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Kansagara D, O'Neil M, Nugent S, et al. Benefits and Harms of Cannabis in Chronic Pain or Post-traumatic Stress Disorder: A Systematic Review [Internet]. Washington (DC): Department of Veterans Affairs (US); 2017 Aug.

Cover of Benefits and Harms of Cannabis in Chronic Pain or Post-traumatic Stress Disorder: A Systematic Review

Benefits and Harms of Cannabis in Chronic Pain or Post-traumatic Stress Disorder: A Systematic Review [Internet].

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RESULTS

LITERATURE FLOW

We included 12 systematic reviews and 48 primary studies after reviewing 10,875 titles and abstracts (Figure 1).

Figure 1. Literature Flow Diagram.

Figure 1

Literature Flow Diagram.

KEY QUESTION 1. What are the effects of cannabis on health outcomes and healthcare utilization for adults who have chronic pain?

KEY QUESTION 1A. Do the effects differ by patient subgroup, such as patient medical and mental health comorbidities?

Summary of Findings

In this systematic review of the literature, we found limited evidence on the potential benefits and harms of cannabis use in chronic pain populations. We found low-strength evidence that cannabis preparations with precisely defined THC:CBD content (most in a 1:1 to 2:1 ratio) have the potential to improve neuropathic pain but insufficient evidence in other patient populations. Most studies are small, many have methodologic flaws, and the long-term effects are unclear given the brief follow-up duration of most studies. The applicability of these findings to current practice may be low, in part because the formulations studied may not be reflective of what most patients are using, and because the consistency and accuracy of labeled content in dispensaries are uncertain.

Two recent systematic reviews examined the efficacy of cannabis and cannabinoids for the treatment of chronic pain,14,15 and reported mixed findings for the management of various chronic pain symptoms related to conditions such as MS, fibromyalgia, peripheral and central neuropathy, human immunodeficiency virus (HIV), rheumatoid arthritis, and cancer. Specifically, across a subset of 8 trials (N=1370) that evaluated non-synthetic cannabinoids (THC or nabiximols), cannabis treatments were associated with a non-significant trend toward benefit (proportion showing greater than 30% reduction in pain: 37% versus 31%; odds ratio [OR] 1.41; 95% confidence interval [CI], 0.99 to 2.00]) compared to placebo and no difference in quality of life among groups.14 While the authors concluded that there is low- to moderate-strength evidence supporting efficacy of cannabis in chronic pain (limited mainly to MS or neuropathic pain), a separate group reviewed and re-analyzed a similar set of published articles, and determined that there is insufficient to low-strength evidence examining the use of medical cannabis to treat chronic non-cancer pain.15 Our own interpretation of the evidence is consistent with the latter review because the vast majority of the trials cited in support of a moderate-strength evidence rating were methodologically flawed. Both reviews found insufficient evidence examining the use of medical cannabis for pain related to other conditions such as cancer, rheumatoid arthritis, and musculoskeletal pain.

While the prior reviews included the pharmaceutical, synthetic prescription medications dronabinol and nabilone, studies of these drugs did not contribute substantially to the body of evidence for chronic pain. There was only one small study with high risk of bias examining the effects of nabilone in chronic pain.

We included eligible trials identified by the prior reviews, and found an additional 8 studies27-34 that met our inclusion criteria and were not included in the prior reviews. Those additional studies included patients with pain related to MS (4 studies) and mixed pain-related conditions (4 studies). Table 2 presents the overall findings of studies that examined pain and other outcomes in patients with chronic pain. Table 3 presents the findings of RCTs that reported pain outcomes.

Table 2. Studies of the Overall Effects of Cannabis in Patients with Chronic Pain.

Table 2

Studies of the Overall Effects of Cannabis in Patients with Chronic Pain.

Table 3. Characteristics and Findingsa of RCTs of the Effects of Cannabis Extracts on Pain Outcomes.

Table 3

Characteristics and Findingsa of RCTs of the Effects of Cannabis Extracts on Pain Outcomes.

