Cannabis for Pain: The Latest Evidence and Clinical Considerations

Chronic pain affects more than 50 million adults in the United States and remains a leading cause of disability, healthcare utilization, and reduced quality of life.¹ Traditional pharmacologic treatments – including nonsteroidal anti-inflammatory drugs (NSAIDs), antidepressants, anticonvulsants, and opioids – are frequently part of pain management treatment plans, yet may be associated with significant adverse effects. In recent years, the opioid crisis has intensified interest in alternative analgesic strategies that may reduce reliance on chronic opioid therapy.

Cannabis and cannabinoid-based therapies have increasingly entered the discussion. The cannabis plant contains numerous biologically active compounds (aka, cannabinoids) that interact with the endocannabinoid system (ECS), a physiologic network involved in the regulation of nociception, inflammation, appetite, and mood.² As legalization and commercialization of cannabis products continue to expand, clinicians are increasingly encountering patients utilizing cannabis-derived therapies for pain relief.

Shifting regulatory attitudes toward cannabis is not new. It started during the early 20th century with laws such as the Marihuana Tax Act of 1937, continued in later decades with the Controlled Substances Act of 1970, and most recently we saw the passage of the Agriculture Improvement Act of 2018 (known commonly known as the Farm bill).³

State-level policy changes in the United States began in 1996 when California legalized medical cannabis. Since then, the vast majority of states have either fully legalized recreational marijuana, decriminalized marijuana, legalized medical marijuana, or instituted other non–prohibition-like efforts – leaving a mere four states with steadfast criminalization mirroring the federal level (Idaho, Wyoming, Kansas, and South Carolina).⁴ These evolving regulatory frameworks have significantly expanded patient access to cannabis-derived products while simultaneously creating challenges related to product quality, regulation, and clinical guidance.

The US Drug Enforcement Administration (DEA) is holding a hearing on potential Scheduling shifts beginning June 29. The potential shift of cannabis from federal Schedule I (C1) to Schedule III (C3) status would carry major implications for pharmacists, pharmacies, and the broader healthcare system by formally acknowledging accepted medical use while maintaining federal control and oversight. Rescheduling would significantly expand healthcare professional involvement in cannabis-related education, dispensing considerations, medication safety monitoring, and regulatory compliance, particularly because federal regulation 21 CFR §1306.26 permits pharmacists to dispense certain Schedule II, III, IV, and V controlled substances without a prescription under specific conditions involving age verification, quantity limitations, recordkeeping, and direct pharmacist oversight.⁵

From a business perspective, Schedule III status would also eliminate restrictive IRS 280E tax limitations for cannabis businesses, potentially strengthening the commercial cannabis market and accelerating healthcare integration, research opportunities, and product standardization.⁶ However, pharmacists would still need to remain vigilant regarding misuse potential, intoxication risks, drug interactions, public perception of safety, and the possibility that broader legal access could increase utilization (similar to other legal substances such as alcohol and tobacco).

The cannabis plant contains more than 100 phytocannabinoids, although two compounds dominate clinical relevance: THC and CBD. THC is the primary psychoactive component of cannabis and acts as a partial agonist at both CB1 and CB2 receptors. Activation of CB1 receptors in the central nervous system produces analgesic effects but is also responsible for euphoria, altered perception, and cognitive impairment. THC is highly lipophilic and rapidly distributes to highly perfused tissues before accumulating in adipose stores.

Cannabidiol exhibits a markedly different pharmacologic profile. CBD has minimal intoxicating properties and interacts with multiple molecular targets beyond the classical cannabinoid receptors. These targets include transient receptor potential channels, serotonin receptors, peroxisome proliferator-activated receptors, and opioid receptor pathways. CBD may also act as a negative allosteric modulator of CB1 receptors and can influence THC metabolism, potentially altering its psychoactive effects.⁷

Several cannabinoid-based medications have been developed with standardized dosing and regulatory approval. Cannabidiol (Epidiolex), an extracted oral CBD solution, is approved for severe pediatric epilepsy syndromes, including Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex.⁸

Synthetic THC products such as dronabinol (Syndros, Marinol) are available as capsules and oral solutions for the treatment of chemotherapy-induced nausea and vomiting as well as AIDS-related anorexia. Nabilone (Cesamet), another synthetic cannabinoid mimicking THC, was approved for refractory chemotherapy-induced nausea but has been discontinued.

Notably, nabiximols (Sativex), a combination THC/CBD oromucosal spray, is approved in several countries outside the United States for multiple sclerosis spasticity.

Although these cannabinoid products provide standardized formulations, most cannabis used for pain management is obtained through state medical cannabis programs or retail dispensaries, where product composition and potency may vary significantly.

