Limited evidence suggests that cannabis may alleviate neuropathic pain in some patients, but insufficient evidence exists for other types of chronic pain. Among general populations, limited evidence suggests that cannabis is associated with an increased risk for adverse mental health effects.

Few methodologically rigorous trials; the cannabis formulations studied may not reflect commercially available products; and limited applicability to older, chronically ill populations and patients who use cannabis heavily.

From 27 chronic pain trials, there is low-strength evidence that cannabis alleviates neuropathic pain but insufficient evidence in other pain populations. According to 11 systematic reviews and 32 primary studies, harms in general population studies include increased risk for motor vehicle accidents, psychotic symptoms, and short-term cognitive impairment. Although adverse pulmonary effects were not seen in younger populations, evidence on most other long-term physical harms, in heavy or long-term cannabis users, or in older populations is insufficient.

Two investigators independently abstracted study characteristics and assessed study quality, and the investigator group graded the overall strength of evidence using standard criteria.

Intervention trials and observational studies, published in English, involving adults using plant-based cannabis preparations that reported pain, quality of life, or adverse effect outcomes.

MEDLINE, Cochrane Database of Systematic Reviews, and several other sources from database inception to March 2017.

To review the benefits of plant-based cannabis preparations for treating chronic pain in adults and the harms of cannabis use in chronic pain and general adult populations.

Cannabis is increasingly available for the treatment of chronic pain, yet its efficacy remains uncertain.

The use of medicinal cannabis has become increasingly accepted in the United States and globally (1, 2). Eight states and the District of Columbia have legalized cannabis for recreational purposes, and 28 states and the District of Columbia have legalized it for medical purposes (3). Between 45% and 80% of persons who seek medical cannabis do so for pain management (4, 5). Among patients who are prescribed long-term opioid therapy for pain, up to 39% are also using cannabis (6, 7). Physicians will increasingly need to engage in evidence-based discussions with their patients about the potential benefits and harms of cannabis use. However, little comprehensive and critically appraised information exists about the benefits and harms of using cannabis to treat chronic pain. The objectives of this systematic review were to assess the efficacy of cannabis for treating chronic pain and to provide a broad overview of the short- and long-term physical and mental health effects of cannabis use in chronic pain and general patient populations.

Methods

Topic Development

This article is part of a larger report commissioned by the Veterans Health Administration (8). A protocol describing the review plan was posted to a publicly accessible Web site before the study began (9).

Data Sources and Searches

We searched MEDLINE, Embase, PubMed, PsycINFO, Evidence-Based Medicine Reviews (including Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness, Health Technology Assessments, and Cochrane Central Register of Controlled Trials), and gray literature sources from database inception through February 2016. We updated this search specifically for new randomized controlled trials (RCTs) and systematic reviews in March 2017. We obtained additional articles from systematic reviews, reference lists, and expert recommendations. We also searched for ongoing, unpublished, or recently completed studies on ClinicalTrials.gov, the International Clinical Trials Registry Platform, the ISRCTN Registry, National Institutes of Health RePORTER, and the Agency for Healthcare Research and Quality Grants On-Line Database. Supplement 1 provides details on the search strategy, which we developed in consultation with a research librarian.

Study Selection

We included English-language studies assessing the effect on nonpregnant adults of plant-based cannabis preparations or whole-plant extracts, such as nabiximols, a nonsynthetic pharmaceutical product with a standard composition and dose (oromucosal spray delivering tetrahydrocannabinol [THC], 2.7 mg, and cannabidiol, 2.5 mg). We did not include synthesized, pharmaceutically prepared cannabinoids, such as dronabinol or nabilone, because they are not available in dispensaries, and the efficacy of synthetic cannabinoid preparations for chronic pain was examined in 2 recent reviews (10, 11). We broadly defined plant-based cannabis preparations to include any preparation of the cannabis plant itself (for example, cannabis cigarettes and oils) or cannabis plant extracts to capture the variety of products available in U.S. dispensaries (12).

