Author(s): Sara Flores, MD, Revati Mummaneni, MD, Alyssa Anderson, MD, Helena Drolshagen, MD, Anthony Loffredo, MD
Originally published: February 5, 2025 Last updated: February 5, 2025
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Overview and Description

Chronic pain is a complex and multifactorial condition defined by the International Association for the Study of Pain (IASP) as pain that persists for more than 3 months.1 In the United States, chronic pain affects over 50 million adults, contributing to substantial healthcare costs and decreased productivity.2 More recent studies estimate the average annual economic burden of chronic pain to be approximately $23,705 per patient with chronic pain.3 Despite its prevalence and impact, chronic pain remains inadequately managed.

As the exact mechanism of chronic pain is multifactorial and not completely understood, treatment of this condition is consequently difficult. Unlike acute pain, which serves a protective role, chronic pain persists long after tissue damage has healed and is driven by complex mechanisms such as central sensitization and maladaptive neuroplastic changes.4,5 In the early stages of chronic pain, nociceptive mechanisms responding to harmful stimuli are dominant. Over time, the nervous system becomes hyperresponsive, leading to amplified pain perception.4,5 Psychological factors, such as depression and anxiety, may exacerbate the experience of pain, while social factors, such as isolation, can perpetuate disability and suffering.

Relevance to Clinical Practice

Pharmacologic treatment options, including non-opioid analgesics, antidepressants, muscle relaxants, and anticonvulsants, are frequently prescribed for chronic pain but may offer only modest benefit in pain relief and function. Opioids, though effective for short-term pain relief, are associated with significant risks, including dependency and worsening pain sensitivity over time.6 This has left providers sometimes without options for treatment of chronic pain. Emerging therapies, including cannabis and psychedelics, offer potential as adjunctive treatments in chronic pain rehabilitation.

Cannabinoids

As limitations for conventional therapy become more evident, cannabis has emerged as a promising, although controversial option for the management of chronic pain. The therapeutic properties of cannabis are attributed to a diverse array of cannabinoids which can be broken into three broad categories: endogenous cannabinoids, phytocannabinoids derived from the cannabis plant, and artificially produced synthetic cannabinoids. Phytocannabinoids include cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), which interact with the endocannabinoid system. This system modulates nociception through CB1 and CB2 receptors, predominantly located in the central nervous system and immune cells, respectively (image 1). These receptors are involved in the GABAergic and Glutamatergic systems and have a variety of primary and downstream effects upon analgesia, antiemesis, euphoria, and sedation, amongst others.

Chronic pain is one of the most common reasons patients seek medical cannabis, accounting for 45%–80% of its use according to some studies.7 Nabiximols and dronabinol (synthetic cannabinoids) show moderate evidence for chronic pain management, spasticity, and appetite stimulation.8 Additionally, qualitative reporting describes significant perceived benefits including pain control, sleep quality, and physical and mental health, as well as a reduced reliance on other medications.9,10 Building on its potential role for chronic pain management, CBD (a phytocannabinoid) is widely recognized for its anti-inflammatory properties which contribute to its therapeutic effect. At the molecular level, CBD interacts with several key receptors, as outlined in image 2, potentially playing a crucial role in the management of chronic pain.11 Despite growing evidence supporting CBD’s anticancer, antioxidant, neuroprotective and immunosuppressive properties, the Food and Drug Administration (FDA) has only approved Epidiolex (a purified form of CBD) for the treatment of seizures associated with Dravet or Lennox-Gastaut syndrome.

Image 2. CBD Receptor Interactions and Effects on Cytokines (Based on Sunda11)

ReceptorsEffect on Cytokines
Adenosine A2A/ENT ReceptorsDownregulates TNF-α, IL-6, IL-12, and MMP-9 Upregulates IL-10
CB2/CB1 ReceptorDownregulates TNF-α, COX-2, iNOS, IL-4, IL-5 and IL13
CPR55 ReceptorDownregulates MMP-9 and TNF-α Upregulates IL-10 and Ca2+ regulation
TRPV ReceptorDownregulates IL-2, IL-4 and IFN-γ
PPARγ ReceptorUpregulates CAT, GST and Mn-SOD