Clinical evidence evaluating cannabis for pain management has expanded over the past two decades. Early systematic reviews and randomized trials suggested potential benefits for neuropathic pain conditions.

Reports & Systematic Reviews

The 2017 National Academies of Sciences, Engineering, and Medicine report concluded that there is substantial evidence supporting the use of cannabis or cannabinoids for chronic pain in adults.⁶

More recent systematic reviews have produced more nuanced conclusions. Randomized trials evaluating inhaled cannabis, oral cannabinoids, and synthetic THC preparations have demonstrated modest reductions in pain intensity compared with placebo. However, heterogeneity in study designs, product formulations, and outcome measures complicates interpretation of these findings.

A 2018 Cochrane Review of 16 studies illustrated that 10% of the 1,750 participants withdrew due to adverse events from cannabis-based medicines, compared to 5% with placebo.⁹ There was not enough evidence to determine if cannabis-based medicines increase the frequency of serious adverse events compared with placebo, and there was no information about long-term risks.

Additionally, the review stated that cannabis-based medicines: ⁹

• probably increase the number of people achieving pain relief of 30% or greater compared with placebo

• may increase nervous system adverse events compared with placebo.

The review authors further found that psychiatric disorders occurred in 17% of participants using cannabis-based medicines and in 5% using placebo.

A 2021 BMJ review of 32 randomized controlled trials involving 5,174 patients concluded that there was a “small to very small increase” in the proportion of patients with pain relief, function improvement, and sleep quality, while concurrently experiencing several transient side effects.¹⁰

A 2020 American Heart Association review published in Circulation determined that cannabis had inconclusive efficacy evidence for conditions including Alzheimer’s disease, anxiety, depression, tumors, Crohn’s disease, ulcerative colitis, heart failure, ischemia, hepatitis C, Huntington’s disease, metabolic syndrome, obesity, diabetes, Parkinson’s disease, and sleep. The review further concluded that cannabis showed possible evidence (moderate) for long-term opioid utilization, dystonia (involuntary movements), and glaucoma, and known evidence (conclusive/substantial) for pain (neuropathic, fibromyalgia, cancer), cachexia, nausea/vomiting, multiple sclerosis, and epilepsy.¹¹

The AHRA Review

The Agency for Healthcare Research and Quality’s (AHRQ) Living Systematic Review on Cannabis and Other Plant-Based Treatments for Chronic Pain represents one of the most comprehensive and continuously updated analyses of cannabinoid therapies for chronic pain.

This living systematic document evaluates randomized controlled trials and observational studies examining plant-based cannabis products for chronic pain conditions, including neuropathic pain, fibromyalgia, and musculoskeletal pain. Results are published at least annually upon comprehensive review of the most recent and relevant clinical studies.¹² A rather novel strategy to say the least.

To date, the review has analyzed more than 20 randomized controlled trials involving several thousand participants. Results demonstrated that products containing balanced THC and CBD ratios were associated with small statistically significant improvements in pain severity compared with placebo. Across several trials, patients receiving THC/CBD combinations experienced an approximate 0.5 to 1.0 point reduction on a 10-point pain scale relative to placebo.

Additionally, one can appreciate that approximately 30% of patients receiving cannabinoid therapies achieved at least a 30% reduction in pain intensity compared with approximately 20% of patients receiving placebo. The elephant in the room at that point is debating whether a one-point pain scale reduction of 10% difference in patients achieving 30% pain reduction is clinically significant.

Functional improvements were also observed in some trials, although the magnitude of benefit was generally modest. Improvements in sleep quality were reported in several studies evaluating chronic neuropathic pain. However, cannabinoid therapies were associated with increased rates of adverse events. Dizziness was reported in approximately 15% to 20% of patients receiving cannabinoid products compared with 5% to 10% of placebo recipients. Sedation and somnolence were reported in approximately 10% to 15% of patients. Gastrointestinal adverse effects including nausea occurred in roughly 8% to 12% of participants. As with any medication, side effects demand attention.

Evidence supporting CBD-dominant products alone for chronic pain was considerably weaker. Trials evaluating CBD-only formulations generally demonstrated minimal or no statistically significant improvement in pain outcomes compared with placebo. The review therefore concluded that THC-containing products appear to be the primary drivers of analgesic effects in cannabis-based therapies.

The AHRQ review ultimately concluded that cannabinoids may provide modest improvements in chronic pain severity and function, particularly in neuropathic pain conditions, but that the overall magnitude of benefit remains relatively small and must be balanced against potential adverse effects.

