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 4 A. L. Halberstadt / Behavioural Brain Research xxx (2014) xxx-xxx Fig. 4. Signaling pathways coupled to the 5-HT 2Areceptor. Abbreviations : AA, arachidonic acid; 2-AG, 2-arachidonoylglycerol; ARF, ADP-ribosylation factor-1; DAG, diacyl-glycerol; DGL, diacylglycerol lipase; ERK1/2, extracellular-regulated kinases 1 and 2; GRB, growth factor receptor-bound protein 2; IP3, inositol triphosphate; p38 MAPK, p38 mitogen-activated protein kinase; MEK1/2, mitogen/extracellular signal-regulated kinases 1 and 2; MKK3/6, MAPK kinases 3and 6; MKK4, MAPK kinase 4; MEKK, MAPK kinase kinase; PA, phosphatidic acid; PC, phosphatidyl choline; PIP 2, phosphatidylinositol 4,5-biphosphate; PKC, protein kinase C; PKN, protein kinase N; PL, phospholipids; PLC/H9252, phospholipase C/H9252; PLD, phospholipase D; SHC, Src homology 2 domain containing transforming factor; SOS, son of sevenless homolog. and the VR dimension involves elementary and complex visual hallucinations and perceptual illusions (see Table 1). Mescaline, psilocybin, and DMT produce profound increases in OB, AED and VR scores [52-56]. Another instrument is the Hallucinogen Rat-ing Scale (HRS), which was speciﬁcally designed to measure the effects of parenteral DMT [57] Double-blind studies have conﬁrmed the APZ and the HRS can distinguish the effects of psilocybin and mescaline from those of (+)-methamphetamine, methylphenidate, and 3,4-methylenedioxyethylamphetamine [53,55,58]. Ayahuasca also elicited signiﬁcantly greater effects than (+)-amphetamine on 4 of 6 subscales of the HRS [48]. A double-blind crossover study comparing DMT and the NMDA antagonist (S)-ketamine found DMT produces effects that more closely resemble the positive symptoms of schizophrenia, whereas the effects of (S)-ketamine are more similar to the negative and catatonic symptoms of schizophrenia [59]. Subjects experienced vivid visual hallucinations after treatment with DMT but not with (S)-ketamine; this difference was reﬂected by scores in the VR dimension of the APZ-OAV, which was more strongly affected by DMT than by (S)-ketamine. Another notable difference between Table 1 Core dimensions of the APZ [52]. Dimension Symptoms assessed Oceanic Boundlessness (OB) Positive derealization Positive depersonalization Altered sense of time Positive mood Mania-like experience Anxious Ego Dissolution (AED) Anxious derealization Thought disorder Delusion Fear of loss of control Visionary Restructuralization (VR) Elementary hallucinations Visual pseudohallucinations Synesthesia Changed meaning of percepts Facilitated recollection Facilitated imaginationketamine and serotonergic hallucinogens is that ketamine does not produce mystical experiences [60], whereas hallucinogens induce these states with some reliability [58,61-64]. Vollenweider and colleagues have conducted a psycho-metric assessment of APZ-OAV data pooled from 43 studies with psilocybin, (S)-ketamine, and the entactogen 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) [65]. Examination of the factorial structure of the APZ-OAV revealed the OB, AED and VR scales are multidimensional, and Vollenweider et al. were able to extract 11 new homogenous APZ-OAV scales that are very effective at differentiating the subjective effects of psilocybin, (S)-ketamine, and MDMA. There are clear differences in the relative magnitude of drug effects on several of the new scales; for example MDMA has strong effects on blissful state, (S)-ketamine produces the largest increase in disembodiment, and complex imagery and elementary imagery are most strongly inﬂuenced by psilocybin Fig. 5 compares the effects of psilocybin and placebo on the new homogeneous APZ-OAV subscales. In summary, even though there are some similarities between the subjective effects of serotonergic hallucinogens, NMDA antago-nists, psychostimulants, and entactogens, the effects produced by the latter three drug classes are clearly distinct from those elicited by classical hallucinogenic drugs. 3. 2. Tolerance and cross-tolerance Tachyphylaxis (tolerance) develops rapidly to the effects of classical hallucinogens. If LSD and DOM are administered repeat-edly at daily intervals tolerance is observed after 1-3 days and there is eventually nearly a complete loss of response [66-69]. Tolerance occurs with a variety of phenylalkylamine, indolealky-lamine, and ergoline hallucinogens, and compounds from these classes exhibit symmetrical cross-tolerance [37,41,42,68,70-72]. Importantly, cross-tolerance does not occur between LSD and (1) (+)-amphetamine [46], (2) the anticholinergic N-methyl-3-piperidyl benzilate [73], or (3) /Delta19-tetrahydrocannabinol [47]. Similar ﬁndings have been reported by parallel studies in laboratory animals [74-79]. The fact that serotonergic hallucinogens produce202 203204205206207208209210211212213214215216217218219220221222 223224225226227228229230231232233234235236237238239240241242243244 245 246 247248249250251252253254255256257