Psilocybin as a partial agonist of the 5-HT2A receptor

“The modulating effects of serotonin on dopamine neurotransmission are not well understood, particularly in acute psychotic states. positron emission tomography was used to examine the effect of psilocybin on the in vivo binding of [11c]raclopride to d2-dopamine receptors in the striatum in healthy volunteers after placebo and a psychotomimetic dose of psilocybin (n = 7). psilocybin is a potent indoleamine hallucinogen and a mixed 5-ht(2a) and 5-ht(1a) receptor agonist. psilocybin administration (0.25 mg/kg p.o.) produced changes in mood, disturbances in thinking, illusions, elementary and complex visual hallucinations and impaired ego-functioning. psilocybin significantly decreased [11c]raclopride receptor binding potential (bp) bilaterally in the caudate nucleus (19%) and putamen (20%) consistent with an increase in endogenous dopamine. changes in [11c]raclopride bp in the ventral striatum correlated with depersonalization associated with euphoria. together with previous reports of 5-ht receptor involvement in striatal dopamine release, it is concluded that stimulation of both 5-ht(2a) and 5-ht(1a) receptors may be important for the modulation of striatal dopamine release in acute psychoses. the present results indirectly support the hypothesis of a serotonin-dopamine dysbalance in schizophrenia and suggest that psilocybin is a valuable tool in the analysis of serotonin-dopamine interactions in acute psychotic states. copyright (c) 1999 american college of neuropsychopharmacology.”

“Increasing evidence suggests a link between attention, working memory, serotonin (5-ht), and prefrontal cortex activity. in an attempt to tease out the relationship between these elements, this study tested the effects of the hallucinogenic mixed 5-ht1a/2a receptor agonist psilocybin alone and after pretreatment with the 5-ht2a antagonist ketanserin. eight healthy human volunteers were tested on a multiple-object tracking task and spatial working memory task under the four conditions: placebo, psilocybin (215 microg/kg), ketanserin (50 mg), and psilocybin and ketanserin. psilocybin significantly reduced attentional tracking ability, but had no significant effect on spatial working memory, suggesting a functional dissociation between the two tasks. pretreatment with ketanserin did not attenuate the effect of psilocybin on attentional performance, suggesting a primary involvement of the 5-ht1a receptor in the observed deficit. based on physiological and pharmacological data, we speculate that this impaired attentional performance may reflect a reduced ability to suppress or ignore distracting stimuli rather than reduced attentional capacity. the clinical relevance of these results is also discussed.”

“Background: serotonin (5-ht) 1a and 2a receptors have been associated with dysfunctional emotional processing biases in mood disorders. these receptors further predominantly mediate the subjective and behavioral effects of psilocybin and might be important for its recently suggested antidepressive effects. however, the effect of psilocybin on emotional processing biases and the specific contribution of 5-ht2a receptors across different emotional domains is unknown. methods: in a randomized, double-blind study, 17 healthy human subjects received on 4 separate days placebo, psilocybin (215 μg/kg), the preferential 5-ht2a antagonist ketanserin (50 mg), or psilocybin plus ketanserin. mood states were assessed by self-report ratings, and behavioral and event-related potential measurements were used to quantify facial emotional recognition and goal-directed behavior toward emotional cues. results: psilocybin enhanced positive mood and attenuated recognition of negative facial expression. furthermore, psilocybin increased goal-directed behavior toward positive compared with negative cues, facilitated positive but inhibited negative sequential emotional effects, and valence-dependently attenuated the p300 component. ketanserin alone had no effects but blocked the psilocybin-induced mood enhancement and decreased recognition of negative facial expression. conclusions: this study shows that psilocybin shifts the emotional bias across various psychological domains and that activation of 5-ht2a receptors is central in mood regulation and emotional face recognition in healthy subjects. these findings may not only have implications for the pathophysiology of dysfunctional emotional biases but may also provide a framework to delineate the mechanisms underlying psylocybin’s putative antidepressant effects. © 2012 society of biological psychiatry.”

