Chronic pain education: past, present, and future of psychedelics for the management of chronic pain

Introduction

Known for their capacity to alter perception and consciousness, psychedelics are increasingly being explored for therapeutic applications in treating conditions such chronic pain, major depressive disorder, and post-traumatic stress disorder.^1,2 Despite historical stigmas and legal restrictions, recent changes in legislation and the United States Food and Drug Administration (FDA) recognition are driving renewed interest in these substances. To keep pace with this expanding field, medical education needs to integrate formal training on psychedelics. This report addresses the history, pharmacology, current state of psychedelic education, and outlines a proposed curriculum to prepare future clinicians for the evolving landscape.

Description of problem

Classic psychedelics, such as lysergic acid diethylamide (LSD), psilocybin, and N, N-dimethyltryptamine, primarily act as 5HT_2A receptor partial agonists, influencing areas of the brain involved in mood, perception, and decision-making.¹ Historically, these substances were used in spiritual and cultural rituals for thousands of years. The discovery of LSD in 1938 by Albert Hofmann marked the beginning of modern psychedelic research, with psychedelics gaining widespread popularity in the 1950s and 60s.

Activation of these receptors increases glutamate release, an excitatory neurotransmitter, disrupting neural circuits, and contributing to the effects of these drugs. Research has demonstrated that psychedelics can promote synaptic growth, release oxytocin, and exhibit anti-inflammatory effects.³ Magnetic resonance imaging (MRI) studies suggest that psilocybin can disrupt connections between the anterior hippocampus and the default mode network, potentially explaining some therapeutic effects.⁴

Psychedelics have a dose-dependent effect profile (Table 1). Low doses, known as microdosing, may cause mild side effects such as nausea and mood changes, while moderate doses can induce pronounced hallucinations, anxiety, and physiological changes.⁵ “Heroic dosing,” or very high/macro doses, can lead to intense hallucinations and significant cardiovascular effects.⁵ Research supports microdosing for conditions such as attention deficit hyperactivity disorder (ADHD) and depression, while macrodoses show promise in treating depression, substance use disorders, and end-of-life anxiety.⁶ Challenges include side effects, legal restrictions, and the need for careful clinical oversight.

Table 1.

Summary of psychedelic dosing strategies and known side effects. Actual dosages are not given.

Dose level	Side effects
Low (micro)	Nausea/vomiting, subtle changes in cognition and mood, and mild perceptual changes
Moderate	Pronounced changes in thought process and emotion, visual and auditory hallucinations, increased risk of anxiety, panic, and tachycardia
High (macro)	Intense hallucinations with profound alterations in perceptions of reality, severe anxiety/panic, significant changes in heart rate and blood pressure

However, societal concerns led to the passage of the Controlled Substance Act in 1970, classifying most psychedelics as Schedule I drugs, indicating a theoretically “high” potential for abuse with no accepted medical use.⁷ This designation significantly restricted research.⁷ In recent years, attitudes have shifted, with the FDA granting “breakthrough therapy designation” to some psychedelics such as psilocybin. This status has facilitated research into their therapeutic potential. From 2015 to 2020, psychedelic use among people over age 12 increased by over 40% in the United States with over 7.1 million reporting use between 2019 and 2020.⁸ Despite the increase in use, the integration of psychedelic education in medical training is limited.

Psychedelic-related curricula has had a growing interest and there are positive attitudes among medical students toward psychedelics’ therapeutic potential, despite limited formal knowledge.⁹ Informal educational models such as interest groups, journal clubs, and lecture series, such as the Stanford Psychedelic Science Group, offer insights into the field but are not standardized across medical schools. There is a call for support from influential organizations that shape medical curricula, starting with individual medical school curriculum committees and continuing into residency and fellowship programs.

Pain medicine, in particular, could benefit from incorporating psychedelic education into the International Association for the Study of Pain’s (IASP) curriculum, which already emphasizes a multidisciplinary approach.¹⁰ Organizations such as the American Board of Anesthesiology could utilize these updated educational outlines to prepare future physicians for board examinations that include emerging therapies.

Clinical solution

The ethical, legal, and cultural complexities surrounding psychedelics pose significant barriers to their inclusion in formal medical curricula. Ethical concerns focus on ensuring safety and efficacy while balancing the potential for misuse with patient autonomy and informed consent. Legally, psychedelics remain Schedule I substances, similar to cannabis, creating a complicated landscape for research and clinical use. The federal classification and varying state laws complicate prescribing capabilities and highlight the need for clinicians to stay informed about changing regulations. Culturally, psychedelics carry a stigma from their association with the counterculture movements of the 1960s and the “war on drugs.” Shifting public perception toward acceptance involves addressing these historical biases while emphasizing the need for scientific rigor in psychedelic research.

A psychedelic curriculum should begin in the preclinical years of medical education and continue through clinical training (Table 2). This approach would establish a foundational understanding of mechanisms of action, historical perspectives, therapeutic use cases, and current research trends. Preclinical training should involve didactic lectures, online modules, small group discussions, standardized patient simulations, and guest lectures from experts in the field.

Table 2.

Preclinical, clinical, and interdisciplinary learning objectives for a psychedelic curriculum.