No studies directly compared effects according to patient comorbidity. Rather, we describe detailed findings according to patient subgroup below.

Detailed Findings According to Patient Subgroup

Multiple Sclerosis (MS)

Two prior systematic reviews and 4 additional published trials examined the effects of cannabis-based preparations on pain and spasticity in patients with MS. Overall, there is low-strength evidence to support cannabis-based treatments for the potential to improve pain, spasticity, and sleep in select populations with MS, but results were inconsistent across studies. The body of evidence is limited by the paucity of methodologically rigorous studies, inconsistent findings across studies, the lack of long-term outcomes, and the small number of patients included in many trials. Moreover, the largest low risk of bias trial used restrictive entry criteria which may reduce the applicability of the evidence to broader populations.

A recent systematic review included 11 (2,653 participants) trials examining the use of cannabis preparations compared with placebo (it also included studies of synthetically produced cannabinoids which are not covered in our review).14 The authors of this review found low- to moderate-strength evidence mostly from trials of nabiximols on spasticity in MS. However, the findings were mixed with evidence of no effect on some spasticity related outcomes and small effects on others. Moreover, 9 of 11 trials had high or unclear risk of bias; only 2 of the trials were found to be at low risk of bias.

One RCT analyzed data from 414 patients from 33 outpatient neurology and rehabilitation centers in the United Kingdom (UK).53 Patients were randomized to cannabis extract (containing 2.5 mg THC) and matched placebo capsules. The study had a 5-week dose titration phase and a 10-week maintenance phase; the maximum allowable dose was 25 mg daily. The study results did not identify a significant effect on mean change in spasticity between groups (mean changes in groups were 1.24 and 0.92 for cannabis extract and placebo, respectively). On secondary outcome measures, there were no differences in timed 10-minute walk test, self-reported mobility, disability score, or general health. Participants randomized to cannabis extract had a greater likelihood of self-reported improvement on 3 of 9 symptom categories (including spasticity, pain, and spasms).

In a study of 277 patients with MS, patients were randomized to cannabis extract (contained 2.5 mg THC) and matched placebo capsules.54 The study had a 2-week dose titration phase and a 10-week maintenance phase; the maximum allowable dose was 25 mg. The proportion of patients who achieved significant relief from muscle stiffness was 29.4% in the cannabis group versus 15.7% in the placebo group (OR 2.26; 95% CI, 1.24 to 4.13; P = .004, one-sided). Secondary analyses were also in favor of the cannabis group, as patients reported improvements in body pain, muscle spasms, and sleep quality.

Another systematic review focused on non-cancer pain treatment and covered literature over the same time frame. This review differed in that it intentionally re-analyzed data excluding unpublished studies (most of which were industry-funded). They identified 4 studies (510 participants) examining the efficacy of cannabis preparations for patients with pain related to MS (2 other studies examined synthetically produced cannabinoids, which are not part of our review).15 The authors concluded that there was low-strength evidence showing no significant difference between cannabis preparations and placebo in improving pain in patients with MS.

We identified an additional 4 trials (314 participants) examining cannabinoids to treat spasticity and/or pain in patients with MS.27-30 Two studies were rated as low risk of bias,27,30 one was at high risk of bias,28 and one was unclear.29 In a large multicenter European trial with low risk of bias (N=241), patients with MS and moderately severe spasticity were randomized to open-label nabiximols or placebo if they initially experienced at least a 20% reduction in spasticity Numeric Rating Scale (NRS) during an open-label nabiximols run-in period. Over half (52.2%) of participants failed to meet this criteria and were not enrolled. Active treatment consisted of nabiximols, containing 2.7 mg THC and 2.5 mg CBD delivered via oromucosal spray. Participants self-titrated their dose; the maximum permitted dose was 12 sprays in any 24 hour period. The intervention lasted for 12 weeks, with the final follow-up visit 2 weeks after treatment completion. The intervention group experienced a significant reduction in mean spasticity score from baseline to end of treatment compared with the placebo group (change in mean NRS score -0.84 [95% CI, -1.29 to -0.40]). The number of responders (defined as at least a 30% improvement in spasticity from baseline) was significantly higher in treatment versus placebo (74% versus 51%; OR 2.73; 95% CI, 1.59 to 4.69). The study medication was also superior to placebo for 6 of 15 secondary outcomes.