When considering the clinical application of cannabis, it is important to recognize the distinct forms in which it is available and the implications of these variations on medical decision making. Cannabis can be administered through inhalation (smoking or vaporization), oral tinctures, edibles, oils, and topical creams, each with differing pharmacokinetics. These forms allow patients to customize their treatment regimens to address individual health goals or preferences, albeit, often without the guidance of medical personnel. Factors such as prior experience with cannabis, gender, and therapeutic goals influence the choice of administration route.7,9 Additionally, many patients engage in “dose layering,” or combining cannabinoid delivery methods and dosages to achieve optimal symptom relief. This real-world complexity underscores the need for clinical studies to better reflect and address individualized practices.

The diverse administration methods of cannabis treatments highlight the challenges in establishing standardized clinical guidelines. Overall, evidence for its role in chronic pain management remains inconsistent. Systematic reviews indicate low-strength evidence supporting modest benefits of cannabis preparations with specific THC-to-CBD ratios, typically between 1:1 and 2:1, for neuropathic pain.7,12 A study from the Journal of Cannabis Research provides dosing recommendations for CBD/THC for neuropathic, nociplastic, and mixed chronic pain based on a modified Delphi process.13 It outlines three initiation protocols—routine, conservative, and rapid—described in images 3–5.13

While these protocols offer a structured approach to treating chronic pain with cannabis, the overall literature on dosing regimens remains inadequate, underscoring the need for further research to clarify its clinical application.

Images 3-5 from Bhaskar, A., Bell, A., Boivin, M. et al. Consensus recommendations on dosing and administration of medical cannabis to treat chronic pain: results of a modified Delphi process. J Cannabis Res 3, 22 (2021). https://doi.org/10.1186/s42238-021-00073-1

While cannabis is often perceived as a safer alternative to opioids, the adverse effects of cannabis use are an important clinical consideration. Common adverse effects of cannabis use include nausea, dizziness, fatigue, and appetite changes.7,12 There is also potential for serious mental health and adverse cognitive effects, although data is currently insufficient to characterize the magnitude of risk or in whom the risk is highest.7,14 Adverse effects including paranoia, psychosis and schizophrenia, have been associated with cannabis use, though the latter is linked to familial predisposition.15 Despite common perception, cannabis does have addiction potential. In overall users there is a 9% addiction potential with the risk of addiction increasing in those beginning usage in adolescence and in daily users where addiction potential is projected at 25-50%.15

Psychedelics

After losing favor in the 1960s during the counterculture movement, psychedelics are re-emerging as potential treatments for chronic pain. Currently, there are no legal means for a physician in the United States to prescribe psychedelics for clinical use but there are studies under special DEA clearance for clinical research.

There are three main classes of psychedelics: phenethylamines, tryptamines, and ergolines. These classes have a shared mechanism of action as serotonergic 5-HT2A receptor agonists. The key psychedelics that are the mainstay of research and offer clinical consideration for treatment of chronic pain are psilocybin and N,N-Dimethyltryptamine (DMT, ayahuasca) from the tryptamine class, as well as lysergic acid diethylamide (LSD) from the ergolines class.16 Dosing and route of administration for commonly utilized psychedelics in clinical research are summarized in image 6.

The mechanism of action of psychedelics targets several pathways contributing to chronic pain. The primary action of psychedelics in the context of chronic pain is functioning as 5-HT2A receptor agonists. Through descending inhibition, targeting these receptors reduces nociceptive signals and aids in the inhibition of pain.16 Psychedelics also achieve antinociceptive effects through several secondary actions. Chronic pain is known to disrupt the default mode network of the brain that is active during passive tasks and times of rest. Psychedelics work to correct this disruption through introducing a high entropy state, utilizing neuroplasticity for the formation of new neuronal networks and pruning of existing connections contributing to the pathological pain state. Additionally, psychedelics reduce inflammation in the brain associated with chronic pain states via inhibition of tumor necrosis factor (TNF), an important proinflammatory mediator. Finally, psychedelics have non-analgesic effects that address the complex psychiatric associations with chronic pain. The impact of psychedelics on the neuropsychiatric domain is demonstrated to occur through targeting 5-HT receptors located in areas of the brain associated with memory and emotion, as well as through non-pharmacological effects such as mindfulness and emotional openness.17,18 Though research is ongoing, studies support that these actions of psychedelics result in a reduction in anxiety and depression, which if left untreated are known to exacerbate symptoms of chronic pain patients.16 In addition to their primary action as 5-HT2A receptor agonists, these secondary functions allow psychedelics to have lasting analgesic effects even after the active compounds have been metabolized (image 7).

