This study (2015) reviews the evidence on the neuropsychopharmacology of such substances as LSD, psilocybin, and mescaline.
Abstract
“Serotonergic hallucinogens, such as (+)-lysergic acid diethylamide, psilocybin, and mescaline, are somewhat 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-HT2A receptor is the primary site of hallucinogen action. The 5-HT2A receptor 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.”
Author: Adam L. Halberstadt
Summary
Hallucinogens enhance the frequency of spontaneous EPSCs and IPSCs in layer V pyramidal neurons by enhancing recurrent glutamatergic and GABAergic network activity.
The serotonin2A receptor activates phospholipase A2 through a complex signaling cascade that involves MAP kinases and arrestin2/Src/Akt. Hallucinogens activate the 5-HT2A receptor through a C-terminal tail. Rabin RA, Regina M, Doat M, Winter JC, Kurrasch-Orbaugh DM, Watts VJ, Barker EL, Nichols DE, Garcia EE, Smith RL, Sanders-Bush E, Gq protein, Serotonin 2A receptor signaling, and -arrestin-2 interactions. Isbell H, Wolbach AB, Miner EJ, Logan CR, Hollister LE, Rosenberg DE, Isbell H, Miner EJ, Isbell H., and Wolbach AB, Isbell H., et al., compared the effects of psilocybin, mescaline, and LSD-25 on human subjects. A comparison of LSD-25 with ()-9-trans-tetrahydrocannabinol (THC) and attempted cross tolerance between LSD and THC was performed by Rosenberg DE, Wolbach AB, Miner EJ, Isbell H. Ayahuasca, Salvia divinorum, and d-methamphetamine have similar psychoactive effects in humans, and the standardized psychometric assessment of altered states of consciousness (APZ) is a valid tool for assessing abnormal mental states.
Using psilocybin to investigate the relationship between attention, working memory, and the serotonin 1A and 2A receptors in humans. Psilocybin induces visual hallucinations, positive bias in facial recognition, and goal-directed behavior through serotonergic subreceptors. Psilocybin induces deficits in automatic and controlled inhibition in healthy human volunteers, which are attenuated by ketanserin. Serotonin and schizophrenia are also discussed, as well as the discriminative stimulus properties of DOM and DOI. DPT, a substituted tryptamine, has hallucinogen-like effects in rodents and may be mediated by serotonin 5-HT1A and 5-HT2A receptors. Appel JB, Cunningham KA, Colpaert FC, Niemegeers GJE, Janssen PAJ, et al. used drug discrimination procedures to characterize hallucinogenic drug actions, and Appel JB, Cunningham KA, Smith RL, Barrett RJ, Sanders-Bush E, studied the effects of AL-38022A on the discriminative stimulus properties of LSD. Eckler JR, Rabin RA, Winter JC, Marona-Lewicka D, Thisted RA, Nichols DE. LSD induces distinct temporal phases in the behavioral pharmacology of dopamine D2 receptor-mediated inhibition.
LSD and DOI induce discriminative stimulus properties in the rat anterior cingulate cortex, which are mediated by 5-Hydroxytryptamine (serotonin)2A receptors. These effects are different from the effects of LSD induced by phenethylamine hallucinogens. LSD, 5-HT (serotonin), and the evolution of a behavioral assay. Psychopharmacology (Berl) 2005;182:197 – 204. LSD and lisuride are agonists of dopamine D3 receptors, but not of 5-HT2A receptors, and lisuride’s behavioral effects overlap with those of 5-HT2A receptors, but not with those of 5HT2C receptors. Agonist-directed trafficking of signaling at serotonin 5-HT2A, 5-HT2B and 5-HT2CVSV receptors mediated calcium mobilisation and Gq/11 activation in CHO cells. Lisuride is effective in the treatment of acromegaly, pathological hyperprolactinemic states, cluster headache, Restless Legs Syndrome, and depression. It also increases the selectivity of drug discrimination procedures.
(+)-Lysergic acid diethylamide and lisuride can induce hallucinations in mice, and the head twitch response produced by 5-methoxy-N1,N1-dimethyltryptamine and p-chloroamphetamine can be used to study the effects of drugs on the central actions of 5-hydroxytryptamine. The head twitch response is induced by hallucinogens such as 2,5-dimethoxy-4-(n)-propylthiophenethylamine (2C-T-7) and superpotent N-benzyl derivatives. PET imaging studies have shown that the 5-HT2A receptor agonist [11 C]Cimbi-36 is safe for use in humans. Ketanserin, a selective 3 H-ligand for serotonin2 receptor binding sites, is a neurotransmitter that induces head-twitches in the rat. The head-shakes are mediated by 5-HT2A receptors and are modulated by novel 5-HT2A/2C antagonists, D1 antagonists and 5-HT1A agonists. Keiser MJ, Setola V, Irwin JJ, Laggner C, Abbas AI, Hufeisen SJ, et al. predicted new molecular targets for known drugs. Halberstadt AL, Koedood L, Powell SB, Geyer MA.
