Classic Psychedelic Drugs: Update on Biological Mechanisms

This comprehensive review article (2022) explores the neurobiological mechanisms through which psychedelics exert their effects in light of recent research. The pharmacological and neuroplastic effects are discussed as well as the hypothesized functional network models of psychedelic states. How these psychedelic states correlate with altered self- and emotion-processing is also explored.

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.”

Authors: Franz X. Vollenweider & John W. Smallridge

Summary

Introduction

Classic psychedelics are indoleamines, phenylalkylamines, mescaline, and synthetic “amphetamines” that produce profound alterations in perception, cognition, emotion, and self-consciousness. They have been used by humans for millennia for spiritual and medicinal purposes.

Bibliography

Pharmacopsychiatry DOI 10.1055/a-1721-2914 ISSN 0176-3679 2022. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License.

AbStrAct

Renewed interest in psychedelics in the treatment of psychiatric disorders warrants a better understanding of the neurobiological mechanisms underlying the effects of these substances. Recent studies have revealed that psychedelics affect serotonergic receptor subtypes located in cortico-thalamic and cortico-cortical feedback circuits of information processing.

During the 1950s and 1960s, LSD and psilocybin were extensively investigated for the treatment of different psychiatric disorders. However, the association of psychedelics with the counterculture and concerns over misuse led to the placement of psychedelics in a restrictive regulated drug category in 1976.

In the early 1990s, human psychedelic research was resumed in healthy volunteers by employing different new brain imaging techniques and concepts borrowed from cognitive neurosciences.

Recent studies demonstrate that psychedelics affect the brain primarily via the 5-HT2A receptor, but also via the GABA, dopamine and glutamate systems. Psychedelics can change the sense of self, enhance mood and shift emotion processing to the positive, and facilitate prosocial behavior.

In this review, we discuss the phenomenology and key psychological dimensions of psychedelic-induced altered states of consciousness, as measured by standardized psychometric scales, and the potential state and trait predictors of the acute responses to psychedelics.

Phenomenology and Predictors of Psychedelic States

The experience of ego-dissolution is associated with increased sensory and emotional arousal, distinct changes in cognitive functions, the release of emotions, and increased capacity for introspection. In a supportive and controlled setting, medium to high doses of psychedelics can trigger a pleasurable self-dissolution associated with bliss, feelings of oneness, and insightfulness. At larger doses, psychedelics might induce a pleasurable “mystical-type” experience or a more psychologically challenging or psychotic-like response characterized by fear of losing control over thinking and one’s autonomy, delusions of grandeur, impairment of reasoning, and anxiety or panic.

Although the intensity of the psychedelic experience depends most critically on the dosage, several non-pharmacological factors are also important in shaping the quality of the acute psychedelics experience. The Altered State of Consciousness Questionnaire (ASC) measures the five core dimensions of the psychedelic experience.

The OB-related blissful “mystical-type” experience can be measured by the Mysticism Scale (M-Scale) or by the Mystical Experience Questionnaire (MEQ30), and both scales correlate highly with the OB score of the 5D-ASC scale.

A positive self-dissolution or mystical-type experience was predicted by high scores on personality traits, being well and relaxed the day(s) before and during drug intake, and using a mindful attention and emotion regulation strategy. High cognitive-emotional re-appraisal capacity, high neuroticism, younger age, and an impersonal laboratory setting predicted unpleasant and anxious reactions to psilocybin, and high absorption capacity, esthetic sensibility, and VIS predicted heightened visual perception, reduced stimulus-color consistency, and changed meaning.

Given the current experimental limitations, further studies are needed to replicate these findings using well-power, placebo-controlled designs, and more diverse populations.

A better understanding of non-pharmacological variables is crucial for the fine-tuning of the acute experience and for producing enduring beneficial effects after drug intake. However, not every study found an increase in openness as a personality trait or a correlation between the overall mystical experience and the enduring therapeutic effects.

Receptor activation and pharmacological effects of psychedelics

Psilocybin, DMT, and LSD act as partial agonists upon 5-HT1, 5-HT2, 5-HT6, and 5-HT7 receptors, while mescaline and DOI are selective agonists at 5-HT2A, 5-HT2B, and 5-HT2C sites. The 5-HT2A receptor is thought to contribute to the attention-disrupting effects of psilocybin in humans.

The Altered State of Consciousness Questionnaire (5D-ASC) and the Mysticism Scale (M-Scale) are used to predict acute and long-term effects of psychedelics. High trait openness, absorption capacity, optimism about life, non-judgmental emotion regulation strategy, older age, pleasant ambiance, supportive music, meditation practice, and high emotional re-appraisal capacity predict positive experiences.