Recent studies have demonstrated a clinical role for psychedelics in the treatment of several specific chronic pain disorders. Leading areas of efficacy include analgesia for cancer-related pain that targets both physical and psychological distress, with one study demonstrating a reduction in patient pain scores and more persistent pain relief when treated with LSD compared to hydromorphone and meperidine.17,19 Studies in phantom limb pain have also yielded promising preliminary reports demonstrating persistent reduction in phantom limb pain, reduced pain intensity and improved sensation when psilocybin is used in conjunction with mirror visual-feedback.17,20 Additionally, psychedelics have demonstrated efficacy with headaches, both as preventive and abortive treatment for cluster headaches, as well as decreasing frequency, duration and pain severity of migraine headaches.20,21

In comparison to other medications used for the treatment of chronic pain, such as opioids, psychedelics present a more favorable side effect profile. This includes a low abuse potential due to no physiological addiction or dependence, no risk of organ damage or neurotoxicity, and no withdrawal symptoms. Frequent psychedelic use can result in rapid tolerance and cross-tolerance between drugs in the psychedelics class, therefore dosing is recommended to be spaced out at least three days. Though adverse effects are rare, they include paranoia, anxiety, panic attacks, and prolonged psychosis. People at risk for these adverse effects typically have a family history of mental illness. Consideration for caution with psychedelics use should be taken in patients with a history of cardiovascular disease due to vasoconstrictive properties of psychedelics, a family history of mental illness, and those with concurrent psychoactive medication use.16

Commonly classified as an atypical psychedelic, ketamine is an anesthetic agent increasingly recognized for its role in pain management. Although not currently FDA approved, intravenous ketamine infusions for chronic refractory pain are within the guidelines of the American Society of Anesthesiology.22,23 Ketamine is a derivative of phencyclidine with analgesic, antidepressant, and psychomimetic effects.22,23 Its primary mechanism of action involves antagonism of central nervous system (CNS) N-methyl-D-aspartate receptors (NMDAR), reducing neuronal activity.22,23 There is some research to suggest that this leads to a reduction in neuroinflammation and central sensitization, both significant contributors to the pain pathway.22,23 Ketamine also interacts with other non-NMDA pathways, including opioid receptor activation at high doses, contributing to its effects on pain and mood regulation.23 In addition to its analgesic properties, ketamine has shown promise in alleviating depression and anxiety, common comorbidities in individuals with chronic pain.23

Ketamine can be administered via multiple routes, including intravenous (IV), intramuscular, insufflation/intranasal, oral, topical, and rectal.22,23 Dosing regimens for these routes, as outlined in 2018 consensus guidelines, are illustrated below (table 1). Ketamine is both water and lipid soluble, which allows for rapid distribution throughout the body and efficient crossing of the blood-brain barrier.23 It is metabolized by the hepatic cytochrome P450 system, with a half-life of approximately 2.3 ± 0.5 hours. Due to its stimulatory effects on the sympathetic nervous system, ketamine is often preferred in trauma or shock settings.23 However, potential side effects, including psychomimetic, gastrointestinal, and cardiovascular effects, necessitate careful patient selection to ensure safe administration.22,23

Reproduced from Cohen SP, Bhatia A, Buvanendran A, et al. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Chronic Pain From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists Regional Anesthesia & Pain Medicine 2018;43:521-546 with permission from BMJ Publishing Group Ltd.

