Bedside to bench: the outlook for psychedelic research

Abstract

There has recently been a resurgence of interest in psychedelic compounds based on studies demonstrating their potential therapeutic applications in treating post-traumatic stress disorder, substance abuse disorders, and treatment-resistant depression. Despite promising efficacy observed in some clinical trials, the full range of biological effects and mechanism(s) of action of these compounds have yet to be fully established. Indeed, most studies to date have focused on assessing the psychological mechanisms of psychedelics, often neglecting the non-psychological modes of action. However, it is important to understand that psychedelics may mediate their therapeutic effects through multi-faceted mechanisms, such as the modulation of brain network activity, neuronal plasticity, neuroendocrine function, glial cell regulation, epigenetic processes, and the gut-brain axis. This review provides a framework supporting the implementation of a multi-faceted approach, incorporating in silico, in vitro and in vivo modeling, to aid in the comprehensive understanding of the physiological effects of psychedelics and their potential for clinical application beyond the treatment of psychiatric disorders. We also provide an overview of the literature supporting the potential utility of psychedelics for the treatment of brain injury (e.g., stroke and traumatic brain injury), neurodegenerative diseases (e.g., Parkinson's and Alzheimer's diseases), and gut-brain axis dysfunction associated with psychiatric disorders (e.g., generalized anxiety disorder and major depressive disorder). To move the field forward, we outline advantageous experimental frameworks to explore these and other novel applications for psychedelics.

Keywords: DMT; MDMA; ayahuasca; ketamine; mechanism of action (MOA); psilocybin; psychedelics; salvinorin.

FIGURE 1

Therapeutic applications of psychedelics that have been demonstrated clinically. The clinical efficacy is likely mediated synergistically by multiple mechanisms of action. The size of each circle is proportional to the amount of evidence for this mechanism of action. There are circles left empty as a reminder for the yet validated mechanisms.

FIGURE 2

Psychedelics functionally dissolve high-level networks, disrupt hierarchical predictive coding, and induce a high entropy state. (A) This is a visualization of hierarchical predictive coding as used in formulating the Relaxed Brain Under Psychedelics Theory (ReBUS). In this computation architecture, sensory input arrives at the sensory epithelia and is compared with descending predictions. The prediction error is passed forward into hierarchies to update expectations at higher levels (blue arrow). Posterior expectations then generate predictions of representations in lower levels via descending predictions (teal arrow). Neuronal network computation tries to minimize the prediction errors at each level of the hierarchy, which appears as free energy minimization in the landscape of neuronal dynamics. Psychedelics sensitizes higher-level expectations to incoming sensory information and attenuates predictive coding. This can be represented as a flattening the free energy landscape, which allows computational flexibility. (B) This decrease in intra-network and increase in inter-network activity can also be denoted as an increase in entropy, or number of possible states within the multi-dimensional matrix of possible network states. High entropy states lend themselves to higher cognitive flexibility. (C) Between-network connectivity between nodes (spheres) within these networks (distinct colors) is enhanced under psychedelics, further disrupting typical function of the affected networks. (D) The intra-network (or within-network) variance for various neural networks, notably the DMN and salience networks, is significantly increased under the influence of psilocybin. This disruption of coordinated within-network activity is akin to functional disintegration of neural networks. (A,D) are adapted from Carhart-Harris et al Pharmacol. Rev. (2019) and Carhart-Harris et al Front. Hum Neuroscience (2014), respectively. (D) is adapted from Petri et al J. R. Soc. Interface (2014).

FIGURE 3

Psychedelics (e.g., DMT, DOI, LSD) are potent plasticity inducing compounds, e.g., psychoplastogens. Psychedelics can increase neuritogenesis, spinogenesis, and synaptogenesis. The capacity for psychedelics to induce neuronal plasticity might mediate therapeutic efficacy against mood disorders such as depression.

FIGURE 4

Psychedelics may modulate HPA axis signaling. (A) This schematic shows the healthy stress response within the Hypothalamus-pituitary-adrenal axis within the neuroendocrine system. The hypothalamus (1), which is composed of multiple sub-regions (colored), secretes corticotropin-releasing hormone (CRH), which induces Adrenocorticotropic hormone (ACTH) secretion from the anterior pituitary (2), which induces cortisol release from the adrenal gland. Cortisol imparts various metabolic effects and regulates the HPA axis in a negative feedback loop. (B) This schematic shows the pathway for stimulation of melatonin. In response to day-light, the superchiasmatic nucleus (SCN), a subregion of the hypothalamus, will release GABA which will allow for downstream excitation of the Superior Cervical Ganglion (SCG). The SCG will release norepinephrine directly onto the pineal gland which produces melatonin. Melatonin will regulate SCN activity in a negative feedback loop and regulate circadian rhythm, immune function, and the endocrine system. (C) The neurons in the hypothalamus which produce CRF can be directly excited by norepinephrine or serotonin and inhibited by opioids and GABA. Psychedelics, e.g., LSD and salvinorin A, may directly regulate HPA activity by acting directly on these CRF-producing neurons. This is merely one example, there are multiple nodes within the HPA, and other endocrine systems, which express receptors that would have an affinity to various psychedelic compounds.

FIGURE 5

Glial cells, e.g., oligodendrocytes (green), astrocytes (purple), and microglia (orange), modulate a wide array of neuronal (orange) processes. (A) Microglia, the resident immune cell of the brain, mediates phagocytosis of debri, and have even been implicated in synaptic pruning (a crucial process in memory formation). (B) Astrocytes and microglia also release neutrophins, e.g., BDNF and GDNF, growth factors, e.g., NGF, and cytokines, e.g., IL-10. (C) Tessellating astrocyte networks, syncytium, composed of gap-junctions (astrocyte-astrocyte communication) and tripartite synapses (neuron-astrocyte communication) has been proposed to mediate higher-level cognitive processes. Although astrocytes are electrically inert, they mediate information processing via Ca²⁺ wave oscillations. Also, astrocytes express receptors for all neurotransmitters and neuromodulators, allowing for accurate sensing of neuronal network activity. (D) Oligodendrocytes primarily mediate myelination of axons, however, astrocytes regulate this process as well. (E) Astrocytes form a tripartite synapse by encasing neuronal pre-synaptic and post-synaptic terminals. They can regulate neuronal plasticity, e.g., synaptogenesis, and tune synaptic strength. (F) Astrocytes regulate blood brain barrier (BBB) activity, i.e., increase cerebrovascular blood flow in response to neuronal activity, and facilitate nutrient transport to neurons.

FIGURE 6

Psychedelics can affect gene expression. (A) Histone (blue cylinder) modification, e.g., methylation, acetylation, ubiquitination, and phosphorylation, can impact gene expression by adjusting chromatin morphology. (B) DNA methylation, by which methyl groups are added to the DNA backbone, can suppress gene transcription. (C) Finally, miRNA can cleave mRNA and repress translation, or mark mRNA for degradation., ultimately silencing expression.

FIGURE 7

Psychedelics can affect gene expression. Review of the various components of the Gut-Brain axis which may modulate the effects of psychedelic compounds.

FIGURE 8

Review of possible mechanisms of action by which various psychedelic compounds may attenuate the pathophysiology of and enhance recovery from neurodegenerative disorders.

FIGURE 9

Review of possible mechanisms of action by which various psychedelic compounds may attenuate the pathophysiology of and enhance recovery from brain injury disorders.

FIGURE 10

Review of possible mechanisms of action by which various psychedelic compounds may attenuate intestinal inflammation.