spontaneous activity in the locus ceruleus it was shown that the effects of LSD on cat behavior are by activating GABAA inputs, and they enhance sensory re- dissociated from raphe responses and involve postsynaptic sponses of the locus ceruleus by activating excitatory inputs serotonin activity (15). The same year, Peroutka and Snyder via N-methyl-D-aspartate (NMDA) receptors (24). 5- (16) reported the discovery of multiple serotonin receptor HT2A-receptor antagonists block these effects. In rat piri- types. A high density of 5-HT1A autoreceptors was found form cortex, both 5-HT and hallucinogens at 5-HT2A re- on raphe neurons, which explained the direct inhibition of ceptors excite GABAergic interneurons, which then induce this system by LSD (17). Based on the ability of receptor inhibitory postsynaptic potentials (25). In prefrontal cortex, antagonists to block hallucinogen discrimination in ani- the opposite occurs, where the drugs release glutamate and mals, it was proposed that hallucinogens