To address the efficacy of cannabis for treating chronic pain, we included controlled clinical trials and cohort studies. This review focuses specifically on pain outcomes, although our larger report and search were designed to include other outcomes, such as sleep and quality of life (8). Because data about harms in the general population might be applicable to chronic pain populations, we examined harms broadly and reported whether the data were derived from studies of the general population or populations with chronic pain. To capture potential cannabis-related harms that may be of interest to clinicians and patients, but whose prevalence has not been well-characterized in larger-scale observational studies, we also included case series and descriptive studies of “emerging harms.” Supplement 2 provides the criteria we used for study selection.

We searched for primary literature and systematic reviews; we dual-reviewed 5% of identified abstracts and all of the included full-text articles to ensure reliability. Disagreements were resolved by a third reviewer. Given the broad scope of this review, we summarized data from existing systematic reviews. We included only reviews that clearly reported their search strategy, reported inclusion and exclusion criteria, and appraised the internal validity of the included trials (13). We prioritized the most recent reviews and those with the broadest scope. In addition, we included individual studies that met inclusion criteria and either were published after the end search date of the included review or were not included in a prior systematic review.

Data Extraction and Quality Assessment

For all reports, 2 investigators abstracted details of study design, setting, patient population, intervention, and follow-up, as well as important co-interventions, health outcomes, health care use, and harms.

Two reviewers independently assessed each trial (including those that were identified from a prior systematic review) as having low, high, or unclear risk of bias (ROB) for the pain outcome using a tool developed by the Cochrane Collaboration (14). Disagreements were resolved by consensus. To assess the ROB of observational studies for the pain outcome, we considered potential sources of bias most relevant to this evidence base and adapted existing assessment tools (15, 16) (Supplement 3).

Data Synthesis and Analysis

For the subgroup of neuropathic pain studies, we did a study-level meta-analysis of the proportion of patients experiencing clinically significant (≥30%) pain relief (Supplement 4), and we used the profile-likelihood random-effects model (17) to combine risk ratios. We assessed the magnitude of statistical heterogeneity among the studies using the standard Cochran chi-square test, the I2 statistic (18). All analyses were done using Stata/IC, version 13.1 (StataCorp). Clinical heterogeneity, variation in outcomes reported, and the small number of trials precluded meta-analysis for other subgroups and outcomes, so we reported these qualitatively. After group discussion, we classified the overall strength of evidence for each outcome as high, moderate, low, or insufficient on the basis of the consistency, coherence, and applicability of the body of evidence as well as the internal validity of individual studies (19, 20).

Role of the Funding Source

The U.S. Department of Veterans Affairs Quality Enhancement Research Initiative supported the review but had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review, and approval of the manuscript; or decision to submit the manuscript for publication.

Results

After reviewing 13 674 titles and abstracts, we included 13 systematic reviews and 62 primary studies (Figure). Table 1 provides study-level details and the ROB rating for each of the chronic pain trials. Table 2 summarizes findings, including the ROB rating, by pain subgroup. Table 3 summarizes the harms in both pain and general populations. Supplement 5 provides additional study-level data from pain studies not included in prior reviews and from studies on general harms.

Figure. Literature flow diagram. * Includes Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Health Technology Assessments, and Cochrane Central Register of Controlled Trials.

Table 1. Characteristics and Findings of RCTs on Cannabis Extracts for Treating Chronic Pain*

Table 2. Summary of Evidence of the Benefits of Cannabis in Populations With Chronic Pain

Table 3. Summary of Evidence for the Harms of Cannabis in Chronic Pain and General Adult Populations

Effects of Cannabis in Treating Chronic Pain

We identified 22 RCTs (21–42) from 2 recently published systematic reviews (10, 11) and an additional 8 studies (5 RCTs [43–47] and 3 cohort studies [48–50]) that met our inclusion criteria and were not included in prior reviews. The primary methods of continuous pain assessment were a visual analogue scale from 0 to 100 mm and a numerical rating scale (NRS) from 0 to 10 (where 0 indicated no pain and 10 indicated the worst possible pain). Some of the studies identified the proportion of participants who had clinically significant improvements in pain intensity (defined as ≥30% reduction, or approximately 2 points on the NRS and 20 mm on the visual analogue scale).

