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15 Articles in Volume 20, Issue #6
Using Photobiomodulation to Treat Trigeminal Neuralgia
20/20 with Mark Wallace: Where Cannabis Fits into Pain Practice
A Commentary on Opioid Stewardship: Fentanyl, Sufentanil, and Perioperative Pain
Adherence and Relapse – How to Maintain Long-Term Gains in Patients with Chronic Conditions
Advanced Practice Matters with Theresa & Jeremy: COVID, Pain, and Power
Analgesics of the Future: Janus Kinase Inhibitors
Case Report: Quadratus Lumborum Block for Managing Pathologic Pain to the Hip
Chronic Pain and the Short-term Effects of Medical Cannabis
Differential Diagnosis: Polymyalgia Rheumatica or Rheumatoid Arthritis
Genicular Nerve Blocks: Field Tips on Prognostic Value and Technical Considerations
Guideline Update: ACR Promotes Pharmacologic Treatment for Osteoarthritis
Navigating New York's Medical Marijuana Program: A Patient Handout
Person-Centered Care: Lessons from the VA’s Whole Health Model
Psychedelics for Chronic Pain: Is It Time?
Resident’s Corner: What Pain Medicine Education is Missing in the COVID Era

Psychedelics for Chronic Pain: Is It Time?

Psilocybin, MDMA, and other psychedelic drugs are growing in therapeutic interest and use – could they be game-changers in the pain management space, either for chronic conditions or their psychiatric comorbidities?

The results of our recent election were remarkable for several reasons, some not having anything to do with our new president. The growing acceptance of marijuana was confirmed by its legalization for recreational use in several states, and, perhaps even more indicative of the times, psilocybin, among other Schedule 1 drugs, was decriminalized in the District of Columbia and authorized to be studied and used therapeutically in Oregon. Psilocybin is the active compound found in “magic mushrooms.” (More on Oregon’s Measure 110.)

Psilocybin and MDMA are in Phase 3 studies for depression and PTSD – could they also help to relieve chronic pain?

While there has been increasing interest in and research on the use of psychedelics, such as psilocybin and MDMA (aka, ecstasy or molly), for depression, anxiety, PTSD, and other psychiatric  disorders, little research has been conducted to date on the use of psychedelics for chronic pain. Although clinical evidence for the use of psychedelic substances in chronic pain is limited, studies and case reports over the past 50 years have shown potential benefits in cancer pain, phantom limb pain, and cluster headache.1 In addition, a recent study showed that psilocybin could be helpful as part of group therapy to relieve the demoralization experienced by long-term AIDS survivors.2 As a psychological state characterized by helplessness, hopelessness, giving up, and subjective incompetence, demoralization has been linked to stress and adverse health outcomes such as chronic pain.


Historical Perspective

Classic psychedelics – including lysergic acid diethylamide (LSD), mescaline, 3,4-methylenedioxymethamphetamine (MDMA), and psilocybin –  have been administered as sacraments since ancient times. They have served as the catalysts for mystical experiences throughout various cultures and religions, in which they helped promote a strong sense of unity. Even now, clinical trials are underway to assess the effects of psychedelics on the attitudes of professional religious leaders.

In the 1950s and 1960s, psychedelics   gained interest within the psychiatry and neuroscience communities whose work contributed to the emerging field of molecular neuroscience. Promising results were reported for these drugs’ use in the treatment of end-of-life psychological distress and addiction, and they helped researchers study the neurobiological bases of psychological disorders. Several studies have suggested that non-medical use of psychedelics is associated with positive mental health outcomes but these substances have also caused harm to some individuals (more on this below).3

Research into classic psychedelics ended in the early 1970s, however, recreational use grew along with the counterculture. In recent years, though, there has been a renewed spike in research which has demonstrated the potential for classic psychedelics to treat mental health disorders. MDMA is in Phase 3 clinical testing, having received breakthrough designation from the FDA in 2017 for PTSD. The drug appears to cause the release of presynaptic serotonin, prolactin, and oxytocin, leading to decreased activity of the amygdala and increased activity of the prefrontal cortex. These changes induce a calm state that allows patients to re-examine and process traumatic memories into a more manageable series of events, thereby gaining control over their life stories. An analysis of Phase 2 studies showed that 54% of subjects treated with MDMA could no longer be diagnosed with PTSD, as opposed to 23% of those receiving placebo.4

Psilocybin is also in clinical development for depression, alcohol use disorder (AUD), and anorexia nervosa, among other conditions. The FDA assigned psilocybin a breakthrough therapy designation in 2018 and institutions such as the UC San Diego Arthur C. Clarke Center for Human Imagination have gotten involved. Along with other campus groups, they launched the Psychedelics and Health Research Initiative (PHRI), whose mission is to study the potential of psilocybin and other related compounds to promote healing and help manage pain. (More on this work on our new sister site, Psycom Pro.)

