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LSD-25 W, Ai-d i m eth y I try pta m I n e Mescaline

Hallucinogens. Fig. 1. The structures of the natural neurotransmitter serotonin, and the hallucinogens, psilocin, psilocybin, LSD-25, DMT, and mescaline. The chemical similarity between serotonin, psilocin, and LSD is the underlying basis for the interaction between tryptamines and serotonin receptors.

phenyl ring separated by two carbon atoms from a basic amino group.

The second major class of hallucinogens is comprised of the ► tryptamines, represented by DMT and psilocy-bin, also shown in Fig. 1. The natural neurotransmitter

► serotonin is a tryptamine, and is shown for comparison. Although structurally more complex, close examination reveals that LSD (LSD-25) also contains a tryptamine fragment within its structure; thus it can be considered to be a special case of a tryptamine.

Popularity of these substances began to increase dramatically in the early 1960s, when LSD became easily available and inexpensive. This story began in 1943, when Swiss natural product chemist Albert Hofmann, working at the Sandoz laboratories in Basel, Switzerland, accidentally discovered the very powerful hallucinogenic effects of a semi-synthetic ► ergot derivative he had first prepared in 1938. This substance, lysergic acid-N, N-diethylamide, became known as LSD (or LSD-25), or simply "acid." The extremely potent effects of LSD were manifest following oral doses as low as 25-50 mg. Sandoz initially made LSD available to psychologists and clinical investigators in the belief that it produced a model psychosis, so that psychiatrists might gain insight into the nature of mental illness, although it is now recognized that the effects of LSD have distinct differences from the symptoms of ► schizophrenia.

It should be noted that the discovery of LSD preceded only by a few years the isolation and identification of the neurotransmitter ► serotonin from gut tissue, and its subsequent detection in mammalian brain. It was quickly observed that LSD incorporated a tryptamine moiety in its structure, which also was the essential core template of serotonin itself. The relative temporal conjunction of these two events catalyzed an intense research focus on the role of serotonin in the brain and its involvement in brain functioning. That interest by the neuroscience community continues to the present time and has led to several new types of therapeutics, including the SSRI class of

antidepressants, and treatments for migraine headache, among others. It is rarely appreciated that the discovery of LSD had such a direct and profound effect on the neurosciences.

Following his discovery of LSD, Dr. Albert Hofmann then studied a number of natural plant materials that were employed in religious rituals by South American Indians. The first of these was the mushroom Psilo-cybe Mexicana ("teonanacatl," or flesh of the gods), which had been used by the Aztecs. He was able to isolate and characterize the active principle, a substituted tryptamine derivative that he named psilocybin. A minor product in this mushroom is the non-phosphorylated molecule, known as psilocin. It is now known that psilocybin is hydrolyzed by phosphatases after ingestion, and that psi-locin is the active hallucinogenic substance.

Dr. Hofmann then proceeded to isolate and identify the active principle in Ololuiqui, obtained from the seeds of a species of morning glory also employed by the Aztecs. In that case the active substance surprisingly proved to be lysergic acid amide, a molecule chemically very closely related to LSD.

These substances largely remained academic curiosities until the 1960s, when Harvard psychology professor Timothy Leary began to promote and encourage the widespread use of LSD, particularly among the college age population with his mantra, "turn on, tune in, drop out.'' A strong governmental and law enforcement response resulted, and interest in these substances among scientists and clinicians fell off for many decades as a result of increased restrictions on their availability and use, as well as a sort of widespread social taboo that discouraged their further exploration. In addition, government funding agencies were no longer interested in supporting work on these substances unless it was related to understanding their abuse properties. These factors all came into a confluence that stifled research on hallucinogens for nearly four decades. Fortunately, that situation has slowly begun to improve, and there are now several clinical studies underway in the USA and elsewhere that are assessing the medical value of hallucinogens in carefully controlled settings.

Mechanisms of Action

Very early animal studies of LSD demonstrated that it markedly affected brain serotonin systems. Indeed, the fact that LSD incorporated a tryptamine fragment within its structure reinforced early experimental results indicating an effect on brain serotonin systems. There was much initial debate as to whether LSD "blocked" serotonin systems, or enhanced the activity of serotonin systems, and it took about 30 years before a consensus emerged that LSD, and other hallucinogens, acted as agonists or partial agonists at serotonin receptors. At the present time there is a scientific consensus that hallucinogens have, as their primary site of action, agonist activity at cortical serotonin receptors of the 5-HT2A subtype (Nichols 2004). Although numerous animal behavioral studies had strongly supported that conclusion, the definitive study was carried out by Franz Vollenweider, where pre-administration of the serotonin ► 5-HT2A receptor antagonist ketanserin was able to block the hallucinogenic effects of psilocybin in man (Vollenweider et al. 1998). ► PET studies also have demonstrated that hallucinogens produce a global increase in rate of cerebral glucose metabolism with significant and most marked increases in the frontomedial and frontolateral cortex, temporome-dial and anterior cingulate cortex, and a somewhat lesser response in the basal ganglia.