Neuropathic Pain

Thirteen trials examined the effects of cannabis-based preparations on neuropathic pain (Table 1). Participants had central or peripheral neuropathic pain related to various health conditions. Of these studies, 11 were rated as having low ROB (24, 27, 28, 30, 31, 33, 36, 39, 40, 43, 47), 1 as having unclear ROB (26), and 1 as having high ROB (35). Overall, we found low-strength evidence that cannabis may alleviate neuropathic pain in some patients (Table 2). Studies generally did not find clinically significant between-group differences on continuous pain scales, but a higher proportion of intervention patients had clinically significant pain relief up to several months later. Across 9 studies, intervention patients were more likely to report at least 30% improvement in pain (risk ratio, 1.43 [95% CI, 1.16 to 1.88]; I2 = 38.6%; P = 0.111) (Supplement 4). Most studies were small, few reported outcomes beyond 2 to 3 weeks, and none reported long-term outcomes.

In the largest RCT, 246 patients with peripheral neuropathic pain self-titrated nabiximols up to a maximum dosage of 24 sprays per day or received a placebo (27). Those who completed the study (79 in the nabiximols group and 94 in the placebo group) and responded positively to the intervention had a significant decrease in pain (odds ratio, 1.97 [CI, 1.05 to 3.70]). However, among all participants, including those who did not have an intervention response, the reduction in the NRS pain score did not reach clinical or statistical significance. The second-largest RCT with low ROB included 55 patients with HIV-associated sensory neuropathy who were randomly assigned to smoke either 3.56% THC cigarettes or a placebo 3 times per day for 5 days. Among those who completed the study, 52% (n = 13) of the treatment group had a clinically significant reduction in pain compared with 24% (n = 6) of the placebo group (33).

A 1-year prospective cohort study (n = 431) of patients with nociceptive and neuropathic chronic noncancer pain provides information about long-term treatment effects (50). Cannabis users had a reduction in average pain intensity (using a visual analogue scale from 0 to 10) that was stable across 4 time points over 1 year, but the change was small and not clinically significant (0.92 [CI, 0.62 to 1.23]).

Multiple Sclerosis

Nine trials examined the effects of cannabis-based preparations on pain among patients with multiple sclerosis (MS) (Table 1). Participants generally had intractable body pain or neuropathic pain related to a clinically confirmed diagnosis of MS. Three of these trials were rated as having low ROB (29, 42, 44), 5 as having unclear ROB (22, 37, 38, 41, 45), and 1 as having high ROB (32). Overall, we found insufficient evidence to characterize the effects of cannabis on pain in patients with MS (Table 2) because of the small number of methodologically rigorous studies, inconsistent findings across studies, lack of long-term outcomes, and small number of patients included in the trials.

Of the 3 low-ROB trials, 1 found small but clinically nonsignificant alleviation of pain at 5 weeks, 1 foundno difference in outcome, and a larger trial found that more intervention patients reported relief from body pain at 12 weeks (28.0% vs. 18.7%; P = 0.028) (29).

Cancer Pain

Three trials (n = 547) examined the effects of cannabis-based preparations on pain among patients with cancer-related pain (Table 1). Participants had moderate to severe intractable pain related to a clinically confirmed diagnosis of cancer, although the exact cause of pain was unspecified. Two studies were rated as having unclear ROB (23, 25), and 1 study was rated as having high ROB (34). Overall, these trials provide insufficient evidence because of the small number of studies and their methodological limitations, including high attrition, exclusion of patients with variable pain scores, use of some nonvalidated measures, and lack of clarity about randomization and blinding procedures (Table 2).

