Please cite this article in press as: Halberstadt AL. Recent advances in the neuropsychopharmacology of serotonergic hallucinogens. Behav Brain Res (2014), http://dx. doi. org/10. 1016/j. bbr. 2014. 07. 016ARTICLE IN PRESSG Model BBR 9035 1-22 Behavioural Brain Research xxx (2014) xxx-xxx Contents lists available at Science Direct Behavioural Brain Research jou rn al hom epage: www. elsevier. com/locate/bbr Research report Recent advances in the neuropsychopharmacology of serotonergic hallucinogens Adam L. Halberstadt∗Q1 Department of Psychiatry, University of California San Diego, La Jolla, CA, United States h i g h l i g h t s Serotonergic hallucinogens are classiﬁed as phenylalkylamines and indoleamines. The two classes of hallucinogens produce similar subjective effects in humans and show cross-tolerance. Hallucinogen effects are primarily mediated by the serotonin 5-HT2A receptor. Many effects of hallucinogens are mediated in the prefrontal cortex. a r t i c l e i n f o Article history: Received 18 April 2014 Received in revised form 7 July 2014 Accepted 8 July 2014 Available online xxx Keywords:Psychedelic5-HT2A receptor Head twitch Prefrontal cortex Visual effectsa b s t r a c t Serotonergic hallucinogens, such as (+)-lysergic acid diethylamide, psilocybin, and mescaline, are some-what enigmatic substances. Although these drugs are derived from multiple chemical families, they all produce remarkably similar effects in animals and humans, and they show cross-tolerance. This article reviews the evidence demonstrating the serotonin 5-HT 2Areceptor is the primary site of hallucinogen action. The 5-HT 2Areceptor is responsible for mediating the effects of hallucinogens in human subjects, as well as in animal behavioral paradigms such as drug discrimination, head twitch response, prepulse inhibition of startle, exploratory behavior, and interval timing. Many recent clinical trials have yielded important new ﬁndings regarding the psychopharmacology of these substances. Furthermore, the use of modern imaging and electrophysiological techniques is beginning to help unravel how hallucinogens work in the brain. Evidence is also emerging that hallucinogens may possess therapeutic efﬁcacy. © 2014 Published by Elsevier B. V. 1. Introduction Hallucinogenic drugs have been used by humans for thousands of years, but western scientists only became interested in these substances beginning in the late 1800s. These agents produce pro-found changes in consciousness. Because other drug classes can sometimes produce effects that overlap with those of the hallu-cinogens, it has been important to develop a formal deﬁnition for these compounds. This has turned out to be a difﬁcult and con-tentious task. Hallucinogens have been deﬁned as agents that alter thought, perception, and mood without producing memory impair-ment, delirium, or addiction [1,2]. However, this deﬁnition is overly broad because it fails to exclude a wide-range of agents that are generally not classiﬁed as hallucinogens, such as cannabinoids and NMDA antagonists. It is now recognized that hallucinogens produce ∗Correspondence to: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0804, United States. Tel. : +1 619 471 0525. E-mail addresses: ahalberstadt@ucsd. edu, ahalbers@ucsd. edusimilar discriminative stimulus effects [3] and act as agonists of the serotonin-2A (5-HT 2A) receptor [4]. Therefore, it has been proposed [5] that in addition to having the characteristics listed above, hal-lucinogens should also bind to the 5-HT 2Areceptor and produce full substitution in animals trained to discriminate the prototyp-ical hallucinogen 2,5-dimethoxy-4-methylamphetamine (DOM). For this reason, hallucinogens are often categorized as classical hal-lucinogens or serotonergic hallucinogens. This article will review the pharmacology of hallucinogens, including their mechanism-of-action, their effects in animals and humans, and recent ﬁndings regarding how they interact with speciﬁc brain regions. 2. Pharmacology of hallucinogens 2. 1. Receptor interactions Classical hallucinogens can be divided into two main struc-tural classes: indoleamines and phenylalkylamines [6]. Indoleamines include the tetracyclic ergoline (+)-lysergic acid diethylamide (LSD) http://dx. doi. org/10. 1016/j. bbr. 2014. 07. 016 0166-4328/© 2014 Published by Elsevier B. V. 1 2 3 4 5 6 7 8 9101112 13 14 15 1617181920 21 22232425262728 29 30 31323334353637383940414243 44454647484950515253 54 55 56 5758