Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders

This review (2020) gives a high-level overview of psychedelics and their (potential) role in the treatment of mental disorders.

Abstract

“Renewed interest in the use of psychedelics in the treatment of psychiatric disorders warrants a better understanding of the neurobiological mechanisms underlying the effects of these substances. After a hiatus of about 50 years, state-of-the art studies have recently begun to close important knowledge gaps by elucidating the mechanisms of action of psychedelics with regard to their effects on receptor subsystems, systems-level brain activity and connectivity, and cognitive and emotional processing. In addition, functional studies have shown that changes in self-experience, emotional processing and social cognition may contribute to the potential therapeutic effects of psychedelics. These discoveries provide a scientific road map for the investigation and application of psychedelic substances in psychiatry.”

Authors: Franz X. Vollenweider & Katrin H. Preller

Notes

This paper is included in our ‘Top 10 Articles for Psychedelic Novices‘

Summary

In this article, we review the advances that have taken place in recent years in the study of psychedelic substances. We discuss potential therapeutic effects and highlight knowledge gaps.

The neurobiology of psychedelics

The classic psychedelics comprise three main classes of chemicals, including plant- derived indoleamines, phenylalkylamines and semi- synthetic ergolines. These compounds are selective agonists of 5- HT2 receptors.

After a hiatus of about 50 years, studies have begun to reveal the neurobiological mechanisms underlying the effects of psychedelics. These studies provide a scientific road map for the investigation and application of psychedelic substances in psychiatry.

Psilocybin can also exert antidepressant or neuroplastic effects in humans, and may increase striatal dopamine concentrations via 5-HT1A receptor activation. LSD may also increase dopamine concentrations via dopamine D2 receptor activation.

5-HT2A receptors are highly expressed in layer 5 pyramidal neurons in the cortex and are particularly enriched in the PFC. Psychedelics may exert different modulatory effects across cortical regions, depending on the dose, the specific drug used and – presumably – the density of 5- HT2A receptors in different neuronal populations.

LSD and DOI induce increased L5p neuron activity in the PFC, which is mediated by an increase of glutamate release and a subsequent activation of postsynaptic AMPA receptors. However, activation of presynaptic 5-HT2A receptors on thalamocortical afferents may also contribute to this increase.

Altered activity and connectivity

5-HT2A receptor activation can have profound neuromodulatory effects, which can be measured using functional MRI or electrophysiological techniques. These studies suggest that thalamic gating, between- network and within- network integration and temporal dynamics are affected by psychedelic compounds.

Evidence for altered thalamic gating is presented. It is suggested that psychedelics disrupt thalamic gating by stimulating 5- HT2A receptors located in several parts of the cortico-striato-thalamo- cortical (CSTC) feedback loop, resulting in a feedforward information overload of the cortex and subsequent disruption of cortico- cortical integration of distributed neuronal activity.

The CSTC model is supported by evidence that psychedelics disrupt sensorimotor gating and are associated with alterations in cognitive functioning. Two neuroimaging studies have provided further support for this model.

Using functional global brain connectivity, it was found that the integration of sensory and somato-motor brain networks increased and the disintegration of associative brain networks decreased after LSD and psilocybin administration. This finding is consistent with the crucial role of the 5-HT2A receptor in systems- level changes induced by psychedelics. FiguRe 2 presents an integration of the reported changes in thalamic gating discussed above with the neuroimaging results obtained under the influence of psychedelics. Two additional studies have investigated the effects of LSD on global brain connectivity, but did not show overlapping results.

Several studies have demonstrated changes in functional connectivity between nodes of different intrinsic brain networks after the administration of psychedelics, however, the results reported have often been inconsistent91.

Evidence for altered entropy can be observed as changes in fast electrophysiological dynamics. These changes can influence the precision of neuronal message transfer. Psychedelics reduce the precision of high-level priors and increase bottom-up information flow, which increases the entropy and complexity of accompanying neuronal dynamics. This is reflected in increased sample entropy, increased repertoire of different brain states, and increased Shannon entropy.