Other or Mixed Pain Conditions

Two trials (21, 46) and 3 cohort studies (48–50) examined the effects of cannabis-based preparations on pain among patients with other or mixed pain conditions, including fibromyalgia, rheumatoid arthritis, and inflammatory abdominal pain (Table 1). One trial was rated as having unclear ROB (21), and 1 was rated as having high ROB (46). One observational study was rated as having low ROB (50), and the other 2 were at high ROB (48, 49). Overall, evidence was insufficient because of the inconsistent results and the paucity of methodologically rigorous studies (Table 2). Limitations of individual studies include lack of follow-up, inadequate allocation concealment, selection bias, high attrition, and lack of inclusion of nonnaive cannabis users.

Harms of Cannabis Use

General Adverse Events Among Patients With Chronic Pain

Data from 2 systematic reviews examining cannabis for chronic pain suggest that cannabis use may be associated with a higher risk for short-term adverse effects (10, 11). However, the rates of adverse events did not significantly differ between groups in the additional pain trials we reviewed. Although most reported adverse events were mild, such as dizziness and lightheadedness, some were serious, such as suicide attempts, paranoia, and agitation (Table 3). An additional prospective observational study did not detect a difference in serious adverse events between a cannabis group (12.5% ± 1.5% THC, 2.5 g/d) and control group (adjusted incidence rate ratio for event, 1.08 [CI, 0.57 to 2.04]) (50).

Medical Harms in the General Population

Moderate-strength evidence from 2 well-designed cohort studies (52, 53) suggests that low levels of cannabis smoking do not adversely affect lung function over about 20 years in young adults, but some evidence suggests that daily use may cause adverse pulmonary effects over an extended period (Table 3). Because of methodological limitations, including a lack of longitudinal exposure measurement and potential recall bias, 2 studies (55, 56) give insufficient evidence about the effect of cannabis use on the risk for cardiovascular events. A meta-analysis (59) of 9 case–control studies provides low-strength evidence that cannabis use is not associated with an increased risk for head and neck cancer (odds ratio, 1.02 [CI, 0.91 to 1.14]). Another meta-analysis (57) of 6 case–control studies provides low-strength evidence of no elevated risk for lung cancer with cannabis use (odds ratio, 0.96 [CI, 0.66 to 1.38]). Insufficient evidence exists about the effects of cannabis on testicular (60) or transitional cell cancer (61) (Table 3).

Mental Health and Cognitive Harms in the General Population

One systematic review (64) and 8 studies (65–71, 74) consistently found an association between cannabis use (specifically related to THC content) and the development of psychotic symptoms (low strength of evidence) (Table 3). The association was seen both in populations at risk for psychotic spectrum disorders and in average-risk populations. The possibility that cannabis contributes directly to the development of psychotic symptoms is supported but not proved by biological plausibility, evidence of a dose–response relationship, prospective cohort studies, and small experimental studies.

A systematic review of 6 longitudinal studies provides low-strength evidence of an association between cannabis use and exacerbation of manic symptoms in patients with known bipolar disorder. The review found higher incidence of new-onset mania symptoms among populations without a diagnosis of bipolar disorder (pooled odds ratio, 2.97 [CI, 1.80 to 4.90]) (63).

Two systematic reviews of studies in general populations provide moderate-strength evidence that active, long-term cannabis use is associated with small to moderate negative effects on many domains of cognitive function, but evidence on cognitive effects in past users is insufficient (72, 73).

A meta-analysis of 4 epidemiologic studies found significantly increased odds of suicide death (pooled odds ratio, 2.56 [CI, 1.25 to 5.27]) with any cannabis use. However, our confidence in the findings is limited by inconsistent findings among included studies, inadequate assessment of exposure, and inadequate adjustment for confounding among the studies (insufficient strength of evidence) (62, 64).