Although the 5-HT2a receptor appears to be the essential target for hallucinogens, it may not provide the entire explanation for their pharmacology. That is, activation of this receptor maybe a necessary, but not sufficient action to understand all of their effects. For example, the phenethylamine-type of hallucinogens have nearly comparable affinity and efficacy at both the 5-HT2A and 5-HT2C receptor types, and there has been no drug available that is a specific agonist only for the 5-HT2A receptor. The tryptamines and LSD present a similar pharmacological profile with respect to these two receptor subtypes, but in addition also have high affinity and efficacy at the serotonin 5-HT1A receptor subtype. Activation of this receptor in the brainstem raphe nuclei suppresses their firing, which would have profound consequences for serotonin tone throughout the brain. These receptors also are expressed at high density in regions of the limbic system, and one would expect activation of the receptors in these brain areas also to have behavioral consequences. Nevertheless, a contribution of the 5-HT1A receptor to the psycho-pharmacology of tryptamine hallucinogens has not been elucidated.

LSD presents the most complex pharmacology of all of the known hallucinogens, and its effects may not be simply explained by a serotonergic mechanism. In addition to its high affinity and efficacy at the 5-HT2A, 5-HT2C, and 5-HT1A receptors, it acts at a variety of additional serotonin receptors. It also has activity at alpha-2 adrenergic receptors, as well as dopamine receptors, particularly the D2-like family of dopamine receptors. It is presently unclear, how, or if, any of these other interactions might account for the unique psychopharmacology and potency of LSD.

Interestingly, the pioneer LSD researcher Dr. Daniel X. Freedman described the psychopharmacological effects of LSD in man as occurring in two temporal phases. The initial phase was considered psychedelic and euphoric, whereas after this initial phase, the effects of LSD in many subjects resembled paranoid psychosis, with ideas of reference and paranoid ideation. Temporally dependent pharmacology has not been reported for any of the other hallucinogens. Recent studies in rats have shown that the effects of LSD in rats also occur in two temporal phases. Nevertheless, there is good evidence that LSD does activate brain dopamine systems, and this action of LSD may be relevant to its human psychopharmacology (Marona-Lewicka et al. 2008). In particular, there is some evidence that the dopamine D4 receptor may play a role in the action of LSD, at least in rat behavior models (Marona-Lewicka et al. 2008).

Recent studies also have pointed to a role of ► glutamate in the action of hallucinogens. Administration of hallucinogens to rats or mice leads to increased extracellular levels of glutamate (Benneyworth et al. 2007).

Animal Models

The most useful and widely employed animal model for studying hallucinogens is the ► drug discrimination paradigm, an operant procedure that has been used in rats, mice, monkeys and pigeons. This method is very sensitive, so that doses of drugs can be used that do not produce overt behavioral effects. Typically, rats (or mice) are trained in a two-lever operant chamber using positive reinforcement, to discriminate between injections of saline and a particular drug, such as LSD. Animals are taught to associate one lever with the saline injection, and the other with the injection of the "training drug,'' e.g., LSD. Emitting a response on the appropriate lever results in reinforcement. Over a period of 2-3 months rats reliably learn this discrimination task so that administration of either saline or the drug results in a preponderance of lever pressing responses only on the lever associated with that treatment condition. Various treatments can then be employed in attempts to antagonize the response, or drugs can be administered that are thought to have a similar pharmacology, so that conclusions can be drawn about the mechanism of action. In the absence of human clinical trials, this method has been used to predict whether a novel molecule may have hallucinogenic effects in man.

Hallucinogens do not produce many other behavioral responses in animal models that are particularly useful. They generally do not affect locomotor activity per se, except at high doses, although they may alter patterns of locomotor and exploratory activity in rodents. They are not self-administered, and are not considered to be reinforcing. Hallucinogens do disrupt ► prepulse inhibition (PPI), which is based on the finding that a weak prepulse reduces the startle reflex to a given, usually acoustic, stimulus.

Pharmacokinetics

Most of the hallucinogens are well absorbed. LSD, mescaline, and psilocybin are all active after oral

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