The remaining 3 trials revealed mixed findings. In a 5-day treatment study, patients with MS treated with THC 7.5 mg had no significant differences in any outcome (limb weakness, limb spasticity, limb coordination, gait impairment, reflexes) based on physician rating, though patient self-reported spasticity was lower when on THC versus placebo when doses were 7.5 mg or higher.28 In a double-blind cross-over trial with 20 patients with MS or other neurological diagnosis, participants received each of THC, CBD, THC and CBD, and placebo for 2 weeks in randomized order.30 Study findings were mixed: pain relief assessed with a Visual Analog Scale (VAS) was improved for both the THC and CBD groups relative to placebo, but not the group receiving THC and CBD combined; spasm VAS score improved following use of THC and combined THC and CBD; spasticity improved for THC only; and no significant improvements were seen in coordination or bladder control. Study medications, relative to placebo, were not consistently associated with significant treatment benefit on other secondary outcome measures. In a 5-site study of 36 patients who demonstrated a positive response to nabiximols during an open-label phase, participants were randomized to 4 weeks of continued nabiximols use or placebo.29 Those randomized to placebo were more likely than participants randomized to nabiximols to demonstrate a treatment failure (defined as increase in spasticity, addition of anti-spasticity medicine, or treatment drop-out): treatment failure was observed in 44% of the nabiximols group versus 94% of the placebo group (hazard ratio [HR] 0.335; 90% CI, 0.162 to 0.691). Findings on secondary outcomes were mixed. The risk of bias from this trial is unclear, as it was underpowered and participants who withdrew from the trial may have returned to taking other medications before returning for formal study withdrawal visit.

Neuropathic Pain

Thirteen trials examined the effects of cannabis-based preparations on neuropathic pain (Table 3). Participants had central or peripheral neuropathic pain related to various health conditions. Of these studies, 11 trials were determined to be at low ROB,33,35-38,41-46 1 as having unclear ROB,40 and 1 as having high ROB.39 Overall, we found low-strength evidence that cannabis may improve pain in some patients with neuropathic pain. Studies generally did not find clinically significant differences on continuous pain scales between groups, but a higher proportion of intervention patients experienced clinically significant pain relief at up to several months of follow-up. In a meta-analysis of nine studies that reported ≥ 30% pain reduction, intervention patients were more likely to report improvement in pain (RR 1.43, 95% CI 1.16 to 1.88; I2=38.6%, p = 0.111; Figure 2). Most studies were small, few reported outcomes beyond 2 to 3 weeks, and none reported long-term outcomes.

Figure 2. Odds of achieving ≥ 30% pain reduction with cannabis compared to placebo in trials of patients with neuropathic pain.

Figure 2

Odds of achieving ≥ 30% pain reduction with cannabis compared to placebo in trials of patients with neuropathic pain.

In the largest RCT, 246 patients with peripheral neuropathic pain self-titrated nabiximols up to a maximum allowable dose of 24 sprays/day or received a placebo.41 Those who completed the study (79 nabiximols and 94 placebo) and responded positively to the intervention demonstrated a significant decrease in pain (OR 1.97, 95% 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 scale did not reach clinical or statistical significance. The second-largest low ROB RCT included 55 patients with HIV-associated sensory neuropathy who were randomized to smoke either 3.56% THC cigarettes or placebo 3 times daily for 5 days. Among those who completed the study, 52% (n=13) of the treatment group demonstrated a clinically significant (> than 30%) reduction in pain compared to 24% (n=6) in the placebo group.35

A one-year prospective-cohort study (n=431) among patients with nociceptive and neuropathic chronic non-cancer pain provides information about long-term treatment effects.31 Cannabis users experienced a reduction in average pain intensity (VAS) that was stable across 4 time points over a one-year period among cannabis users, but the change was small and not clinically significant (0.92 change, 95% CI 0.62 to 1.23).