Psychedelics and Chronic Pain Mechanism

The mechanism for chronic pain is still not fully understood, although it is known that pain signals experienced over time cause a peripheral and central sensitization that transforms into a chronic physical and emotional pain experience. Research described by Joel P. Castellanos, MD, at the University of California San Diego, and colleagues, has shown that the mind-altering qualities of psychedelics, which can be attributed to serotonin 2A(5-HT2A) receptor agonism, can “reset” areas of functional connectivity (FC) in the brain that play prominent roles in many central neuropathic states.1

The mechanisms for providing analgesia are not clear but the similarity between 5-HT2A activation pathways of psychedelics and the nociceptive modulation pathways in humans make for several possibilities. The alterations in FC seen with psychedelic use suggest a way these agents could help reverse the changes in neural connections seen in chronic pain states such as cluster headache, complex regional pain disorder, phantom limb pain, and tinnitus.1

“Given the current state of the opioid epidemic and limited efficacy of non-opioid analgesics,” says Dr. Castellanos, “it is time to consider further research on psychedelics as analgesics in order to improve the lives of patients with chronic pain conditions.

But Are Psychedelics Safe?

In a letter to the editor following Dr. Castellano’s review, Mukhodomi and Mukhodomi urged caution against the addictive and side effect potential of chronic use of psychedelics.5 In response, Dr. Castellanos and colleagues wrote that a review of several studies found that lifetime use of psychedelics did not increase the risk of mental health disorders, panic attacks, or cognitive function.6 Moreover, while agreeing with preclinical research showing that LSD is a dopamine2 receptor agonist, they note that other D2 agonists, such as apomorphine, bromocriptine, pramipexole, and ropinirole, have never been found to be addictive.

Mukhodomi and Mukhodomi also questioned how psychedelics would be controlled for medical purposes.5 In their response, Dr. Castellanos and colleagues agreed that psychedelics’ medical use should proceed like any other prescription drug, comparing its development to ketamine. Ketamine, which produces hallucinogenic effects and has long been used as a recreational drug, was approved last year for the treatment of severe depression. “If ketamine can be used safely as an antidepressant medication, then there is no reason to think that psilocybin can not also be used safely as long as it is administered to patients under controlled conditions with proper screening and preparation,” wrote Dr. Castellanos.6

Psychedelics and Health Research Initiative

It is worth noting that one of the catalysts for the development of PHRI was an accident involving UC San Diego researcher Albert Yu-Min Lin, which resulted in the amputation of his leg. When nothing could relieve his phantom limb pain, including the use of mirror-visual-feedback (MVF), he added psilocybin.7  A single psilocybin/MVF session resulted in an immediate and profound reduction in debilitating pain.

While research has shown that exposure to psychedelic drugs promotes neuroplasticity, psilocybin’s effect against phantom limb pain may be because it causes new functional brain connections and pathways to form in brain regions that support body self-image and the experience of pain.

On the other hand, says Fadel Zeidan, MD, associate director for research at the UC San Diego Center for Mindfulness, it could be that the profound psychedelic experience, like mindfulness meditation,   facilitates a “restart mechanism” that modulates the feeling of pain. Psychedelics produce states of mind and brain connectivity that are similar to those of experienced meditators, and psychedelics and mindfulness are mutually supportive, according to Dr. Zeidan.

“MDMA and psilocybin have different mechanisms of action, but they may both act to disrupt overly stable functional neural networks,” wrote Andrew Penn, RN, in Psycom Pro.8 For example, someone with depression whose default experiential mode is an incapacitating rumination that prevents her from focusing on external tasks may, after psilocybin, be able to shift into a more flexible state that allows greater interaction with the demands of the environment.

The team at PHRI plans to study psychedelics to gain a better understanding of how they can be used to treat pain, as well as the mechanisms of action by which they produce their effects and how this understanding can shed light on the healthy functioning of the brain. Beginning with a pilot study on the effect of psilocybin on phantom limb pain, they plan to continue their research with clinical trials and brain imaging research.

Last updated on: November 19, 2020
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Ketamine for Chronic Pain Management: Current Role and Future Directions
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