“RATIONALE: both glutamate and serotonin (5-ht) play a key role in the pathophysiology of emotional biases. recent studies indicate that the glutamate n-methyl-d-aspartate (nmda) receptor antagonist ketamine and the 5-ht receptor agonist psilocybin are implicated in emotion processing. however, as yet, no study has systematically compared their contribution to emotional biases.nnobjectives: this study used event-related potentials (erps) and signal detection theory to compare the effects of the nmda (via s-ketamine) and 5-ht (via psilocybin) receptor system on non-conscious or conscious emotional face processing biases.nnmethods: s-ketamine or psilocybin was administrated to two groups of healthy subjects in a double-blind within-subject placebo-controlled design. we behaviorally assessed objective thresholds for non-conscious discrimination in all drug conditions. electrophysiological responses to fearful, happy, and neutral faces were subsequently recorded with the face-specific p100 and n170 erp.nnresults: both s-ketamine and psilocybin impaired the encoding of fearful faces as expressed by a reduced n170 over parieto-occipital brain regions. in contrast, while s-ketamine also impaired the encoding of happy facial expressions, psilocybin had no effect on the n170 in response to happy faces.nnconclusion: this study demonstrates that the nmda and 5-ht receptor systems differentially contribute to the structural encoding of emotional face expressions as expressed by the n170. these findings suggest that the assessment of early visual evoked responses might allow detecting pharmacologically induced changes in emotional processing biases and thus provides a framework to study the pathophysiology of dysfunctional emotional biases.”

“Hallucinogens, including mescaline, psilocybin, and lysergic acid diethylamide (lsd), profoundly affect perception, cognition, and mood. all known drugs of this class are 5-ht 2a receptor (2ar) agonists, yet closely related 2ar agonists such as lisuride lack comparable psychoactive properties. why only certain 2ar agonists are hallucinogens and which neural circuits mediate their effects are poorly understood. by genetically expressing 2ar only in cortex, we show that 2ar-regulated pathways on cortical neurons are sufficient to mediate the signaling pattern and behavioral response to hallucinogens. hallucinogenic and nonhallucinogenic 2ar agonists both regulate signaling in the same 2ar-expressing cortical neurons. however, the signaling and behavioral responses to the hallucinogens are distinct. while lisuride and lsd both act at 2ar expressed by cortex neurons to regulate phospholipase c, lsd responses also involve pertussis toxin-sensitive heterotrimeric g i/o proteins and src. these studies identify the long-elusive neural and signaling mechanisms responsible for the unique effects of hallucinogens. © 2007 elsevier inc. all rights reserved.”

“Schizophrenia patients exhibit impairments in prepulse inhibition (ppi) of the startle response. hallucinogenic 5-ht(2a) receptor agonists are used for animal models of schizophrenia because they mimic some symptoms of schizophrenia in humans and induce ppi deficits in animals. nevertheless, one report indicates that the 5-ht(2a) receptor agonist psilocybin increases ppi in healthy humans. hence, we investigated these inconsistent results by assessing the dose-dependent effects of psilocybin on ppi in healthy humans. sixteen subjects each received placebo or 115, 215, and 315 microg/kg of psilocybin at 4-week intervals in a randomized and counterbalanced order. ppi at 30-, 60-, 120-, 240-, and 2000-ms interstimulus intervals (isis) was measured 90 and 165 min after drug intake, coinciding with the peak and post-peak effects of psilocybin. the effects of psilocybin on psychopathological core dimensions and sustained attention were assessed by the altered states of consciousness rating scale (5d-asc) and the frankfurt attention inventory (fair). psilocybin dose-dependently reduced ppi at short (30 ms), had no effect at medium (60 ms), and increased ppi at long (120-2000 ms) isis, without affecting startle reactivity or habituation. psilocybin dose-dependently impaired sustained attention and increased all 5d-asc scores with exception of auditory alterations. moreover, psilocybin-induced impairments in sustained attention performance were positively correlated with reduced ppi at the 30 ms isi and not with the concomitant increases in ppi observed at long isis. these results confirm the psilocybin-induced increase in ppi at long isis and reveal that psilocybin also produces a decrease in ppi at short isis that is correlated with impaired attention and consistent with deficient ppi in schizophrenia.”

“© the author(s) 2014. despite suggestive early findings on the therapeutic use of hallucinogens in the treatment of substance use disorders, rigorous follow-up has not been conducted. to determine the safety and feasibility of psilocybin as an adjunct to tobacco smoking cessation treatment we conducted an open-label pilot study administering moderate (20 mg/70 kg) and high (30 mg/70 kg) doses of psilocybin within a structured 15-week smoking cessation treatment protocol. participants were 15 psychiatrically healthy nicotine-dependent smokers (10 males; mean age of 51 years), with a mean of six previous lifetime quit attempts, and smoking a mean of 19 cigarettes per day for a mean of 31 years at intake. biomarkers assessing smoking status, and self-report measures of smoking behavior demonstrated that 12 of 15 participants (80%) showed seven-day point prevalence abstinence at 6-month follow-up. the observed smoking cessation rate substantially exceeds rates commonly reported for other behavioral and/or pharmacological therapies (typically <35%). although the open-label design does not allow for definitive conclusions regarding the efficacy of psilocybin, these findings suggest psilocybin may be a potentially efficacious adjunct to current smoking cessation treatment models. the present study illustrates a framework for future research on the efficacy and mechanisms of hallucinogen-facilitated treatment of addiction.”

