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 A. L. Halberstadt / Behavioural Brain Research xxx (2014) xxx-xxx 13 scenes, objects, and people (see Fig. 5). The visual imagery induced by hallucinogens is extremely vivid and can be observed with the eyes open or closed. When scientists began to experiment with mescaline at the end of the nineteenth century almost all of their work focused on the visual phenomenology [387-392]. Despite its highly subjective nature, the drug-induced imagery has been characterized in great detail [393,394]. Heinrich Klüver [393] was the ﬁrst to recognize that all of the elementary geometric hallu-cinations induced by mescaline are elaborated variations of four basic forms, which he called form constants : (a) tunnels and fun-nels, (b) spirals, (c) lattices and checkerboards, and (d) cobwebs. The form constants are not unique to hallucinogens and can occur during a variety of hallucinatory states, including migraine aura [395], epilepsy (Horowitz et al., 1967), sensory isolation [396], viewing ﬂickering light [397,398], and electrical cortical stimula-tion [399,400]. Several theoretical explanations for geometric visual halluci-nations have been proposed based on retinocortical mapping and the architecture of V1 [401-405]. According to these mathemat-ical models, excitation of V1 neurons produces self-organizing patterns of activity that correspond to Klüver's form constants. The excitation of V1 is presumably driven by 5-HT 2Areceptors because ketanserin blocks the visual hallucinations induced by psilocybin [85,89]. There are moderate to high densities of 5-HT2Areceptors in V1 [349,350,353,406], with the highest level occurring in geniculorecipient sublayer IVc/H9252 [350]. Similar to other cortical regions, almost all glutamatergic pyramidal neu-rons and very few GABAergic interneurons in V1 express 5-HT 2A m RNA [407,408]. A recent electrophysiology study conducted in anesthetized macaque monkeys revealed that DOI produces a com-bination of excitatory and inhibitory effects in V1, exciting neurons with low ﬁring rates and inhibiting neurons with high ﬁring rates [407]. Since neuronal ﬁring in V1 is driven by visual stimuli, one possible interpretation is that DOI reduces the response to visual input while enhancing spontaneous internally driven activity. It is fairly well-established that hallucinogens reduce retinocortical transmission [409-411]. Indeed, psilocybin inhibits N170 visu-ally evoked potentials in human subjects via 5-HT 2A[89,412]. Visual input stabilizes network activity in V1 by driving inhibitory interneurons [413]. Therefore, a reduction of visual input, cou-pled with an increase in the excitability of pyramidal neurons, could destabilize network activity in area V1, generating patterns of neuronal ﬁring that are perceived as geometric form con-stants. In contrast to the elementary visual hallucinations, which are linked to area V1, complex visual hallucinations probably arise from 5-HT 2Aactivation in higher level visual areas. There is evi-dence that excitation of Brodmann area (BA) 19 and BA 37 can produce complex visual hallucinations [414-416]. Among patients with Parkinson's disease, approximately 22% experience complex visual hallucinations [417]. Their visual hallucinations are linked to elevated levels of 5-HT 2Areceptor binding in ventral visual pathway [418,419], and can be ameliorated by blocking 5-HT 2Areceptors. For example, a PET imaging study with [18F]setoperone found that visual hallucinations in Parkinson's patients are associated with unusually high levels of 5-HT 2Abinding in the inferooc-cipital gyrus (BA 19), fusiform gyrus (BA 20 and BA 37), and inferotemporal gyrus (BA 20) [418]. According to another study conducted post-mortem, Parkinson's patients with visual halluci-nations show elevated levels of 5-HT 2Abinding in the inferolateral temporal cortex (BA 21) [419]. Two clinical trials have shown that the selective 5-HT 2Ainverse agonist pimavanserin reduces the severity of hallucinations in Parkinson's disease [420,421]. The atypical antipsychotics clozapine and risperidone, which block the 5-HT 2Areceptor, are also effective against the visual hallucinations [422-424]. 6. Summary Despite the complexity of hallucinogen effects, we are beginning to understand how these substances work in the brain. The 5-HT 2A receptor was ﬁrst identiﬁed about thirty years ago as a possible site of action of hallucinogens. It is now clear that most of the effects of hallucinogens are mediated by 5-HT 2Aactivation. Although the vast majority of this evidence was derived from studies in animals, the resumption of human studies with hallucinogens has provided additional support. Recent clinical trials have provided a highly detailed charac-terization of hallucinogen effects. However, most of this work has focused on one hallucinogen (psilocybin). By comparison, very lit-tle is known about the effects of other agents. This is especially true for ergoline and phenylalkylamine hallucinogens. One of the most characteristic properties of hallucinogens is how unpredictable their effects can be. The exact nature of the experience is highly variable and depends on the mood and expectations of the subject (the “set”) as well as the environment in which the drug is ingested (the “setting”) (Bercel et al., 1955) [425-427]. Depending on the cir-cumstances, the effects of hallucinogens may be perceived as being highly pleasurable or highly aversive (e. g., Aldous Huxley's descrip-tion of mescaline as “heaven and hell”). Although hallucinogens act in a relatively unspeciﬁc manner [428], and hence a broad range of experiences are possible, previous clinical studies have conﬁrmed that there is also a great deal of similarity between the effects of different hallucinogens. In other words, although it is impossible to predict exactly what type of experience will be produced by, for example, LSD or psilocybin, it appears that for the most part any experience produced by LSD can also occur with psilocybin. Thus, volunteers could not identify any clear differences between the subjective effects of those two compounds when administered by blind dosing [37-39,41]. However, those studies need to be repeated using modern psychometric assessment methods. Addi-tionally, it is not clear to what extent those ﬁndings extend to other hallucinogens, or even to higher doses of LSD and psilocybin. One potentially unique aspect of the LSD experience is that it reportedly occurs in two distinct temporal phases [206,427,429,430], but this needs to be conﬁrmed by future investigations. It appears that 5-HT 2Aactivation is a common characteristic of serotonergic hallucinogens and is responsible for mediating their shared effects, but this does not eliminate the possibility that other receptors may play an ancillary role. There are pharmaco-logical differences between the phenalkylamine, tryptamine, and ergoline classes, as well as between speciﬁc compounds within each class, and these differences could potentially inﬂuence the subjective effects [20]. The receptors activated by hallucinogens may be analogous to individual musical notes that can be played in combination to generate chords associated with unique subjective impressions [431], with 5-HT 2Areceptor activation being akin to the root note. Extramural investigations have attempted to categorize the existence of subtle subjective differences between the effects of different hallucinogens (e. g., [432,433] ). However, it is not clear to what extent the apparent differences between individual compounds are inﬂuenced by expectation and by other factors. There are also dose- and route-dependent variations in the effects of hallucinogens, which can alter both the intensity and the qualitative nature of the response. Furthermore, even individual subjects may experience markedly different responses to the same drug on different occasions [434]. The possibility exists that for hallucinogen effects, there may be just as much intra-drug variabil-ity as there is inter-drug variability. Only detailed, well-controlled clinical trials comparing multiple compounds over a wide range of doses will answer these questions. Nevertheless, it seems to be fairly well established that there are marked qualitative differences between the effects produced by serotonergic hallucinogens and by1075 10761077107810791080108110821083108410851086108710881089109010911092109310941095109610971098109911001101110211031104110511061107110811091110111111121113111411151116111711181119112011211122112311241125112611271128112911301131113211331134113511361137113811391140 1141 114211431144114511461147114811491150115111521153115411551156115711581159116011611162116311641165116611671168116911701171117211731174117511761177117811791180118111821183118411851186118711881189119011911192119311941195119611971198119912001201120212031204