Several clinical practice guidelines on pain management have addressed the role of cannabis and cannabinoid-based therapies in pain management. A BMJ Clinical Practice Guideline recommends considering a trial of noninhaled medical cannabis or cannabinoids for patients with chronic cancer or even non-cancer pain when standard therapies are inadequate.¹³

The National Institute for Health and Care Excellence (NICE) guideline reviewed cannabis-based medicinal products for chronic pain and concluded that evidence remains limited and mixed, recommending cautious use primarily in refractory cases under specialist supervision.¹⁴

Clinical practice guidelines published in the journal Cannabis and Cannabinoid Research support cannabinoid-based medicines as potential monotherapy, replacement therapy, or adjunctive treatment options for chronic and neuropathic pain management.¹⁵

The American College of Occupational and Environmental Medicine (ACOEM) guidelines generally do not recommend cannabinoids for chronic pain due to insufficient evidence regarding long-term efficacy and safety, particularly in occupational settings.¹⁶

Finally, the American Society of Pain & Neuroscience (ASPN) published consensus recommendations acknowledging potential benefit for select chronic pain populations, while emphasizing careful patient selection, product standardization, and ongoing monitoring because of continued evidence limitations.¹⁷

Despite potential therapeutic benefits and supportive guidelines, cannabis use carries several safety concerns that must be considered when evaluating cannabinoid therapies. Acute adverse effects commonly include dizziness, sedation, cognitive impairment, tachycardia, anxiety, and impaired coordination. Higher doses of THC may produce intoxication and psychiatric symptoms such as paranoia or panic.

Chronic cannabis exposure can lead to cannabis use disorder (CUD), characterized by problematic use, tolerance, and withdrawal symptoms. Epidemiologic data suggest that approximately 9% to 30% of cannabis users may develop CUD, with higher risk among individuals initiating use during adolescence.¹⁸

Emergency department visits related to cannabis exposure have increased in recent years – particularly with the availability of high-potency THC products and edible formulations – leading to concerning scenarios such as cannabinoid hyperemesis syndrome. Additionally, pediatric exposures associated with cannabis edibles have also become an increasing concern, propelling a need to educate parents and caregivers about secure storage.

Drug Interactions

Drug interactions represent an important clinical consideration as well. Cannabinoids may alter drug metabolism through cytochrome P450 enzyme modulation, protein binding displacement, and additive sedative effects. Both THC and CBD interact with hepatic cytochrome P450 enzymes that are responsible for metabolizing a large proportion of prescription medications. CBD has been shown to inhibit several CYP enzymes, particularly CYP2C19 and CYP3A4, while THC may act as a substrate or inhibitor of multiple CYP isoenzymes.

These metabolic interactions can increase serum concentrations of medications metabolized by these pathways. Clinically relevant interactions have been reported with drugs including warfarin (Coumadin), clobazam (Sympazan, Onfi), tacrolimus (Prograf), anticonvulsants, and certain antidepressants.¹⁹

Cannabinoids demonstrate high plasma protein binding, often exceeding 90%, exemplifying the most common clinically significant cannabinoid interactions. Highly protein-bound medications such as warfarin, phenytoin (Dilantin), tacrolimus, cyclosporine, and valproic acid (Depakote) may theoretically experience altered free drug concentrations when administered concurrently with cannabinoids. As multiple case reports illustrate, careful deliberation for utilization followed by close monitoring is recommended when cannabinoids are utilized in patients receiving medications with high protein binding and/or narrow therapeutic indices.

Additive sedative interactions represent another important safety consideration. THC-containing products can produce central nervous system depression and may potentiate sedative effects when combined with opioids, benzodiazepines, sedative hypnotics, antipsychotics, or antihistamines. These additive effects may increase the risk for cognitive impairment, respiratory depression, and falls, particularly among older adults.

Labeling Accuracy

CBD products are generally available as three distinct types: full spectrum (CBD + all other cannabinoids), broad spectrum (CBD + all other cannabinoids except THC), and isolate (CBD alone). However, even beyond the product type, there’s a larger consideration for labeling accuracy.

Studies evaluating commercially available CBD products have demonstrated significant discrepancies between labeled and actual cannabinoid content. One widely cited investigation found that approximately 69% of CBD products sold online were inaccurately labeled, with some products containing substantially higher or lower concentrations of CBD than advertised.²⁰

Contamination with pesticides, heavy metals, or residual solvents has also been reported in certain cannabis products. These concerns highlight the need for improved regulatory oversight and standardized manufacturing practices. Perhaps the day will come where specific products or companies are as well known for standardized product content as major beer brewers or liquor distillers are today – providing the same exact contents in every single product container. Or perhaps more apropos to healthcare, similar to prescription and over-the-counter pain medications.