Clinical studies have demonstrated intravenous and oral/intranasal ketamine’s efficacy in both acute and chronic pain settings.22,23 For acute pain, most of the data focuses on perioperative settings, where ketamine reduces postoperative pain and/or opioid consumption for a minimum of 24 hours, particularly in painful surgeries such as thoracic, upper abdominal, and orthopedic procedures.23 Ketamine is also recommended for opioid-tolerant or opioid-dependent patients, where it has been shown in a few randomized control trials to have some success in reducing postoperative pain and long-term opioid use.23

In chronic pain, ketamine has shown efficacy in managing neuropathic pain and related conditions, as evidenced by several double-blind randomized controlled trials.23 These studies highlight that ketamine infusions significantly reduce pain compared to placebo, with reductions ranging from 25% to 45% during treatment, although effects often diminish shortly after.23 Conditions such as spinal cord injury pain, phantom limb pain, and postherpetic neuralgia demonstrate promising outcomes with significant pain reduction during or immediately after infusion.23 However, results are mixed for fibromyalgia and complex regional pain syndrome (CRPS), with limited long-term benefits and inconsistent findings across studies.23

Cutting Edge/Unique Concepts/Emerging Issues

With developments in research on the use of cannabis and psychedelics for the treatment of chronic pain, many questions remain regarding legality of these substances for clinical use. Although not legal federally to possess or utilize in the United States, marijuana has gained legality at the state level in 41 states. As detailed in Image 8, the state specific parameters for legal use of marijuana varies for recreation and medicinal purposes on a state-by-state basis. The opposing federal and state laws regarding legal marijuana use and further restrictions on distribution of cannabis products pose barriers to prescribing cannabis for clinical purposes broadly in the United States.

Despite promising research for the clinical use of psychedelics for specific types of chronic pain, significant legal hurdles remain inhibiting physicians from prescribing these potentially therapeutic medications. With the success of recent psychedelic trials, the FDA has assigned psychedelics “breakthrough therapy” status which serves to accelerate approval of use as a medication.24 Despite this designation by the FDA, the classification of psychedelics as a Schedule 1 drug by the Drug Enforcement Agency (DEA) stands as an additional hurdle. Any drug designated as Schedule 1 cannot be lawfully prescribed in the United States. Potentially, the findings of the FDA could influence the DEA to reconsider the classification of psychedelics. However, with the current federal restrictions in addition to specific state law restrictions, there are no legal means for a physician in the United States to prescribe psychedelics for clinical use aside from special DEA clearance for clinical research.16 If in the future psychedelics were approved for clinical use in the United States, it is unlikely that physicians would be able to prescribe them as a take home medication. Rather, they would be administered by a trained clinician in a controlled clinical setting under specific protocol.23

Gaps in Knowledge/Evidence Base

It is essential that further research be carried out regarding standardizing dosing regimens, frequency of administration, duration of treatment, and safe distribution of cannabis and psychedelics for the treatment of chronic pain. The current literature on the role of cannabis in the management of chronic pain is limited by inconsistent regulatory frameworks, product variability, and limited long-term safety data. A significant challenge in both clinical use and research of cannabis arises from the complex nature of cannabis as a plant-based product rather than a single, standardized compound. This complexity results in wide variations in the THC-to-CBD ratios across products influenced by the manufacturing process and delivery methods. Future research should also prioritize distinguishing between plant-based cannabinoids vs synthetic cannabinoids, such as nabilone and dronabinol, as their differing pharmacokinetics and therapeutic profiles may impact their efficacy and safety profile in clinical application. Cannabinoid-based pharmacology shows potential in treating certain populations and subtypes of pain, but further rigorous research is necessary to address these challenges and establish cannabinoids as a reliable and effective treatment option.

Clinical research for psychedelics has yielded positive results for specific types of chronic pain including headaches/migraines, cancer pain, and neuropathic pain, however evidence from current studies is low-level with small sample sizes. Further analysis is needed to determine if the hallucinogenic effects of psychedelics are needed to obtain clinical benefit for patients with chronic pain. This can be analyzed through comparison of microdosing with sub-hallucinogenic effect versus dosing with hallucinogenic effect. Another area that can be explored more is psychedelic-assisted psychotherapy for patients with chronic pain, focusing on the nonpharmacologic effect of psychedelics in the context of the psychologic and physiologic complex relationship of chronic pain.19

References

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Author Disclosures

Sara Flores, MD
Nothing to Disclose

Revati Mummaneni, MD
Nothing to Disclose

Alyssa Anderson, MD
Nothing to Disclose

Helena Drolshagen, MD
Nothing to Disclose

Anthony Loffredo, MD
Nothing to Disclose