Psilocybin-induced deficits in automatic and controlled inhibition are attenuated by ketanserin in healthy human volunteers

The serotonin-2A receptor (5-HT(2A)R) has been implicated in the pathogenesis of schizophrenia and related inhibitory gating and behavioral inhibition deficits of schizophrenia patients. The hallucinogen psilocybin disrupts automatic forms of sensorimotor gating and response inhibition in humans, but it is unclear so far whether the 5-HT(2A)R or 5-HT(1A)R agonist properties of its bioactive metabolite psilocin account for these effects. Thus, we investigated whether psilocybin-induced deficits in automatic and controlled inhibition in healthy humans could be attenuated by the 5-HT(2A/2C)R antagonist ketanserin. A total of 16 healthy participants received placebo, ketanserin (40 mg p.o.), psilocybin (260 μg/kg p.o.), or psilocybin plus ketanserin in a double-blind, randomized, and counterbalanced order. Sensorimotor gating was measured by prepulse inhibition (PPI) of the acoustic startle response. The effects on psychopathological core dimensions and behavioral inhibition were assessed by the altered states of consciousness questionnaire (5D-ASC), and the Color-Word Stroop Test. Psilocybin decreased PPI at short lead intervals (30 ms), increased all 5D-ASC scores, and selectively increased errors in the interference condition of the Stroop Test. Stroop interference and Stroop effect of the response latencies were increased under psilocybin as well. Psilocybin-induced alterations were attenuated by ketanserin pretreatment, whereas ketanserin alone had no significant effects. These findings suggest that the disrupting effects of psilocybin on automatic and controlled inhibition processes are attributable to 5-HT(2A)R stimulation. Sensorimotor gating and attentional control deficits of schizophrenia patients might be due to changes within the 5-HT(2A)R system

Classic Psychedelic Drugs: Update on Biological Mechanisms

Renewed interest in the effects of psychedelics in the treatment of psychiatric disorders warrants a better understanding of the neurobiological mechanisms underlying the effects of these substances. During the past two decades, state-of-the-art studies of animals and humans have yielded new important insights into the molecular, cellular, and systems-level actions of psychedelic drugs. These efforts have revealed that psychedelics affect primarily serotonergic receptor subtypes located in cortico-thalamic and cortico-cortical feedback circuits of information processing. Psychedelic drugs modulate excitatory-inhibitory balance in these circuits and can participate in neuroplasticity within brain structures critical for the integration of information relevant to sensation, cognition, emotions, and the narrative of self. Neuroimaging studies showed that characteristic dimensions of the psychedelic experience obtained through subjective questionnaires as well as alterations in self-referential processing and emotion regulation obtained through neuropsychological tasks are associated with distinct changes in brain activity and connectivity patterns at multiple-system levels. These recent results suggest that changes in self-experience, emotional processing, and social cognition may contribute to the potential therapeutic effects of psychedelics

Psychedelic Cognition – the unreached frontier of psychedelic science

Psychedelic compounds hold the promise of changing the face of neuroscience and psychiatry as we know it. There have been numerous proposals to use them to treat a range of neuropsychiatric conditions such as depression, anxiety, addiction and PTSD; and trials to date have delivered positive results in favour of the novel therapeutics. Further to the medical use, the wider healthy population is gaining interest in these compounds. We see a surge in personal use of psychedelic drugs for reasons not limited to spiritual enhancement, improved productivity, aiding the management of non-pathological anxiety and depression, and recreational interests. Notably, microdosing – the practice of taking subacute doses of psychedelic compounds – is on the rise. Our knowledge about the effects of psychedelic compounds, however, especially in naturalistic settings, is still fairly limited. In particular, one of the largest gaps concerns the acute effects on cognition caused by psychedelics. Studies carried out to date are riddled with limitations such as having disparate paradigms, small sample sizes, and insufficient breadth of testing on both unhealthy and healthy volunteers. Moreover, the studies are majoritarily limited to laboratory settings and do not assess the effects at multiple dosages within the same paradigm nor at various points throughout the psychedelic experience. This review aims to summarise the studies to date in relation to how psychedelics acutely affect different domains of cognition. In the pursuit of illuminating the current limitations and offering long-term, forward-thinking solutions, this review compares and contrasts findings related to how psychedelics impact memory, attention, reasoning, social cognition, and creativity

Psilocybin links binocular rivalry switch rate to attention and subjective arousal levels in humans

Rationale: Binocular rivalry occurs when different images are simultaneously presented to each eye. During continual viewing of this stimulus, the observer will experience repeated switches between visual awareness of the two images. Previous studies have suggested that a slow rate of perceptual switching may be associated with clinical and drug-induced psychosis. Objectives: The objective of the study was to explore the proposed relationship between binocular rivalry switch rate and subjective changes in psychological state associated with 5-HT2A receptor activation. Materials and methods: This study used psilocybin, the hallucinogen found naturally in Psilocybe mushrooms that had previously been found to induce psychosis-like symptoms via the 5-HT2A receptor. The effects of psilocybin (215μg/kg) were considered alone and after pretreatment with the selective 5-HT2A antagonist ketanserin (50mg) in ten healthy human subjects. Results: Psilocybin significantly reduced the rate of binocular rivalry switching and increased the proportion of transitional/mixed percept experience. Pretreatment with ketanserin blocked the majority of psilocybin's "positive” psychosis-like hallucinogenic symptoms. However, ketanserin had no influence on either the psilocybin-induced slowing of binocular rivalry or the drug's "negative-type symptoms” associated with reduced arousal and vigilance. Conclusions: Together, these findings link changes in binocular rivalry switching rate to subjective levels of arousal and attention. In addition, it suggests that psilocybin's effect on binocular rivalry is unlikely to be mediated by the 5-HT2A recepto