The REBUS model hypothesizes that psychedelic-induced increased entropy reflects a relaxation of the precision weighting of priors, leading to decreased top- down and increased bottom- up information flow. However, other studies have not observed reductions in surprise responses.

Psychedelics are used in therapy to release emotion and ease emotionally loaded memory blocks. They increase positive and negative mood, emotional excitation and sensitivity, and can lead to emotional breakthroughs.

Studies have shown that psychedelics can reduce the response to negative emotional stimuli in a controlled research setting. Additionally, psilocybin can increase positive mood by increasing resting-state functional connectivity between the amygdala and the frontal cortex. The results of studies testing the effects of psychedelics on specific cognitive or emotional tasks may be influenced by global impairments, but none of the studies revealed global impairments.

A negative cognitive and emotional bias is a core symptom of major depression disorder. Psychedelics may improve mood by reducing negative emotions.

Psychedelics can have a profound impact on the experienced sense of self, reducing the differentiation between self and others and increasing the perception of self- relevance and meaningfulness of external stimuli.

Recent studies have attempted to identify the neural correlates of ego dissolution by correlating psychometrically assessed subjective alterations in self- experience with brain imaging data. However, different results have been obtained with different methods, suggesting that a single neural correlate of ego dissolution may not exist.

Self- dissolution, often referred to as mystical- type experiences, has been shown to be positively correlated with treatment success in addiction, depression and anxiety in palliative care, and in major depression.

LSD and psilocybin have been shown to acutely modulate social processing in healthy participants12,20,114,138. These effects may reduce social withdrawal behavior and improve the patient – therapist relationship during psychedelic- assisted treatment4.

The long-term effects of psychedelics on social processing have currently scarcely been investigated. However, self-reported increases in interpersonal closeness, positive and altruistic social effects, and emotional empathy have all been reported.

In clinical studies with psilocybin, individuals with various psychiatric conditions identified social factors as contributing to their disease, and reported improvements after psilocybin- assisted therapy. This suggests that psilocybin- assisted therapy may reinstate social reward processing, helping people to overcome their addiction.

The therapeutic relevance of psychedelic-induced mental imagery is currently not well understood. However, it may have long-term beneficial effects on psychosocial functioning and well-being.

Psychedelics are an excellent tool for studying the 5-HT receptor system, particularly when used in combination with specific 5-HT receptor antagonists.

Studies show that the 5- HT2A receptor system is involved in emotional, social and self-processing. A 5- HT2A receptor agonist may be effective in depression and addiction but not in schizophrenia spectrum disorders.

LSD alters self-processing and social cognition, and this effect is blocked by ketanserin. This suggests that aberrant 5- HT2A receptor-mediated sign alling underlies these interdependent changes in self-perception and social processing, and that 5- HT2A receptor antagonists may be beneficial for individuals with incoherent self-experience and social withdrawal.

Studies have shown that psychedelics improve social functioning, reduce negative emotional processing and enhance self-focus. These effects may be trans-diagnostic mechanisms for the treatment of psychiatric illnesses.

Studies in patient populations show that psychedelics may constitute promising therapeutic agents that represent a novel treatment model in psychiatry. However, many open questions remain, including whether the therapeutic effects of these substances are due to their direct effects on brain activity and connectivity or due to the cognitive and psychological experience of an altered state of consciousness.

LSD (Lysergic Acid Diethylamide) is an important psychoactive drug used to treat alcoholism and other disorders. It has many different uses and effects on the brain.

