Classic Psychedelic Drugs: Update on Biological
                    Mechanisms

Vollenweider, Franz X.; Smallridge, John

doi:10.1055/a-1721-2914

Cited by 51 publications

(61 citation statements)

References 241 publications

(440 reference statements)

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“…The reticular nucleus is made of GABAergic interneurons and is thought to be the center of the negative-feedback loop in the thalamus, as it is innervated by other thalamic nuclei while it projects inhibitory inputs back into the thalamus [ 54 ], regulating the amount of information sent into the cortex [ 22 ]. The NMDA antagonists seem to inhibit its activity, leading to the disinhibition of thalamic activity [ 52 ], while psychedelics are hypothesized to stimulate it, leading to the attenuation of thalamic gating [ 23 , 27 , 55 ]. Surprisingly, we observed only half of the expected outcome: while psilocybin dose-dependently increased extracellular GABA levels, ketamine did not affect either glutamatergic or GABAergic neurotransmission; this phenomenon is hard to explain, and further studies should be conducted to address this issue.…”

Section: Discussionmentioning

confidence: 99%

Effect of Psilocybin and Ketamine on Brain Neurotransmitters, Glutamate Receptors, DNA and Rat Behavior

Wojtas

Bysiek

Wawrzczak-Bargieła

et al. 2022

IJMS

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Clinical studies provide evidence that ketamine and psilocybin could be used as fast-acting antidepressants, though their mechanisms and toxicity are still not fully understood. To address this issue, we have examined the effect of a single administration of ketamine and psilocybin on the extracellular levels of neurotransmitters in the rat frontal cortex and reticular nucleus of the thalamus using microdialysis. The genotoxic effect and density of glutamate receptor proteins was measured with comet assay and Western blot, respectively. An open field test, light–dark box test and forced swim test were conducted to examine rat behavior 24 h after drug administration. Ketamine (10 mg/kg) and psilocybin (2 and 10 mg/kg) increased dopamine, serotonin, glutamate and GABA extracellular levels in the frontal cortex, while psilocybin also increased GABA in the reticular nucleus of the thalamus. Oxidative DNA damage due to psilocybin was observed in the frontal cortex and from both drugs in the hippocampus. NR2A subunit levels were increased after psilocybin (10 mg/kg). Behavioral tests showed no antidepressant or anxiolytic effects, and only ketamine suppressed rat locomotor activity. The observed changes in neurotransmission might lead to genotoxicity and increased NR2A levels, while not markedly affecting animal behavior.

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Section: Discussionmentioning

confidence: 99%

Effect of Psilocybin and Ketamine on Brain Neurotransmitters, Glutamate Receptors, DNA and Rat Behavior

Wojtas

Bysiek

Wawrzczak-Bargieła

et al. 2022

IJMS

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“…There is little doubt, however, that stimulation of the neocortical 5-HT2AR is a requirement for the psychedelic experience to occur. Blocking 5-HT2A/5-HT2C receptors with the 5-HT2AR antagonist ketanserin abolishes virtually all of the subjective effects of subsequently given psilocybin, LSD, and DMT in humans [40] and there is a tight correlation between plasma psilocin, cerebral 5-HT2AR occupancy as measured with PET, and the perceived intensity of the psychedelic experience [26]. This means that measuring individuals' plasma psilocin levels can give a good estimate of the brain 5-HT2AR occupancy which facilitates comparisons across individuals [41].…”

Section: Molecular Structural and Functional Neuroplasticity: Neuroim...mentioning

confidence: 99%

Sustained effects of single doses of classical psychedelics in humans

Knudsen

2022

Neuropsychopharmacol.

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The serotonergic classical psychedelics include compounds that primarily activate the brain’s serotonin 2 A receptor (5-HT2AR), such as LSD, psilocybin, and DMT (ayahuasca). The acute effects of these compounds are well-known as are their ability to increase the emotional state both in healthy people and in those with neuropsychiatric disorders. In particular psilocybin, the psychoactive constituent in “magic mushrooms”, has shown great potential for treatment of anxiety and depression. A unique and compelling feature of psychedelics is that intake of just a single psychedelic dose is associated with long-lasting effects. This includes effects on personality, e.g., higher openness, and amelioration of depressive symptoms. This review focuses on these stunning effects and summarizes our current knowledge on which behavioral, biochemical, neuroimaging, and electrophysiological data support that the intriguing effects of psychedelics on the human brain and mind are based on neural plasticity. The review also points to so far understudied areas and suggests research questions to be addressed in future studies which potentially can help to understand the intriguing long-term effects after intake of a single (or a few) psychedelic doses.