Motor and non-motor effects of apomorphine infusion

Apomorphine is a medicine used in the treatment of advanced Parkinson’s disease patients. It is considered in patients who are unable to adequately control motor symptoms with oral medication. Apomorphine is a pump therapy that continuously delivers medication via a needle positioned in the subcutaneous fatty tissue. In the Netherlands, this treatment is now used for more than 20 years.This dissertation investigated the effects of apomorphine on motor and non-motor symptoms of Parkinson’s disease in a group of patients that started treatment in the UMCG and in a group that started treatment in a specialized unit of a nursing home (now called Punt voor Parkinson). In contrary to the common perception, apomorphine is well-tolerated in Parkinson’s disease patients with cognitive dysfunction, visual hallucinations and blood pressure problems (so called orthostatic hypotension), if adequate precautions were taken. In addition, anecdotal evidence suggests a beneficial effect of apomorphine on visual hallucinations, presumably related to its chemical structure with a piperidine moiety. The last part of this dissertation focused on local skin reactions at the site of infusion (so called subcutaneous nodules); a frequent adverse event. We investigated the underlying mechanism of subcutaneous nodules with skin biopsies and allergic testing. It is hypothesized that the occurrence of subcutaneous nodules is due to an allergic reaction, however a positive allergic test is lacking. On the other hand, treatment options were evaluated with skin biopsies showing that dilution of apomorphine and subcutaneous hydrocortisone pretreatment were most effective

Inhibition of alpha oscillations through serotonin-2A receptor activation underlies the visual effects of ayahuasca in humans

Ayahuasca is an Amazonian psychotropic plant tea typically obtained from two plants, Banisteriopsis caapi and Psychotria viridis. It contains the psychedelic 5-HT2A and sigma-1 agonist N,N-dimethyltryptamine (DMT) plus ß-carboline alkaloids with monoamine-oxidase (MAO)-inhibiting properties. Although the psychoactive effects of ayahuasca have commonly been attributed solely to agonism at the 5-HT2A receptor, the molecular target of classical psychedelics, this has not been tested experimentally. Here we wished to study the contribution of the 5-HT2A receptor to the neurophysiological and psychological effects of ayahuasca in humans. We measured drug-induced changes in spontaneous brain oscillations and subjective effects in a double-blind randomized placebo-controlled study involving the oral administration of ayahuasca (0.75 mg DMT/kg body weight) and the 5-HT2A antagonist ketanserin (40 mg). Twelve healthy, experienced psychedelic users (5 females) participated in four experimental sessions in which they received the following drug combinations: placebo+placebo, placebo+ayahuasca, ketanserin+placebo and ketanserin+ayahuasca. Ayahuasca induced EEG power decreases in the delta, theta and alpha frequency bands. Current density in alpha-band oscillations in parietal and occipital cortex was inversely correlated with the intensity of visual imagery induced by ayahuasca. Pretreatment with ketanserin inhibited neurophysiological modifications, reduced the correlation between alpha and visual effects, and attenuated the intensity of the subjective experience. These findings suggest that despite the chemical complexity of ayahuasca, 5-HT2A activation plays a key role in the neurophysiological and visual effects of ayahuasca in humans.Postprint (published version

Semantic activation in LSD: evidence from picture naming

Lysergic acid diethylamide (LSD) is a classic psychedelic drug that alters cognition in a characteristic way. It has been suggested that psychedelics expand the breadth of cognition via actions on the central nervous system. Previous work has shown changes in semantic processing under psilocybin (a related psychedelic to LSD) that are consistent with an increased spread of semantic activation. The present study investigates this further using a picture-naming task and the psychedelic, LSD. Ten participants completed the task under placebo and LSD. Results revealed significant effects of LSD on accuracy and error correction that were consistent with an increased spread of semantic activation under LSD. These results are consistent with a generalised “entropic” effect on the mind. We suggest incorporating direct neuroimaging measures in future studies, and to employ more naturalistic measures of semantic processing that may enhance ecological validity

The effects of psilocybin on cognitive and emotional functions in healthy participants : Results from a phase 1, randomised, placebo-controlled trial involving simultaneous psilocybin administration and preparation

Background: Psilocybin, a psychoactive serotonin receptor partial agonist, has been reported to acutely reduce clinical symptoms of depressive disorders. Psilocybin's effects on cognitive function have not been widely or systematically studied. Aim: The aim of this study was to explore the safety of simultaneous administration of psilocybin to healthy participants in the largest randomised controlled trial of psilocybin to date. Primary and secondary endpoints assessed the short- and longer-term change in cognitive functioning, as assessed by a Cambridge Neuropsychological Test Automated Battery (CANTAB) Panel, and emotional processing scales. Safety was assessed via endpoints which included cognitive function, assessed by CANTAB global composite score, and treatment-emergent adverse event (TEAE) monitoring. Methods: In this phase 1, randomised, double-blind, placebo-controlled study, healthy participants (n=89; mean age 36.1 years; 41 females, 48 males) were randomised to receive a single oral dose of 10 or 25 mg psilocybin, or placebo, administered simultaneously to up to six participants, with one-to-one psychological support - each participant having an assigned, dedicated therapist available throughout the session. Results: In total, 511 TEAEs were reported, with a median duration of 1.0 day; 67% of all TEAEs started and resolved on the day of administration. There were no serious TEAEs, and none led to study withdrawal. There were no clinically relevant between-group differences in CANTAB global composite score, CANTAB cognitive domain scores, or emotional processing scale scores. Conclusions: These results indicate that 10 mg and 25 mg doses of psilocybin were generally well tolerated when given to up to six participants simultaneously and did not have any detrimental short- or long-term effects on cognitive functioning or emotional processing.Peer reviewe