This review (2021) makes the case for using psychedelics to treat pain. Key areas discussed include studies that have directly used psychedelics to treat pain, potential neuro-restorative effects of psychedelics in pain-related states of consciousness, anti-neuroinflammatory and pro-immunomodulatory actions of psychedelics and the safety, legal, and ethical consideration inherent in psychedelics’ pharmacotherapy. Psychedelics could also help to elucidate the mechanism of pain syndromes.

Abstract

“Basic pain research has shed light on key cellular and molecular mechanisms underlying nociceptive and phenomenological aspects of pain. Despite these advances, [we still yearn for] the discovery of novel therapeutic strategies to address the unmet needs of about 70% of chronic neuropathic pain patients whose pain fails to respond to opioids as well as to other conventional analgesic agents. Importantly, a substantial body of clinical observations over the past decade cumulatively suggests that the psychedelic class of drugs may possess heuristic value for understanding and treating chronic pain conditions. The present review presents a theoretical framework for hitherto insufficiently understood neuroscience-based mechanisms of psychedelics’ potential analgesic effects. To that end, searches of PubMed-indexed journals were performed using the following Medical Subject Headings’ terms: pain, analgesia, inflammatory, brain connectivity, ketamine, psilocybin, functional imaging, and dendrites. Recursive sets of scientific and clinical evidence extracted from this literature review were summarized within the following key areas: (1) studies employing psychedelics for alleviation of physical and emotional pain; (2) potential neuro-restorative effects of psychedelics to remediate the impaired connectivity underlying the dissociation between pain-related conscious states/cognitions and the subcortical activity/function leading to the eventual chronicity through immediate and long-term effects on dendritic plasticity; (3) anti-neuroinflammatory and pro-immunomodulatory actions of psychedelics as the may pertain to the role of these factors in the pathogenesis of neuropathic pain; (4) safety, legal, and ethical consideration inherent in psychedelics’ pharmacotherapy. In addition to direct beneficial effects in terms of reduction of pain and suffering, psychedelics’ inclusion in the analgesic armamentarium will contribute to deeper and more sophisticated insights not only into pain syndromes but also into frequently comorbid psychiatric conditions associated with emotional pain, e.g., depressive and anxiety disorders. Further inquiry is clearly warranted into the above areas that have potential to evolve into further elucidate the mechanisms of chronic pain and affective disorders, and lead to the development of innovative, safe, and more efficacious neurobiologically-based therapeutic approaches.”

Authors: Igor Elman, Amanda Pustilnik & David Borsook

Author Highlights:

• There is an unmet need for adequate treatment for chronic pain.

• Psychedelics offer a potential promise for such treatments through neurorestorative effects (dendritic sprouting) and anti-inflammatory effects.

• The utility of psychedelics for chronic pain needs to be rigorously evaluated through appropriate randomized controlled studies

Summary

Highlights

Basic pain research has shed light on key cellular and molecular mechanisms underlying nociceptive and phenomenological aspects of pain. However, there is still a need for novel therapeutic strategies to address the unmet needs of chronic pain patients.

Ketamine, psilocybin, fMRI, brain, connectivity, neurotransmitters, inflammation, immunomodulation, opioids, dendritic plasticity, synaptosomes, analgesics, safety, legal, and ethical considerations were used to review the scientific and clinical evidence on the use of psychedelics for alleviation of physical and emotional pain.

The pain system is normally protective or adaptive, but chronic pain may have adverse effects on an individual’s physical and psychological function and social well-being. Chronic pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, and is notoriously difficult to treat. It affects sensory, emotional, and cognitive processes, and may produce centralization of pain, alter reward processing, and also may Journal Pre-proof.

Chronic pain states and psychiatric illness may be caused by immunomodulatory and inflammatory mechanisms. Novel and improved therapeutic strategies are needed to treat chronic pain. The use of opioid analgesics for acute and chronic pain has been around for millennia, but there are two major concerns: opioid use disorder (OUD) and increased risk of harm from long-term use of opioids for chronic pain.

There are many problems with use of opioids for chronic pain, including overdose and suicide, opioid-induced endocrinopathies and enhanced affective processes such as fear, anxiety and other negative affective states. There is an urgent need to develop alternative therapies with better outcomes while minimizing side effects. Psychedelic drugs are newly emerging as CNS-acting analgesics, with the greatest research interest focused on their defining psychoactive properties and their use in depression.

Psychedelics may have value in treating chronic pain conditions through specific mechanisms, including rapidity and persistence of response, synaptic plasticity, and induction of therapeutic benefit as to other conditions, independent of psychoactive effect and subjective experience.

In this review, we evaluate the potential of psychedelics as analgesics, and discuss the potential consequences of these effects on the brain, including pain, and the legal aspects of psychedelics as analgesics. Psychedelics are powerful psychoactive substances that alter perception and mood and affect numerous cognitive processes. They may be therapeutically beneficial for patients with chronic pain who respond poorly to opioid therapy or other analgesics.