Motor Vehicle Accidents in the General Population

Moderate-strength evidence from a recent meta-analysis of 21 multinational observational studies suggests that acute cannabis intoxication is associated with a moderate increase in collision risk (odds ratio, 1.35 [CI, 1.15 to 1.61]) (51).

Other Harms in the General Population

Long-term cannabis use has been associated with a severe form of cyclic vomiting called cannabinoid hyperemesis syndrome (75–82). Serious infectious diseases, including aspergillosis (83–86) and tuberculosis, have also been associated with smoking cannabis (87, 88). Evidence of the effects of cannabis on violent behavior is mixed (89, 90). Cannabis use was associated with incident cannabis use disorder (adjusted odds ratio, 9.5 [CI, 6.4 to 14.1]) in a large (N = 34 653) prospective cohort study (91). In a cross-sectional study of patients receiving daily opioid therapy for chronic pain, the prevalence of cannabis use disorder was 2.4%, and 13.2% reported having used cannabis in the past 30 days. The prevalence of cannabis use disorder among the subgroup of current users, however, was not reported (92).

Discussion

In our systematic review, we found limited evidence on the potential benefits and harms of cannabis use in chronic pain populations (Tables 2 and 3). We found low-strength evidence that cannabis preparations with precisely defined THC–cannabidiol content (most in a 1:1 to 2:1 ratio) may alleviate neuropathic pain but insufficient evidence in populations with other types of pain. Most studies are small, many have methodological flaws, and the long-term effects are unclear given the brief follow-up of most studies.

Among neuropathic pain studies, we found a discrepancy between continuous and dichotomous pain outcomes. Possible interpretations are that cannabis is simply not consistently effective or that, although cannabis may not have clinically important effects on average, subgroups of patients may experience large effects. We did not find data to clarify which subgroups of patients are more or less likely to benefit.

Our findings complement several recent reviews. In 1 review, the authors concluded that low- to moderate-strength evidence supports the efficacy of cannabis in chronic pain populations, limited mainly to those with MS or neuropathic pain. However, a separate group reviewed and reanalyzed a similar set of published articles and determined that insufficient to low-strength evidence supports the use of cannabis to treat chronic noncancer pain (11). A recent report from the National Academies of Sciences, Engineering, and Medicine examined the biological and clinical effects of cannabis across a broad range of indications and concluded that there is substantial evidence of benefit for patients with chronic pain. Although the overall conclusions seem to differ from our findings, the authors stipulated that the clinical improvements were modest and limited to neuropathic pain (93), and they underscored the urgent need for better research clarifying the effects of cannabis. Our review augments this report by using a systematic approach on a more focused topic (chronic pain and harms) as well as standard terminology for describing the strength of the body of evidence (19).

Even though we did not find strong, consistent evidence of benefit, clinicians will still need to engage in evidence-based discussions with patients managing chronic pain who are using or requesting to use cannabis. Therefore, clinicians must understand what is known and unknown about its potential harms.

We found moderate-strength evidence that light to moderate cannabis smoking does not adversely affect lung function over about 20 years. However, the limited data on the effects of heavy use suggest a possible deleterious effect on lung function over time (52, 53). We found low-strength evidence that light to moderate cannabis use is not associated with lung cancer or head and neck cancer diagnoses independent of tobacco use, but the data are limited to case–control studies and do not address heavy use. We found insufficient evidence examining whether cannabis use is associated with cardiovascular events over the long term.

Cannabis use has potentially serious mental health and adverse cognitive effects, although data are insufficient to characterize the magnitude of risk or in whom the risk is highest. Cannabis seems to be associated with at least small, short-term deleterious effects on cognition in active users, but long-term effects in past users are uncertain. We found a consistent association between cannabis use and the development of psychotic symptoms over the short and long term. A large prospective cohort study in the United States found that cannabis use was associated with a substantial risk for incident cannabis use disorder and a smaller risk for incident alcohol and other substance use disorders (91). Finally, we found some adverse effects that seem to be related to cannabis use and are important for clinicians to know (for example, infectious disease complications, cannabis hyperemesis syndrome, and violent behavior), but the incidence of these effects has not been well-characterized.