Other/Mixed Pain Conditions

Overall, there are a limited number of studies of patients with chronic pain that are not related to MS or neuropathy. Generally, the evidence is inconsistent and of low quality. As noted above in the prior systematic reviews, there were 2 studies with unclear risk of bias which both included patients with cancer-related pain (described more below); 3 other studies had a high risk of bias (and are not summarized here).14,15 We found only 2 additional studies, one low risk of bias RCT33 and one observational study (N=465) (Table 2).31

Of the additional studies, the best evidence for the treatment of mixed pain conditions comes from a randomized, double-blind, placebo-controlled, crossover trial that was conducted in the UK among 34 patients with various pain conditions, 47% of whom were diagnosed with MS.33 Participants were each administered 3 different medicinal cannabis extract preparations (1:1 THC/CBD, CBD only, THC only) and a placebo control group over an 8-week trial period. Participant-reported that pain symptoms decreased significantly among the THC:CBD and THC only groups compared to CBD only and placebo group (P < .001) and 38% (9/24) patients had a decrease in VAS of 50% or more when using active preparations versus placebo. No significant improvements were found on validated measures of sleep, general health, and mood among the THC:CBD and THC only groups. There were no follow-up assessments conducted to determine whether symptom improvements were maintained over time.

An observational prospective-cohort study of 431 patients provides some information about long-term treatment effects.31 This study assessed the efficacy of a standardized herbal cannabis product (12.5% ± 1.5% THC titrated up to a recommended maximum of 5g daily) among patients with chronic non-cancer pain over the course of 1 year. Participants in the cannabis group were defined as “patients using cannabis as part of their treatment” and were compared to individuals from the same clinics who denied using cannabis. Compared with baseline, there was a significant reduction in average pain intensity in cannabis group (0.92 change [95% CI, 0.62 to 1.23]), but not in control group (0.18 change [95% CI, -0.13 to 0.49]) at 1 year after adjusting for demographic variables, other substance use, and pain-related variables. Also, a greater reduction in pain intensity was observed among cannabis users versus controls (1.10 difference [95% CI, 0.72 to 1.56]). The cannabis group reported a significant reduction in mood disturbance, as well as improved physical quality of life compared to controls. All changes were stable across the 3-, 6-, and 12-month follow-ups. The limitations of this study were that the majority (66%) of the cannabis users were experienced, making the generalizability to cannabis-naïve users difficult, and this study reported a high drop-out rate (over 30%), which may be a source of selection bias. Reasons for attrition among the cannabis group included perceived lack of efficacy, experience of adverse events, and/or a dislike of the study product. However, authors noted that those who dropped out were comparable to those who completed the study.

The 2 studies of patients with cancer-related pain had an unclear risk of bias and were both included in one of the aforementioned systematic reviews.56,57 In a randomized, double-blind, placebo-controlled graded dose study, patients with opioid-refractory cancer pain received a placebo or one of 3 doses of nabiximols (low: 1 to 4 sprays per day; medium: 6 to 10 sprays per day; or high: 11 to 16 sprays per day) during a 5-week treatment period. A separate double-blind, placebo-controlled crossover study evaluated cancer patients who each received placebo, 10 and 20 mg of THC, and 60 and 120 mg of codeine over 5 successive days. These studies both found an improvement in cancer-related pain among medical cannabis users who ingested a 10 mg THC capsule over a 7 hour observation period56 and among the low-dose (1 to 4 sprays per day) and medium-dose (6 to 10 sprays per day) nabiximols groups.57 The nabiximols trial also identified a significant change in an opioid composite score that was defined as either a reduction in pain with a stable opioid consumption (morphine equivalent) or a reduction in opioid consumption with stable pain (P = .038) among those only in the low-nabiximols dose group.57 Methodological limitations of the nabiximols trial were a high attrition rate (27%), the exclusion of patients who reported highly variable pain scores over the course of 3 days, and the use of a non-validated sleep measure. The study comparing THC to codeine did not utilize a validated measure of pain.56

KEY QUESTION 2. What are the effects of cannabis on health outcomes and healthcare utilization for adults who have PTSD?