Psychedelic drugs affect glutamatergic neurotransmission, which is involved in the mechanisms of psychedelics’ action. Moreover, tryptamines, phenethylamines and lysergamides improve brain connectivity, which may lead to amelioration of pain symptoms. Psychedelics have been used by many communities since ancient times to treat depression, anxiety, post-traumatic disorder and other conditions. Recent studies have shown that these drugs may have analgesic effects in patients with chronic pain.

A recent interest in understanding psychedelic effects of various drugs including psilocybin, on brain function and resulting therapeutic effects has been spurred on by two main drivers – (1) the relative lack of efficacy of other drugs and (2) more rigorous research on psychedelics for psychiatric disease. There is interest in the potential use of psychedelics for the treatment of chronic pain, based on the experience that these drugs may provide therapeutic benefit in some psychiatric disorders, notably depression.

Psilocybin use attenuates opioid use in OUD, and ECT has been used in treating chronic pain. However, there are limited reports on the use of psychedelics in chronic pain. Although not robust studies in terms of number of patients enrolled, the potential use of psychedelics as analgesics is intriguing. Clinical reports of psychedelics for pain are not common in the peer- reviewed literature, although unsubstantiated reports on the web suggest that ibogaine may have analgesic effects. There are a few clinical trials on the use of psychoactive drugs and pain, including psilocybin, lysergic acid, 3,4-methylenedioxymethamphetame (MDMA), commonly known as ecstasy, and ibogaine. Nonhallucinogenic psychogenic analogues of drugs like ibogaine may still have therapeutic efficacy.

Ketamine is used clinically as an anesthetic and analgesic for acute and chronic pain, and as an antidepressant. It has several interesting actions including: antagonism of glutamatergic NMDA receptors, stimulant and psychedelic effects, and sedation. Ketamine has been used as an antidepressant in refractory patients, including suicidality. The exact mechanism of action is not well known, but NMDA receptor inhibition neurons or interneurons have been postulated.

Ketamine has potent antinociceptive and anti-inflammatory effects, including actions on astrocytes/glial cells, endotoxin induced NF-kappa B and TNF-alpha activations/production, and hippocampal neurons. Ketamine’s effects on patients with refractory depression may target brain related processes, including the CNS. Ketamine also corrects inflammatory bone markers in depression and is protective in asthmatic patients as a bronchodilator.

Psychedelics including Ketamine may alter brain function and structure. Resting state measures of patients with chronic pain have shown decrease in connectivity strength between the medial prefrontal cortex (mPFC) and precuneus in responders vs. non-responders to subanesthetic doses. Ketamine normalizes high gamma power in the anterior cingulate cortex and has anti-inflammatory effects on astrocytes and brain derive neurotrophic factor. Ketamine has been shown to alter cortical areas, which may be a mechanism for the dissociative state.

Ketamine increases connectivity with the thalamus and decreases or inverts connectivity with other cortical areas, which may be why ketamine and possible psychedelics produce their alteration of consciousness/ expansion of consciousness through immediate effects on brain connectivity. Ketamine produces neurochemical effects including increased serotonin release and enhanced function of 5HT2A receptors. It has been used to treat chronic pain conditions including neuropathic pain, complex regional syndrome and fibromyalgia, but there are risks to the use of the drug.

Ketamine, considered a psychedelic by some, has effects that may be in common with other psychedelic drugs that are briefly defined below in the context of the agent being defined as a “scaffold” drug to develop the potential of psychedelics in the treatment of chronic pain.

Psilocybin produces its psychedelic effects via stimulation of the serotonin 2A receptor (5-HT2AR) in the human brain. Human PET studies show occupancy of these receptors in the anterior cingulate and frontal cortex, which correlate with activation as measured by fMRI. Activation of the 5HT2A receptor is to enhance pain, but this is not considered in the context of acute vs. prolonged dosing nor on dose ranging studies. The 5HT2A receptor gene is linked to common migraine, and psilocybin is being evaluated in clinical trials for headache/migraine.

Little is known about the effects of psychedelics on opioid receptors and systems, but evidence suggests that psychedelics may activate descending modulating systems that produce analgesia via cortico-brainstem systems involving the cingulate cortex, the raphe nuclei and the periaqueductal gray.

While chronic pain models show alteration in 5HT2A receptors, alterations in 5HT-2A receptor function is present in depression, which is frequently comorbid with pain. Psilocybin has been shown to alter brain function by altering consciousness, which is not via 5-HT2AR activity. The effects of psilocybin are not blocked by pretreatment with ketanserin, a 5-HT2A/5-HT2C antagonist.

Psilocybin acts on other receptor systems either directly or indirectly, and may produce effects such as increasing glutamate levels, decreasing fMRI surrogate measures of neuronal activity in brain regions, and decreasing opioid dependence and abuse. Psychedelics have been shown to have anti-inflammatory effects in the periphery and the CNS, which may be important in the treatment of chronic pain.