Studies specifically blocking dopaminergic receptors after LSD administration are currently lacking, but high doses of LSD activate TAAR1 receptors in the ventral tegmental area, which may provide a novel target for the treatment of LSD-induced psychotic-like symptoms.

Neuroplastic effects of psychedelics

Preclinical studies have shown that LSD and DOI increase cortical glutamate levels and layer 5 pyramidal cell activity in the prefrontal cortex, which in turn increases the gene expression of brain-derived neurotrophic factor (BDNF). DOI, LSD, psilocybin, and DMT produced structural and functional neuronal plasticity in prefrontal cortical neurons in vitro and in vivo. However, a recent study in mice found that blocking 5-HT2A receptors with ketanserin did not block psilocybin’s neuroplastic and antidepressant-like behavioral effects.

To date, only a few studies have investigated how psychedelics affect the brain. Psilocybin and DOI have been shown to increase neuroplasticity and speed up fear-extinction in mice. LSD increased medial prefrontal cortex excitatory neurotransmission and mTOR signaling in mice, and psilocybin strengthened synaptic transmission in the hippocampus. These effects were independent of 5-HT2A receptor activation, at least in these paradigms tested so far. There is a correlation between BDNF plasma levels 48 hours post-treatment and symptom improvements in ayahuasca for depression, but not in LSD. Further studies are needed to investigate how these neuroplastic effects relate to long-lasting symptom improvements.

States

Recent human neuroimaging studies support the hypothesis that psychedelic compounds alter thalamic gating, signal diversity, cortical connectivity, and temporal dynamics.

Thalamic gating model

Psychedelics disrupt the cortico-striato-thalamo-cortical (CSTC) feedback loops, which are crucial in gating external and internal information to the cortex and thereby regulating the level of consciousness and attention. This could ultimately cause the increased sensory perception, cognitive disturbances, and ego-dissolution that arise in psychedelic experiences.

LSD dose-dependently reduced firing activity of reticular thalamus GABAergic neurons and increased firing activity of infralimbic prefrontal pyramidal neurons in mice, leading to cognitive impairments. LSD increased functional connectivity between the thalamus and sensory-somatomotor cortical regions, decreased connectivity to the temporal cortex, and decreased control of the ventral striatum over the thalamus. According to the hypothesis that disruption of thalamic gating leads to sensory overload of the frontal cortex, psilocybin increases prefrontal glucose metabolism, and psilocybin decreases prefrontal and temporal CBF. However, the interpretation of such changes depends on the analytical methods used.

Perturbational imaging, such as EEG combined with TMS, can be used to assess drug-induced changes in brain state in real-time. This technique is currently being used to probe psychedelic-induced changes in cortico-thalamo-cortical dynamics in humans.

Neural Entropy model

The “entropic brain hypothesis” states that altered states of consciousness can be indexed through the information-theoretic measure of the entropy of key parameters of brain activity. This entropy increases with the intensity of the psychedelic experience and is also correlated with increased Shannon entropy. A mechanistic simulation model of the entropic effects of LSD suggests that 5-HT2A receptor activation leads to an increase in the overall entropy of the neural signals, but not uniform across brain regions.

The working hypothesis of psychedelic drug effects on cortico-striato-thalamo-cortical and cortico-cortical circuits of information flow is based on data obtained from studies with LSD and DOI in animals and humans. 5-HT2A receptors are found in the apical dendrites of layer 5 pyramidal neurons and on GABAergic interneurons in the cortex. LSD and DOI increase extracellular glutamate levels via activation of 5-HT2A receptors on deep layers 5 and 6 pyramidal neurons, as well as on Lp6 neurons projecting to L5p neurons. This increases glutamate release and promotes synaptic plasticity via AMPA and NMDA receptor-dependent mechanisms. L5P neurons affect both thalamic and cortical processing, and are thought to couple thalamo-cortical and cortico-cortical loops of information streams with each other. Psychedelics appear to affect this extended thalamo-cortical broadcasting system and thus consciousness as a whole.

LSD and psilocybin decrease the top-down information flow from the frontal cortex, leading to decreased bottom-up information flow and increased signal diversity. This may explain why psilocybin and DMT reduce the sensation of body touch and the experience of disembodiment.

Models of information processing and neuronal population coding are important tools for interpreting neurophysiological changes induced by psychedelic drugs. However, distinguishing correlation from causation remains a challenge for neuroscience in general. When borrowing terminology from other disciplines, it is important to anchor the terminology to signal properties and the experimental paradigm used. Spontaneous activity is the preferred terminology, and can be considered structured noise and therefore a measure of signal diversity.