KEY QUESTION 2A. Do the effects differ by patient subgroup, such as patient medical and mental health comorbidities?

Summary of Findings

There are very few methodologically rigorous studies examining the effects of cannabis in patients with PTSD. We found only 2 observational studies which suggest that cannabis is potentially associated with neutral effects on PTSD or depression symptom severity, and employment status, and negative effects in terms of violent behavior, drug and alcohol abuse, and suicidal ideation. However, the strength of evidence is rated as insufficient due to the potential for bias in the 2 included studies in this review and the small number of controlled studies reporting data on benefits and harms of cannabis for treating PTSD symptoms. We found no evidence addressing whether effects differed according to other comorbidities in patients with PTSD.

Detailed Findings

We found one systematic review16 and only 2 primary studies60,61 meeting our inclusion criteria (Table 4), primarily because most of the literature on cannabis use in populations with PTSD was cross-sectional and/or did not include a comparison group.

Table 4. Studies of the Effects of Cannabis on PTSD Symptoms.

Table 4

Studies of the Effects of Cannabis on PTSD Symptoms.

The systematic review by Wilkinson and colleagues (2016) searched the literature through March 2015,16 and the 2 primary studies we included were not included in their review because they were both published after March 2015. The Wilkinson et al systematic review included 6 studies related to PTSD.62-67 Of the 6 included studies, 3 were on nabilone, a synthetic form of cannabis.62-64 One of these was an RCT, though it included only 10 participants, and the other 2 were retrospective chart review studies. The other 3 studies on non-synthetic forms of cannabis were 2 prospective open-label trials,65,66 and the last was a prospective observational study;67 none of these 3 studies included a control group. Due to the focus on synthetic cannabis or the lack of a control group, none of the 6 primary studies included in the Wilkinson et al (2016) systematic review met our inclusion criteria. In spite of having broader inclusion criteria, the synthesized findings from the Wilkinson et al systematic review suggest that the evidence of the effectiveness of cannabis for reducing PTSD symptoms is insufficient.16

The primary study by Wilkinson et al (2015) examined data from all Veterans in VA specialized intensive PTSD programs from 1992 to 2011, with a total sample size of over 47,000.60 They excluded participants who reported drinking more than 2 alcoholic drinks on one occasion, reported using any other drug 30 days prior to admission, or were referred from a drug or alcohol treatment program. The remaining participants were grouped into “never-users,” “stoppers” who used cannabis prior to but not after admission, “continuing users,” and “starters” who did not use cannabis prior to admission but started after admission. After balancing sample sizes across groups, they compared 4-month post-baseline outcomes for 2,276 Veterans. They included demographic covariates associated with cannabis use and found that continuing users and starters had significantly worse PTSD symptoms and greater drug abuse than never-users and stoppers at 4 months post-baseline. Starters also experienced significantly greater alcohol abuse than the other groups, and continuing users experienced significantly greater alcohol abuse than continuing users after 4 months. Starters experienced significantly more violent behavior at 4 months post-baseline compared to the other groups. There were no significant differences among the groups on employment status.

Johnson et al (2016) examined data at a single time point from Veterans entering a VA-based primary care and mental health integration program.61 This study included 350 Veterans who used cannabis and 350 non-user controls who were matched on age and gender; all cases and controls had PTSD. Compared to cannabis users, controls were significantly more likely to be married, White, employed, and financially stable. There were no significant differences between cannabis users versus controls on PTSD symptom severity or depression symptom severity. The cannabis users were significantly more likely to experience suicidal ideation and reported significantly more alcohol use (reporting on average approximately 6 alcoholic drinks per week compared to approximately 3 drinks per week in the control sample).