Multiple pain conditions including migraine, CRPS, and fibromyalgia have been shown to involve inflammatory processes in the brain, and the anti-inflammatory and immunomodulatory effects of non-psychoactive cannabinoids may have analgesic effects equal to or greater than the THC-derived psychoactive components of cannabis. Psychedelics produce an immediate effect on behavior that is a correlate of effects on brain function. These effects include altered cortical (retrosplenial) areas that alter brain function.

Ketamine may produce a dissociative state in mice that may correlate with a similar state in a patient with focal epilepsy. Perhaps psychedelics can shock the brain into producing new connections that enhance potential recovery/treatment. Studies have shown that psychedelics alter brain networks, including structural and functional studies in patients and healthy volunteers. These studies provide insight into the immediate effects of psychedelics as well as potential long lasting effects following the ‘altered brain state’ or ‘trance process’. Ketamine, a psychedelic, produces immediate and long-term changes in brain networks. These changes may modify circuits that amplify or maintain central components of chronic pain, and psychedelics may be used as potential therapeutics as analgesics for chronic pain through resetting functional connectivity.

Psychedelics have profound effects on sensory, emotional and cognitive processing, placing them in an ideal “theoretical domain” for their potential efficacy as analgesics. They may also act on analgesic pathways, anti-inflammatory, circuit modulator through changes in dendritic connections etc. The psychedelic state is considered to be an elevated “entropy” of brain function, and may reflect changes in unconscious processing or activation/modulation of circuits involved in behaviors including chronic pain.

The setting of use of psychedelics contributes significantly to the therapeutic effect. This notion has also been observed in the analgesic effects of opioids. Neuropharmacological agents including psychedelics may alter neural circuits, including dendritic trees and dendritic spines. These changes may alter functional connectivity, and may be a target for induction of synaptic plasticity in clinical models of chronic pain.

Dendritic tree stability can alter function, and this can be reflected in gray matter volume alterations. Psychedelics can alter dendritic tree stability, and this can contribute to persistent effects of psychedelic use. – Dendritic spine remodeling (spine morphology and density): Dendritic spines are small blobs or protrusions that contain synapses and altered brain function is associated with abnormal dendrite spine integrity. Psychedelics alter dendritic spine structure and contribute to structural plasticity in chronic pain. Psychedelics may alter brain regions involved in pain, including activity-dependent drive, by inducing dendritic density, including synaptic density, to create functional connectivity patterns that ‘normalize’ the pain state. This may be a promising line of research for treating both acute and chronic pain.

Research involving psychedelics is limited by existing legal frameworks and by the vulnerable population of chronic pain patients. Psychedelic drugs are restricted under US law, which is based on a trio of UN conventions dating to the 1960s – 1980s. Researchers must register with the DEA to conduct research on these drugs, and follow restrictive procedures for obtaining the compound. Researchers in other countries signatory to the UN Conventions face similar restrictions, but the legal and social climate is starting to thaw.

Researchers are calling for the DEA to deschedule or reschedule psychedelic drugs, to lift stringent production quotas, and for the Food and Drug Administration to issue emergency use authorizations for these drugs, to help open the door for research and experimental use in other conditions, including chronic pain.

Psychedelics are used for religious, social, and consciousness-expanding purposes, but they also have important medical applications. This raises potential tensions related to designing regulations that guarantee the same degree of rigor and safety as non-psychedelic agents, yet do not supplant or preclude the role of traditional healing and religious practices. Scholars have pointed out that formal regulation of psychedelics could limit autonomy to self-experiment and decenter traditional expertise. Moreover, the medicalization of psychedelics could restrict access to these compounds and their benefits among disadvantaged communities.

To ensure equity of access to psychedelics, a dual-registration system may be appropriate for practitioners who employ psychedelics, in parallel with decriminalization for individuals who self-administer. This system should make clear to patients and clients whether-or-not they are receiving medical treatment. In pain research, psychedelic drugs are used to treat pain. This research involves several considerations, including equitable access, enrolling subjects in trials, and patient-centered collaboration.

Ketamine, an S-isomer of ketamine, is a generic drug available in multiple modes of administration. There has been robust debate about the equity of patenting this therapy, but it would run counter to principles of equitable access to limit access to patented psychedelics. Researchers must be sensitive to patient expectations when studying psychedelics for chronic pain, as they have poor current treatment options, high levels of comorbidity, and high psychological distress.

Research into psychedelics for chronic pain is preliminary, and caution should be exercised before suggesting or even implying known therapeutic benefit. However, recent state-level changes that enable individuals to procure and use many (although not all) psychedelics without risk of prosecution may provide a wealth of ecological data to researchers.

We suggest that psychedelics may have value in treating chronic pain conditions and their associated distress both through psychoactive and significant, non-psychoactive mechanisms. Based on some of these processes, testable hypotheses on therapeutic and preventive interventions based on mechanistically informed psychedelic interventions may be developed.