Preclinical objectives	Clinical objectives
Definition of hallucinogens (general) Definition of psychedelics     ○ Mechanism of action     ○ Description of subclasses (phenethylamines, tryptamines, and ergolines)        ○ Prototypical substances of each class Epidemiology of psychedelic drugs History of psychedelics in medicine Obtaining a psychedelic-oriented history and physical exam	Counseling strategies for informing patients on psychedelic use cases Performing a risk assessment for patients using psychedelic drugs Describing the evidence-base for psychedelics in medicine Crisis management/overdose strategies Critical review of literature on health-related benefits and risks Pharmacokinetics/pharmacodynamics     ○ Common dosages     ○ Routes of administration     ○ Side effects/medication interactions
Interdisciplinary objectives
Current legal framework surrounding psychedelics Ethical considerations (autonomy, informed consent, and misuse potential) Therapeutic use cases/future potential

In clinical training, the focus would shift to applying foundational knowledge in patient care and research, covering risk assessment, patient counseling, crisis management, and legal considerations. Simulation techniques, such as virtual reality, could help students experience the effects of psychedelics firsthand. Educational content should include clinical vignettes and interdisciplinary panels on psychedelic-assisted therapy. Residency and fellowship programs could tailor the curriculum for specific specialties, such as emergency medicine, anesthesiology, psychiatry, and pain medicine. The learning objectives should align with each specialty’s unique requirements to ensure relevance and educational benefit.

The rapid increase in psychedelic research and changing attitudes toward these substances present both an opportunity and a challenge for medical education. While psychedelics show promise in treating chronic pain and mental health conditions, the lack of formal training could hinder their safe and effective integration into medical practice when approved. Additionally, no psychedelic is currently approved by the United States Food and Drug Administration for any indication and with the growing recreational interest, more education surrounding the side effects and management of overdose is crucial. By incorporating psychedelic education early into medical curricula, we can better prepare healthcare professionals to expand therapeutic options and improve patient outcomes.

Board question

Question 1: Which of the following mechanisms is primarily involved in the action of lysergic acid diethylamide (LSD)?

1. Dopamine receptor antagonism

2. GABA receptor agonism

3. 5HT_2A receptor agonism

4. NMDA receptor antagonism

5. Acetylcholine receptor antagonism

Correct Answer: C

1. Dopamine receptor antagonism—Dopamine receptor antagonism is commonly associated with antipsychotic medications (haloperidol and olanzapine) rather than psychedelics. Antipsychotics are used to treat conditions such as schizophrenia and bipolar disorder by dampening dopamine signaling, which can help alleviate symptoms such as hallucinations and delusions.

2. GABA receptor agonism—GABA receptor agonism typically induces anxiolytic effects and can be seen with medications such as benzodiazepines. These medications enhance GABA’s effects, leading to sedation, relaxation, and anxiolytic properties.

3. 5HT_2A receptor agonism. Classic psychedelics, such as LSD and psilocybin, exert their effects primarily through the agonism of 5HT_2A receptors, which are involved in mood, perception, and cognitive processes.

4. NMDA receptor antagonism. NMDA (N-methyl-D-aspartate) receptor antagonism involves blocking glutamate activity at NMDA receptors, which plays a role in excitatory neurotransmission. NMDA receptor antagonists, such as ketamine, can produce dissociative and anesthetic effects rather than the perceptual changes seen with psychedelics. Its dissociative effects differ from the typical hallucinogenic experience produced by classic psychedelics, which involve serotonin receptor activity.

5. Acetylcholine receptor antagonism. Acetylcholine receptor antagonism affects acetylcholine neurotransmission. Anticholinergic drugs, such as scopolamine and atropine, can lead to sedation, dry mouth, confusion, and hallucinations.

Question 2: A 63-year-old woman with a history of chronic lower back pain with a recent exacerbation presents to the emergency department with complaints of muscle rigidity, agitation, and confusion after consumption of mushrooms. Physical exam demonstrates a hyperreflexia, mydriasis, ocular clonus, and diaphoresis. Which of the following was most likely responsible for this patient’s presentation?

1. Ibuprofen

2. Ketamine

3. Scopolamine

4. Sodium naproxen

5. Tramadol

Correct Answer: E

1. Ibuprofen. Ibuprofen does not cause serotonin syndrome as it has no action on the serotonin receptor.

2. Ketamine. Though ketamine does not cause serotonin syndrome, it can lead to similar symptoms such as agitation, confusion, and hallucinations but does not lead to muscle rigidity, ocular clonus, or hyperreflexia. Ketamine does cause vertical nystagmus.

3. Scopolamine. Scopolamine can lead to anti-cholinergic symptoms such as confusion and mydriasis but does not cause muscle rigidity or diaphoresis. Rather, scopolamine can result in anhidrosis.

4. Sodium naproxen. Sodium naproxen does not cause serotonin syndrome as it has no action on the serotonin receptor.

5. Tramadol. Tramadol is a synthetic opioid that inhibits the reuptake of serotonin and norepinephrine. Given the patient’s recent exacerbation of her lower back pain, she may have been prescribed tramadol. Since psilocybin is a partial agonist at the serotonin receptor, the accumulation of serotonin due to tramadol resulted in this patient having serotonin syndrome. Symptoms of serotonin syndrome include agitation, diaphoresis, spontaneous clonus, ocular clonus, tremor, hyperreflexia, hypertonia, hyperpyrexia, muscle rigidity, and mydriasis.

Funding

Authors received no funding for this publication.

Conflicts of interest: T.E. is an equity owner at Vanish Therapeutics, Inc. A.B. is an Advisor for Lin Health. C.L.R. is a content writer for TrueLearn, advisor for Doc2Doc and AugMend Health. IC is a consultant for Layer Health.