KEY QUESTION 3. What are the harms associated with cannabis use in adults?

KEY QUESTION 3A. Do the harms differ by patient subgroup, such as patient medical and mental health comorbidities?

We searched broadly for harms and describe the evidence base for each harm category below. We found no evidence which directly compared risk across different patient subgroups, but we describe relevant information about patient characteristics below as applicable.

General Adverse Events

In the 2 systematic reviews examining cannabis for chronic pain, cannabis was overall associated with a higher risk of short-term adverse effects.14,15 Across all indications (not just chronic pain or PTSD) and treatment formulations (including synthetic cannabinoids), treatment was associated with an increased risk of: any adverse event (OR 3.03; 95% CI, 2.42 to 3.80), serious adverse event (OR 1.41; 95% CI, 1.04 to 1.92), and withdrawal due to adverse event (OR 2.94; 95% CI, 2.18 to 3.96).14 In the review focused on only chronic pain, cannabis was similarly associated with a higher risk of adverse events. While most adverse events were mild, there were possible treatment-related adverse events such as suicide attempts, paranoia, and agitation. In the additional trials that we reviewed, the rates of adverse events did not significantly differ between groups. Side effects were rated as minor and may be considered common effects of cannabis, such as dizziness, relaxation, short-term memory impairment, and mental clouding (Table 2).

One prospective cohort study of 431 patients study assessed the incidence of serious adverse events and adverse events over one year among patients using cannabis for chronic non-cancer pain and found no statistically significant group differences between the cannabis-using group and non-using group on serious adverse events. However, cannabis users were at higher risk for non-serious adverse events.31 The limitations of this study were that the majority (66%) of the cannabis users were experienced, making the generalizability to cannabis-naïve users difficult, and more frequent follow-up times among the exposure group may have artificially inflated the number of adverse events reported by cannabis users.

In addition, Notcutt and colleagues (2004) had 2 participants withdraw or break blinding due to the inability to tolerate cannabis.33 The investigators also had to increase the time interval of the initial dosing titration from 15 minutes to 30 minutes between sprays due to 2 participants experiencing dysphoria and lightheadedness.

Medical Harms

Pulmonary Effects

Overview

One systematic review published in 2007,68 and 2 more recent prospective cohort studies69,70 provide data relevant to the short- and long-term pulmonary effects of cannabis smoking.

Taken as a whole, the literature provides low-strength evidence that low levels of cannabis smoking do not adversely impact lung function over about 20 years in young adults, but there is some evidence suggesting that heavy (ie, daily) use may have the potential to cause adverse pulmonary effects over an extended period of time. There are no studies in older users, or in those with medical comorbidities such as chronic obstructive pulmonary disease (COPD) or heart disease.

Detailed results

There were 12 studies included in the review that directly assessed the short-term effects of inhaled cannabis.68 Most studies found that smoking cannabis was associated with bronchodilation up to about an hour after exposure. One study found that nearly daily cannabis use in a controlled environment was associated with increased airway resistance over 2 months. In general, it is difficult to draw firm conclusions from these short-term, small (N < 35) studies published over 2 decades ago, 4 of which did not control for concomitant tobacco use.

The best evidence examining the long-term effects of cannabis smoking on pulmonary function comes from 2 more recently published prospective cohort studies with low risk of bias (Table 5). In one US study, pulmonary function testing was conducted at baseline and 4 more times over a 20-year follow-up in a cohort of healthy young adults (N=5,016).70 While a similar proportion of participants smoked cannabis or tobacco cigarettes, most cannabis users smoked infrequently (about twice monthly on average). Higher cumulative tobacco exposure was associated with a significant decline in forced expiratory volume (FEV1) and forced vital capacity (FVC), but cannabis exposure was actually associated with an increase in both measures over 20 years. Of note, the trends in lung function were non-linear: FEV1 levels were flat or downtrending among those with substantial levels of cannabis exposure (the equivalent of one joint daily for 7 years or more).