SB 200646A, a 5-HT2C/2B receptor antagonist, has been shown to be selective for 5-HT2C receptors in animal models of antipsychotic activity. This study also showed that 5-HT2C receptors are involved in the control of head-twitch behavior. Serotonin 2C receptor RNA editing in the amygdala of C57BL/6J, DBA/2J, and BALB/cJ mice and effects of 5-HT2A receptor antagonists on prepulse inhibition of the startle response in rats. Mescaline affects rat behavior and brain tissue after a single subcutaneous dose. It also affects 5-HT2A and not 5-HT2C receptors. Varty GB, Higgins GA, Serko A, Hoch P, Cattell JP, Pennes HH. Mescaline and lysergic acid (d-LSD-25) induce disruptions of prepulse inhibition as models to screen antipsychotic drugs. Aronson H, Silverstein AB, Klee GD, Wittmann M, Carter O, Hasler F, Cahn BR, Grimberg U, Spring P, et al. Investigated the effects of lysergic acid diethylamide (LSD-25) on subjective time perception and temporal control of behaviour in humans.
In this article we review the literature on the effects of 5-HT2A receptor stimulation on the discrimination of durations by rats, the effects of 2,5-dimethoxy-4-iodoamphetamine and d-amphetamine on the ability of rats to discriminate the durations and intensities of light stimuli, and the effects of DOM on patterns of exploration. LSD, apomorphine, amphetamine, dizocilpine, phencyclidine, Geyer MA, Adams LM, Geyer MA, Ruiz EM, Masten V, Buell M, Geyer MA, Serotonin release contributes to the locomotor stimulant effects of 3,4-methylenedioxymethamphetamine in rats. Krebs-Thomson K, Paulus MP, Geyer MA. 5-HT2A and 5-HT2C receptors play a role in the locomotor-suppressive effects of LSD. Halberstadt AL, Buell MR, Masten VL, Risbrough VB, Geyer MA, et al. 5-HT2A and 5-HT2C receptors exert opposing effects on locomotor activity in mice. [216] Tanaka S, Young JW, Halberstadt AL, Masten VL, Geyer MA, et al. Van den Buuse M, Ruimschotel E, Martin S, Risbrough VB, Halberstadt AL. 5-HT1A receptor knockout mice show enhanced effects of amphetamine but reduced effects of the hallucinogen, 5-MeO-DMT, on locomotor activity.
A study found that people with schizophrenia had reduced serotonin-2A receptor signaling in the locus coeruleus, which was associated with behavioral tolerance to lysergic acid diethylamide. 5-hydroxytryptamine2 ( 5-HT2) agonists augment noradrenergic locus coeruleus neuronal firing activity and decrease noradrenaline release in the rat hippocampus. Serotonin 5-HT2A receptors are distributed in the central nervous system of adult rats and are involved in the regulation of noradrenergic coerulean neuronal firing. The prepositus hypoglossil nucleus is a major afferent nucleus of the locus coeruleus. The medial prefrontal cortex has a topographical organization of efferent projections, and excitatory amino acid inputs activate noradrenergic locus coeruleus neurons. The 5-HT2A receptor is localized in layer V pyramidal cells of the medial prefrontal cortex. In the rat prefrontal cortex, 5-HT2A serotonin receptors are expressed on pyramidal cells and interneurons, and may be the site of action of hallucinogenic and antipsychotic drugs in pyramidal cell apical dendrites.
5-HT2A and 5-HT1A receptors mediate opposing responses on membrane excitability in the rat association cortex. 5-HT2A, 2C receptor agonist DOB modulates NMDA-evoked responses in the rat medial prefrontal cortex. Serotonin regulates calcium-activated potassium currents in the prefrontal cortex via a phosphatidylinositol 4,5-bisphosphate-dependent mechanism. This mechanism is involved in the regulation of slow afterhyperpolarization currents in the cerebral cortex. Aghajanian GK, Marek GJ, Klodzinska A, Bijak M, Tokarski K, Pilc A. Serotonin induces excitatory postsynaptic potentials in neocortical pyramidal cells and mGlu receptor-mediated pre-frontal cortical excitatory synaptic currents and DOI-induced head shakes. In the nigrostriatal pathway, 5-HT2A receptors modulate anxiety-like behaviors in mice, and in the prefrontal cortex, 5-HT2A receptors modulate synaptic activity in medial prefrontal cortex and increase extracellular glutamate levels.
