Classic Psychedelic Drugs: Update on Biological Mechanisms

Abstract

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.

Fig. 1

Empirical described predictors of acute and long-term effects of Psychedelics. The Altered State of Consciousness Questionnaire (5D-ASC) and the Mysticism Scale (M-Scale) are usually administered shortly after the acute psychedelic experience. Red arrows=positive correlations; blue arrows=negative correlations: a : Scoring high on trait openness , absorption , and optimism about life , being relaxed the day(s) before drug intake intake , using a non-judgmental emotion regulation strategy , pre-experience with ASCs , older age , and a pleasant ambiance , supportive music , and meditation practice were predictive for a positive psychedelic experience (e. g., “Oceanic Boundlessness”) in healthy volunteers (HVs). High emotional re-appraisal capacity reduced the occurrence of distressing experiences (e. g., “Dread of ego-dissolution”) . On the other hand, high neuroticism, young age, and an impersonal laboratory setting predicted unpleasant and anxious reactions to psilocybin in healthy volunteers . In addition, high absorption capacity and esthetic sensibility predicted changes in visual perception and altered meaning of percepts (VIS) . b : Mysticism Total Score (M-Scale or MEQ30) predicted persisting increases in trait openness , mood, well-being, attitudes and psychosocial behaviors in healthy volunteers . The M-Scale subdimensions “unity” and “sacredness” predicted persisting increases in self-acceptance and appreciation for life in healthy volunteers , while “ego dissolution” predicted lasting increases in openness and mood .

Fig. 2

Working hypothesis of psychedelic drug effects on cortico-striato-thalamo-cortical and cortico-cortical circuits of information flow: The schema in Fig. 2 comprises central brain networks on the effects of psychedelic drugs responsible for bottom-up sensory input via the thalamus to the cortex and top-down cortico-striato-thalamic, cortico-thalamic and/or cortico-cortical control of information processing. The model is based mostly on data obtained on the action of LSD and DOI in animals as well as from some studies with LSD and psilocybin in humans. The 5-HT2A receptors are highly expressed in the apical dendrites of layer 5 pyramidal (L5p) neurons in the cortex and are particularly enriched in the prefrontal cortex (PFC) . A smaller proportion is located pre-synaptically on thalamocortical afferents projecting to the neocortex . 5-HT2ARs are also expressed on GABAergic interneurons in the cortex and subcortical structures . LSD and DOI both increase extracellular glutamate levels via activation of post-synaptic 5-HT2A receptors on deep layers 5 and 6 pyramidal neurons (L5p) (stage 1) and on Lp6 (stage 2) neurons projecting to L5p neurons as well as via activation of pre-synaptic 5-HT2A receptors on specific (SP) and non-specific (NSP) thalamocortical afferents . Psychedelics such as LSD can also stimulate 5-HT1A receptors on the hillock on Lp5 and Lp6 neurons (stage 4) and cortical GABAergic interneurons (stage 5) resulting in both inhibition and disinhibition of prefrontal pyramidal cell activity . Furthermore, LSD or DOI are also potent partial agonists at cortical (stage 6) and subcortical (striatal, pallidal or thalamic) (stage 7) 5-HT2A receptors in GABAergic interneurons . Despite this partially inhibitory mechanisms, this LSD- or DOI-induced increased glutamate release produces a striking net-excitatory effect on L5p neurons and promotes synaptic plasticity via AMPA and NMDA receptor-dependent mechanisms . L5P neurons affect both thalamic and cortical processing and have the unique ability to couple thalamo-cortical (stage 8) and cortico-cortical loops (stage 9) of information streams with each other . This is thought to provide a mechanism through which the state and content of consciousness are functionally coupled . Psychedelics appear to affect this extended thalamic-cortical broadcasting system and thus consciousness as a whole, by simultaneously producing sensory flooding and arousal via reduced thalamic gating of interoceptive and exteroceptive stimuli and by altering the meaning and attachment of percepts due to disrupted cortico-cortical interactions . In this model, thalamic gating is thought to be under the control of glutamatergic cortico-striatothalamic and cortico-thalamic loops projecting back to the cortex, in addition to being under the modulatory influence of serotonergic (and dopaminergic) projections from the raphe (and the VTA) to several parts of the CSTC.