“Previously the nmda (n-methyl-d-aspartate) receptor (nmdar) antagonist ketamine was shown to disrupt generation of the auditory event-related potential (erp) mismatch negativity (mmn) and the performance of an ’ax’-type continuous performance test (ax-cpt)–measures of auditory and visual context-dependent information processing–in a similar manner as observed in schizophrenia. this placebo-controlled study investigated effects of the 5-ht(2a) receptor agonist psilocybin on the same measures in 18 healthy volunteers. psilocybin administration induced significant performance deficits in the ax-cpt, but failed to reduce mmn generation significantly. these results indirectly support evidence that deficient mmn generation in schizophrenia may be a relatively distinct manifestation of deficient nmdar functioning. in contrast, secondary pharmacological effects shared by nmdar antagonists and the 5-ht(2a) agonist (ie disruption of glutamatergic neurotransmission) may be the mechanism underlying impairments in ax-cpt performance observed during both psilocybin and ketamine administration. comparable deficits in schizophrenia may result from independent dysfunctions of 5-ht(2a) and nmdar-related neurotransmission.”

“Hallucinogenic psilocybin is known to alter the subjective experience of time. however, there is no study that systematically investigated objective measures of time perception under psilocybin. therefore, we studied dose-dependent effects of the serotonin (5-ht)2a/1areceptor agonist psilocybin (4-phosphoryloxy-n, n-dimethyltryptamine) on temporal processing, employing tasks of temporal reproduction, sensorimotor synchronization and tapping tempo. to control for cognitive and subjective changes, we assessed spatial working memory and conscious experience. twelve healthy human volunteers were tested under placebo, medium (115μg/kg), and high (250μg/kg) dose conditions, in a double-blind experimental design. psilocybin was found to significantly impair subjects’ ability to (1) reproduce interval durations longer than 2.5 sec, (2) to synchronize to inter-beat intervals longer than 2 sec and (3) caused subjects to be slower in their preferred tapping rate. these objective effects on timing performance were accompanied by working-memory deficits and subjective changes in conscious state, namely increased reports of ‘depersonalization’ and ‘derealization’ phenomena including disturbances in subjective ‘time sense.’ our study is the first to systematically assess the impact of psilocybin on timing performance on standardized measures of temporal processing. results indicate that the serotonin system is selectively involved in duration processing of intervals longer than 2 to 3 seconds and in the voluntary control of the speed of movement. we speculate that psilocybin’s selective disruption of longer intervals is likely to be a product of interactions with cognitive dimensions of temporal processing -presumably via 5-ht2a receptor stimulation. © 2007 british association for psychopharmacology.”

“Visual illusions and hallucinations are hallmarks of serotonergic hallucinogen-induced altered states of consciousness. although the serotonergic hallucinogen psilocybin activates multiple serotonin (5-ht) receptors, recent evidence suggests that activation of 5-ht2a receptors may lead to the formation of visual hallucinations by increasing cortical excitability and altering visual-evoked cortical responses. to address this hypothesis, we assessed the effects of psilocybin (215 mug/kg vs placebo) on both alpha oscillations that regulate cortical excitability and early visual-evoked p1 and n170 potentials in healthy human subjects. to further disentangle the specific contributions of 5-ht2a receptors, subjects were additionally pretreated with the preferential 5-ht2a receptor antagonist ketanserin (50 mg vs placebo). we found that psilocybin strongly decreased prestimulus parieto-occipital alpha power values, thus precluding a subsequent stimulus-induced alpha power decrease. furthermore, psilocybin strongly decreased n170 potentials associated with the appearance of visual perceptual alterations, including visual hallucinations. all of these effects were blocked by pretreatment with the 5-ht2a antagonist ketanserin, indicating that activation of 5-ht2a receptors by psilocybin profoundly modulates the neurophysiological and phenomenological indices of visual processing. specifically, activation of 5-ht2a receptors may induce a processing mode in which stimulus-driven cortical excitation is overwhelmed by spontaneous neuronal excitation through the modulation of alpha oscillations. furthermore, the observed reduction of n170 visual-evoked potentials may be a key mechanism underlying 5-ht2a receptor-mediated visual hallucinations. this change in n170 potentials may be important not only for psilocybin-induced states but also for understanding acute hallucinatory states seen in psychiatric disorders, such as schizophrenia and parkinson’s disease.”