Integration

Several neuroimaging studies have investigated the impact of psychedelics on brain network dynamics by measuring resting-state functional connectivity changes between and within intrinsic networks. They found that both drugs increased connectivity of brain regions in sensory and somatomotor networks and decreased connectivity of brain regions in associative networks. Two studies investigating the effects of LSD on GBC, although without using GSR, reported no overlapping results, except for increased functional thalamic connectivity. The decision to use or forgo GSR remains a point of contention. A recent whole-brain model, which incorporates the dynamical mean-field quantitative description of excitatory and inhibitory neuronal populations as well as the associated synaptic gain function, suggests that the effect of LSD on global brain connectivity can be best explained by the regional distribution and density of 5-HT2A receptors. Psychedelics alter the functional network connectivity between the DMN and other intrinsic networks, although no uniform pattern of changes has emerged so far.

Psilocybin, LSD, and DMT decrease functional connectivity within the default mode network (DMN), which is involved in self-other distinction, self-related cognition, and inward-versus outward-directed mentalizing. This decreased FC is correlated with the intensity of the acutely experienced self-dissolution (OB) and predicts positive changes in psychosocial functioning.

MEG/EEG studies reveal that psilocybin, LSD, and DMT reduce spontaneous oscillatory power of low-frequency signals in the DMN, parahippocampal regions, and parieto-occipital and posterior association cortices, and increase low and high gamma power in frontal, temporal, and parieto-occipital cortices. Gamma oscillations are thought to provide a neuronal mechanism for representation, storage, and retrieval of information, and may be involved in many cognitive processes, including autobiographical memory retrieval and awareness of one’s own internal state.

Neural Correlates of Altered Self- and Emotion-Processing in the Psychedelic States

Early clinical observations suggested that psychedelics induce regression of the self, lowering of rational thinking, increased affectivity, and facilitated recall of memory blocks. These mechanisms may contribute to the clinical efficacy of psychedelic-assisted psychotherapy.

Self-Processing

Psychedelics profoundly alter various aspects of the ordinary coherent self-experience. Several studies have attempted to capture the neural correlates of these phenomena by correlating psychometrically assessed subjective alterations in self-experience with brain imaging data.

In fMRI studies, the subjective reports of ego-dissolution correlated with increased global brain connectivity in the somatomotor network and the angular gyrus, and with decreased delta and alpha power in the PCC. Psilocybin-induced spiritual experience and insightfulness correlated with lagged phase synchronization of delta oscillations.

Recent neurocognitive approaches to the self suggest that the self is a multi-layered representation of internal and sensory stimuli, emotions, and cognition, bound to a sense of being, ownership of a body, and a history. A recent study found that psilocybin abolished self-stimuli encoding via a P300 mechanism, and reduced tactile mismatch processing in prefrontal cortex regions that correlated with the extent of disembodiment and changed meaning. This suggests that psilocybin disrupts belief updating within the framework of predictive coding.

The results of this study indicate that there is no clear neural correlate of altered self-experience or ego-dissolution in psychedelic states. However, the investigation of self-referential processing may offer a promising alternative operationalized approach to unravel the neural correlates of altered self and ego-dissolution.

These studies are important for getting a deeper insight into the different organizing principles and processing levels that constitute our self, and for understanding the efficacy of psychedelic-assisted therapy. Clinical observations suggest that reduced self-referential processing and self-centeredness leads to decentering, which facilitates more appropriate reactions to one’s own cognitions and reduces dysfunctional attitudes towards the self. This may be important in psychedelic-assisted psychotherapy of depressed patients.

Emotional Processing

Several studies have shown that psychedelics acutely alter emotion processing, and particularly reduce the response to negative emotional stimuli. Psilocybin and LSD reduced the recognition of negative facial expression in healthy volunteers, and reduced the neuronal response to negative stimuli in the amygdala.

A recent open-label study in depression reported increased amygdala reactivity and decreased amygdala-prefrontal cortex FC one day after psilocybin administration. However, this study did not measure the long-term effects of psychedelics on amygdala reactivity and its clinical relevance.

Conclusion

The biological mechanisms of classical psychedelic drugs remain a promising research endeavor, but a complex socio-political history hinders progress. Psychedelic experiences have broadly defined phenomenological trajectories, which make them accessible to researchers via psychometrics. These experiences can be modified by administering other drugs concomitantly to target specific receptor subtypes. Psychedelic drugs affect neuronal pathways necessary for cortico-thalamic and cortico-cortical feedback circuits, and can participate in neuroplasticity within structures critical for information processing in the brain. These theories are based on biological (statistical) thermodynamics, using the concepts of entropy and information, in combination with the necessary receptor-mediated dynamics.