Overall Clinical Implications

For clinicians managing chronic pain, cannabinoids may one day soon represent a potential adjunctive therapy when conventional treatments provide inadequate relief or are poorly tolerated. These therapies represent an evolving area of pain management research and best practice. While advances in understanding the endocannabinoid system have clarified mechanisms through which cannabinoids can influence nociceptive signaling and inflammatory pathways, limitations remain regarding inconsistent product labeling accuracy, limited long-term safety data, clinically significant drug interactions/contraindications, and of course, side effects.

Treatment decisions therefore must be individualized and incorporate careful patient selection, cautious dose titration, monitoring for adverse effects, and evaluation of potential drug interactions. Patient counseling should emphasize the modest magnitude of analgesic benefit observed in relatively small clinical trials as well as the potential risks associated with cannabis and cannabinoid utilization.

Overall, clinicians are encouraged to remain informed about cannabinoid pharmacology, evolving clinical evidence, and safety considerations before even considering the integration of cannabis-based therapies into multimodal pain management strategies.

Sources

1. Dahlhamer J, Lucas J, Zelaya C, et al. Prevalence of chronic pain and high-impact chronic pain among adults – United States, 2016. MMWR Morb Mortal Wkly Rep. 2018 Sep 14;67(36):1001-1006.

2. Zou S, Kumar U. Cannabinoid receptors and the endocannabinoid system: signaling and function in the central nervous system. Int J Mol Sci. 2018 Mar 13;19(3):833.

3. Gabay M. Federal controlled substances act: controlled substances prescriptions. Hosp Pharm. 2013 Sep;48(8):644-645.

4. DISA Global Solutions. Marijuana Legality Map. Updated May 5, 2026. https://disa.com/marijuana-legality-by-state/

5. National Archives. Code of Federal Regulations. Updated May 8, 2026. https://www.ecfr.gov/current/title-21/chapter-II/part-1306/subject-group-ECFRe4ae2bfb4eae102/section-1306.26

6. Library of Congress. The Application of Internal Revenue Code Section 280E to Marijuana Businesses: Selected Legal Issues. Published February 6, 2026. https://www.congress.gov/crs-product/R46709

7. Kathmann M, Flau K, Redmer A, et al. Cannabidiol modulation of opioid receptors. Naunyn Schmiedebergs Arch Pharmacol. 2006 Feb;372(5):354-361.

8. National Academies of Sciences, Engineering, and Medicine. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. The National Academies Press; 2017.

9. Mucke M, Phillips T, Radbruch L, Petzke F, Hauser W. Cannabis‐based medicines for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2018 Mar 7;3(3): CD012182.

10. Wang L, Hong P J, May C, et al. Medical cannabis or cannabinoids for chronic non-cancer and cancer related pain: a systematic review and meta-analysis of randomised clinical trials. BMJ. 2021;374 :n1034.

11. Page RL, Allen LA, Kloner RA, et al. Medical marijuana, recreational cannabis, and cardiovascular health: A scientific statement from the American Heart Association. Circulation. 2020 Sep 8;142(10):e131-e152.

12. Agency for Healthcare Research and Quality. Living systematic review on Cannabis and other plant-based treatments for chronic pain. Updated: August 4, 2025. https://effectivehealthcare.ahrq.gov/products/plant-based-chronic-pain-treatment/living-review

13. Busse JW, Vankrunkelsven P, Zeng L, et al. Medical cannabis or cannabinoids for chronic pain: a clinical practice guideline. BMJ. 2021;374:n2040.

14. National Institute for Health and Care Excellence. Cannabis-based medicinal products – NICE Guideline NG144. Published November 11, 2019. Updated March 22, 2021. https://www.nice.org.uk/guidance/ng144

15. Bell AD, MacCallum C, Margolese S, et al. Clinical practice guidelines for cannabis and cannabinoid-based medicines in the management of chronic pain and co-occurring conditions. Cannabis Cannabinoid Res. 2024 Apr;9(2):669-687.

16. Feinberg SD, Aronoff GM, Ausfahl J, et al. ACOEM guidelines: cannabis. American College of Occupational and Environmental Medicine. J Occup Environ Med. 2025;67(12):e860-e879.

17. Gill B, Tidwell C, Hagedorn JM, et. al. Consensus Guidelines from the American Society of Pain and Neuroscience for the Use of 60-Day Peripheral Nerve Stimulation Therapy. A NEURON Living Guideline Project*. J Pain Res*. 2025 Jun 24;18:3117-3139.

18. Volkow ND, Baler RD, Compton WM, Weiss SRB. Adverse health effects of marijuana use. N Engl J Med. 2014 Jun 5;370(23):2219-2227.

19. Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev. 2014 Feb;46(1):86-95.

20. Bonn-Miller MO, Loflin MJE, Thomas BF, et al. Labeling accuracy of cannabidiol extracts sold online. JAMA. 2017 Nov 7;318(17):1708-1709.