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“…Their use in psychiatry is expected to bring a paradigm shift in our approach to treating brain disorders as we pay less attention to rectifying “chemical imbalances” and more on achieving selective modulation of neural circuits [ 192 ]. Psychedelic drugs have been shown to regulate the excitatory-inhibitory balance in neural circuits and participate in neuroplasticity within brain structures that are important for the assimilation of key information relevant to sensation, cognition, emotions, and the narrative of self [ 53 ]. In preclinical studies, the administration of LSD and DOI caused an increase in cortical glutamate levels and layer 5 pyramidal cell activity in the prefrontal cortex [ 193 ], attributed to repetitive network activity triggered by activation of postsynaptic 5-HT 2A receptors located in deep layer 5 or 6 pyramidal neurons that project to layer 5 pyramidal neurons.…”

Section: Neurochemical Mechanisms Of Psychedelic Drugs and Their Rela...mentioning

confidence: 99%

“…Additionally, psychedelic drug-induced changes in self-referential processing and emotion regulation have been associated with characteristic changes in brain activity and connectivity patterns at multiple system levels. These alteration in self-experience, emotional processing, and social cognition have been suggested to contribute to the potential therapeutic effects of psychedelics [ 53 ].…”

Section: Neurochemical Mechanisms Of Psychedelic Drugs and Their Rela...mentioning

confidence: 99%

“…Additionally, exploration of psychedelics would facilitate understanding of the serotonin–glutamate receptor hypotheses, as the serotonin–glutamate receptor complex is the target for both the psychedelic drug compounds as well as the atypical and glutamate classes of APDs [ 51 , 52 ]. A renaissance in the interest to study the effects of psychedelics in the treatment of psychiatric disorders warrants a better understanding of the neurobiological mechanisms underlying the effects of psychedelics in schizophrenia [ 53 ]. This narrative review is an attempt to delve deep into neurobiological and neuropsychiatry mechanisms of psychedelics modelling vis-à-vis their role in future drug development in neuropsychiatric disorders including schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

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New Paradigms of Old Psychedelics in Schizophrenia

et al. 2022

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Psychedelics such as lysergic acid diethylamide (LSD), psilocybin (magic mushrooms), and mescaline exhibit intense effects on the human brain and behaviour. In recent years, there has been a surge in studies investigating these drugs because clinical studies have shown that these once banned drugs are well tolerated and efficacious in medically supervised low doses called microdosing. Psychedelics have demonstrated efficacy in treating neuropsychiatric maladies such as difficult to treat anxiety, depression, mood disorders, obsessive compulsive disorders, suicidal ideation, posttraumatic stress disorder, and also in treating substance use disorders. The primary mode of action of psychedelics is activation of serotonin 5-HT2A receptors affecting cognition and brain connectivity through the modulation of several downstream signalling pathways via complex molecular mechanisms. Some atypical antipsychotic drugs (APDs) primarily exhibit pharmacological actions through 5-HT2A receptors, which are also the target of psychedelic drugs. Psychedelic drugs including the newer second generation along with the glutamatergic APDs are thought to mediate pharmacological actions through a common pathway, i.e., a complex serotonin–glutamate receptor interaction in cortical neurons of pyramidal origin. Furthermore, psychedelic drugs have been reported to act via a complex interplay between 5HT2A, mGlu2/3, and NMDA receptors to mediate neurobehavioral and pharmacological actions. Findings from recent studies have suggested that serotoninergic and glutamatergic neurotransmissions are very closely connected in producing pharmacological responses to psychedelics and antipsychotic medication. Emerging hypotheses suggest that psychedelics work through brain resetting mechanisms. Hence, there is a need to dig deeply into psychedelic neurobiology to uncover how psychedelics could best be used as scientific tools to benefit psychiatric disorders including schizophrenia.

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Classic Psychedelic Drugs: Update on Biological Mechanisms

Cited by 51 publications

References 241 publications

Effect of Psilocybin and Ketamine on Brain Neurotransmitters, Glutamate Receptors, DNA and Rat Behavior

Effect of Psilocybin and Ketamine on Brain Neurotransmitters, Glutamate Receptors, DNA and Rat Behavior

Sustained effects of single doses of classical psychedelics in humans

New Paradigms of Old Psychedelics in Schizophrenia

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