Evidence-based nonpharmacologic and nonopioid pharmacologic therapies are the preferred initial methods for treating chronic pain (94). Clinicians may struggle with treating chronic pain in patients who have not responded to first-line treatment, and cannabis may be perceived as a safer strategy in these patients (95). The scale and severity of adverse events, including death, seen with opioids have not been described with cannabis in the literature (although less research is available on cannabis than on opioids) (95). However, no studies have directly compared cannabis with opioids, and no good-quality data exist on how cannabis use affects opioid use and opioid-related adverse effects. Cross-sectional studies suggest an association between co-occurring cannabis use and adverse opioid-related events (that is, misuse or more refills) among patients prescribed opioids (6, 7, 96–98). By contrast, an open-label study found that pain scores and opioid use decreased over 6 months in participants with chronic pain who initiated cannabis treatment, although confidence in the findings is limited by the large number of participants lost to follow-up (99).

The applicability of study data to current practice is limited in several ways. The patient populations in many studies were highly selected, and some studies included a run-in period after which patients who did not respond were excluded from further study. The data on effectiveness largely come from trials examining formulations with precisely defined THC and cannabidiol content, which differs from the reality of clinical practice. Even though dispensaries are increasingly labeling products' content, discrepancies often exist between labeled and measured content (100). Moreover, the dose of THC assessed in many of the studies is substantially lower than that in products commonly available in dispensaries (for example, 2.5 mg of THC vs. a range of 15 to 200 mg) (100).

Finally, the evidence base on harms is limited because studies include relatively few patients who are older, are chronically ill, or have a history of heavy and prolonged cannabis use. In observational studies, the exact dose of exposure to cannabis was rarely known because of recall bias, and the potency (that is, in estimates of cannabis cigarettes smoked per day) was impossible to assess. On the other hand, this imprecision probably mirrors the uncertainty clinicians will face in discussing benefits and harms with their patients.

Our approach to synthesizing the literature also has limitations. Given the broad scope of our review, we relied on existing systematic reviews to identify the best available evidence. However, we also comprehensively searched for and included newer primary studies, included only good-quality systematic reviews, and reassessed the quality of primary pain studies included in prior reviews. We excluded studies of synthetic prescription cannabinoids, in part because these were included in recent reviews and are not available in cannabis dispensaries. Regardless, inclusion of these studies would not have changed our overall findings because so few studies were available, they were methodologically flawed, and they had very small sample sizes. We examined harms in both chronic pain and general populations, although the degree to which harms data in general populations apply to patients with chronic pain is uncertain. Finally, we focused specifically on pain outcomes in patients with chronic pain, but we acknowledge that other outcomes are also important in the treatment of chronic pain. In our larger report, we describe low-strength evidence that cannabis may reduce spasticity and improve sleep in patients with MS. We found insufficient evidence regarding the effects of cannabis on these outcomes in other patient populations and regarding effects on quality of life and functional status in any population (8).

Virtually no conclusive information exists about the benefits of cannabis in chronic pain populations, and limited information is available on harms, so methodologically strong research in almost any area is likely to add to the strength of evidence (see Table 8 of Supplement 5 for a list of important research gaps and Table 9 of Supplement 5 for a list of ongoing studies). Of note, many of the studies we found were done in European countries, suggesting that there may be fewer barriers to conducting cannabis-related research there than in the United States, where barriers are substantial.

Although cannabis is increasingly available for medical and recreational use, little methodologically rigorous evidence examines its effects in patients with chronic pain. Limited evidence suggests that it may alleviate neuropathic pain, but evidence in other pain populations is insufficient. Evidence is also limited on its association with an increased risk for nonserious short-term adverse effects and potentially serious mental health adverse effects, such as psychosis.