Serotonin modulates cortical neurons and networks through 5-HT2A receptors, which are involved in the asynchronous mode of glutamate release in layer V pyramidal cells of the prefrontal cortex. The mechanisms of hallucinogens on neuronal activity are well described in several papers, including Wood, J., Kim, Y. & Moghaddam, B., Llado- Pelfort, L., Mladenovic, L., Gingrich, J. A. & Andrade, R., Zhang, C. & Marek, G. J. Larkum, M., Disner, S. G., Beevers, C. G., Haigh, E. A. & Beck, A. T. discussed the cellular mechanism for cortical associations in their articles. Meltzer, H. Y., Northoff, G., Carhart- Harris, R. L., Brugger, S., Nutt, D. J. & Stone, J. suggest that serotoninrgic mechanisms are targets for existing and novel antipsychotics. Serotonin 2A receptors regulate memory consolidation and extinction in the C57BL/6J mouse model, and psilocybin increases extracellular glutamate levels in the rat prefrontal cortex.

58 studies have shown that positive AMPA receptor modulation rapidly stimulates brain-derived neurotrophic factor release and increases dendritic mRNA translation, 59 studies have shown that BDNF restores long-term potentiation in middle-aged hippocampus, and 60 studies have shown that BDNF restores plasticity at prefrontal cortex synapses. Several studies have shown that 5-HT2A receptors in the ventral pallidum are involved in prepulse inhibition of startle in rats, humans, and animals. These studies have also shown that ketanserin attenuates the effects of psilocybin on prepulse inhibition of startle in humans. A double-blind, placebo-controlled PET study with [18F]FDG revealed that psilocybin, 3,4-methylenedioxyethylamphetamine (MDE) and d-methamphetamine increased brain activation in healthy volunteers and that these effects were accompanied by increased blood flow to the brain.

105 – 106. Tagliazucchi, E., Carhart- Harris, R., Leech, R., Nutt, D. & Chialvo, D. R. (2017). LSD impairs fear recognition and enhances emotional empathy and sociality: implications for psychedelic-assisted psychotherapy. Psilocybin also impairs mismatch negativity generation and AX-continuous performance task and predicts S-ketamine-induced cognitive impairments. Psilocybin biases facial recognition, goal-directed behavior, and mood state toward positive relative to negative emotions through different serotonergic subreceptors, and ketamine and psilocybin produce dissociable effects on structural encoding of emotional face expressions. LSD and psilocybin reduce amygdala activity during processing of fearful stimuli in healthy subjects, and psilocybin enhances positive mood. Psilocybin modulates functional connectivity of the amygdala during emotional face discrimination and LSD preliminarily modulates resting-state amygdala functional connectivity. Psilocybin can alter emotions and brain function up to one month after a single high dose.

Psilocybin-induced alpha oscillations, N170 visual-evoked potentials, and visual hallucinations are accompanied by increased amygdala responses to emotional faces, and changes in amygdala and prefrontal functional connectivity during emotional processing, which may be therapeutic for treatment-resistant depression. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double- blind trial. Psilocybin- occasioned mystical-type experience in combination with meditation and other spiritual practices produces enduring positive changes in psychological functioning and in trait measures of prosocial attitudes and behaviors. Psilocybin-occasioned mystical-type experiences mediate the attribution of personal meaning and spiritual significance 14 months later. Psilocybin- assisted mindfulness training modulates self- consciousness and brain default mode network connectivity with lasting effects.

LSD, DOI, and other hallucinogens are potent partial agonists at 5-HT2A receptors on interneurons in rat piriform cortex, and these hallucinogens enhance pyramidal cell firing in prefrontal cortex through a preferential action on GABA interneurons. Resting-state fMRI confounds and cleanup, global signal regression for functional connectivity MRI, altered global signal topography in schizophrenia, arterial spin labeled perfusion MRI, psilocybin, paroxetine and bupropion effect on resting cerebral blood flow, and a pilot study of 5-HT2AR agonists.

Psilocybin is used in the treatment of tobacco addiction, ayahuasca is used in the treatment of recurrent depression, and a SPECT study is performed on psilocybin and ayahuasca in patients with recurrent depression. Psilocybin for treatment-resistant depression: fMRI- measured brain mechanisms. Brakowski, J., Gasser, P., Palhano- Fontes, F., Grob, C. S., et al. studied lysergic acid diethylamide for anxiety associated with life-threatening diseases.