Extracellular GABA levels in the prefrontal cortex are decreased by mu-opiate receptor activation, and group II metabotropic glutamate receptors are preferentially suppressed by adenosine. This decreases the excitatory postsynaptic currents induced by 5-hydroxytryptamine(2A) in the rat medial prefrontal cortex. DOI-induced activation of the cortex is attenuated by pre-treatment with the mGlu2/3 receptor agonist LY379268. Glutamate receptor activation is involved in 5-HT2 agonist-induced Arc gene expression in the rat cortex. The 5-HT2A-mGlu2 receptor complex is involved in psychosis, and the heteromerization of the two receptors results in a psychoactive behavior. The two faces of the pharmacological interaction of 5-HT2A-mGlu2 are relevance for cellular signaling cascades and interaction through functional brain pathways. The natural hallucinogen 5-MeO-DMT, component of Ayahuasca, disrupts cortical function in rats and is reversed by antipsychotic drugs. Steriade M, McCormick DA, Sejnowski TJ, Nunez A, Amzica F, Tallon-Baudry C, Bertrand O, Peronnet F, Pernier J, Induced gamma-band activity during the delay of a visual short-term memory task in humans.
Gamma-band activation is associated with memory match and utilization, and alpha-gamma versus theta-gamma codes for distinct WM information are involved in working memory. Broadband cortical desynchronization underlies the human psychedelic state, and is reflected in the effects of the South American psychoactive beverage ayahuasca on regional brain electrical activity in healthy volunteers. Gamma oscillatory power is impaired during cognitive control in first-episode schizophrenia, independent of medication status, and is clinically significant. A double-blind, placebo-controlled PET study of psilocybin, 3,4-methylenedioxyethylamphetamine (MDE) and d-methamphetamine in healthy volunteers demonstrated increased frontal and paralimbic activation, and a default mode of brain function. The authors of this text discuss the relationship between cerebral blood flow and synaptic activity in the cerebellar cortex, and how this relationship relates to the fMRI signal.
Serotonin-2A receptors in the neocortex of the rhesus monkey are activated through a glutamate-dependent mechanism, and prefrontal neurons transmit signals to posterior parietal cortex that reflect executive control of cognition. Gross-Isseroff R, Salama D, Israeli M, Biegon A. Autoradiographic analysis of 3-hydroxytryptamine binding in the human brain postmortem: effect of suicide. Gross-Isseroff R, Salama D, Israeli M, Biegon A. Autoradiographic analysis of age-dependent changes in serotonin 5-HT2 receptors of the human brain postmortem. Carhart-Harris RL, Leech R, Williams TM, Erritzoe D, Abbasi N, Bargiotas T, et al. found that psilocybin-induced decrease in amygdala reactivity correlates with enhanced positive mood in healthy volunteers. Psilocybin induces hippocampal neurogenesis and increases c-Fos expression in intercalated neurons of the amygdala, which are required for expression of fear extinction. These effects are mediated by serotonin 1A/2A receptor agonists.
The basal ganglia-thalamocortical circuits are parallel substrates for motor, oculomotor, “prefrontal” and “limbic” functions. Serotonin 2A receptors are involved in the consolidation and extinction of fear memory in C57BL/6J mice. Middleton FA, Strick PL, Di Martino A, Scheres A, Margulies D, Kelly, Uddin L, Shehzad Z, et al. A revised neuroanatomy of frontal-subcortical circuits. Psilocybin, a preferential 5-HT2A agonist, inhibits prepulse inhibition of startle in healthy human volunteers depending on interstimulus interval, and DOI disrupts prepulse inhibition of startle in rats via 5-HT2A receptors in the ventral pallidum. Siegel RK, Jarvik ME, Becker C, Elliott MA, Allefeld C, Pütz P, Kastner K, Wackermann J, Horowitz MJ, Adams JE, Rutkin BB, Tass P, Ermentrout GB, Cowan JD, Geometric visual hallucinations Euclidean symmetry and the functional architecture of striate cortex.