Table 5. Observational Studies of Cannabis Use and Cardiopulmonary Outcomes.

Table 5

Observational Studies of Cannabis Use and Cardiopulmonary Outcomes.

A birth cohort study (N=1,037) from New Zealand similarly found that FEV1 and FVC increased over time, though the change was small and not statistically significant. Most cannabis users had relatively low rates of cumulative exposure.69 Of note, higher rates of cumulative exposure were associated with a small increase in measures of airway resistance.

The prior systematic review also examined long-term pulmonary effects of cannabis. There were 3 cohort studies; the rest were cross-sectional. One of the cohort studies was an earlier interim follow-up from the New Zealand birth cohort study. Another older study examined the effects of “nontobacco” cigarette smoking, but did not have detailed information about cannabis exposure specifically and did not have pulmonary function data for many participants. A third study followed a convenience sample of healthy young adults (mean age 33 years) over up to 8 years of follow-up.71 About one-third of the participants were heavy habitual cannabis smokers (3.5 joints per day on average), 28% smoked cannabis and tobacco, 17% smoked tobacco only, and 22% smoked neither. About two-thirds of participants had 2 or more FEV1 measures over time, and there was a similar mix of baseline smoking status in those lost to follow-up and those followed longitudinally. The authors found that, while there was a significant decline in FEV1 among tobacco users, cannabis smoking was not associated with a greater decline in FEV1 than nonsmoking.

Cardiovascular Events

Overall, there was insufficient evidence from 2 studies about the effect of cannabis use on the risk of cardiovascular events. Two publications reported analyses from the Myocardial Infarction Onset Study in which nearly 4,000 patients were interviewed just after suffering a myocardial infarction (Table 5). One study assessed the relationship between cannabis use at the time of this baseline interview and subsequent mortality over an average of 12.7 years of follow-up.72 There was no information about longitudinal exposure to either cannabis or tobacco use which makes it very difficult to assess the relationship between cannabis exposure and long-term mortality. The other analysis was a case-crossover study which compared the risk of myocardial infarction within one hour of cannabis use compared to periods of non-use based on one's pattern of use over the prior year.73 This study had a high risk of bias because recall bias was a significant issue with this study and it was not clear how the authors accounted for tobacco use.

Cancer

There was low-strength evidence mainly from case-control studies that cannabis use does not appear to be associated with a higher risk of head and neck or lung cancer (Table 6). There was insufficient evidence from a smaller number of methodologically limited studies about the effects of cannabis on testicular or transitional cell cancer. We found no evidence examining the effects of cannabis on other types of cancer.

Table 6. Observational Studies of Cannabis Use and Cancer Risk.

Table 6

Observational Studies of Cannabis Use and Cancer Risk.

Head and neck cancer

A meta-analysis of 9 case-control studies (n=5,732 cases) showed that cannabis use was not associated with head and neck cancer (OR 1.02; 95% CI, 0.91 to 1.14).74 Results were generally consistent across studies and there was no evidence of dose-response effect. The analyses are inherently limited by recall bias and there was a very wide range of ever cannabis use across studies, though results were consistent across different study populations.

Lung cancer

One international IPD meta-analysis of 6 case-control studies (n=2,159 cases) found no association between habitual cannabis use (≥ 1 joint-year) and lung cancer among middle-aged patients (OR 0.96; 95% CI, 0.66 to 1.38).75 The results were consistent across different analyses, intensity of use, age of first use, and after excluding patients who had used cannabis within 2 years of diagnosis. Though the study was generally well-conducted, recall bias is an inherent limitation. The results apply most closely to persons with relatively light cannabis use as there were very few patients with a history of intense use. While this was a large study, there were few patients who were both habitual cannabis users and who had never smoked tobacco.

A large 40-year cohort study (N=49,231; n=189 lung cancer cases) from Sweden had a high risk of bias because of significant methodologic flaws including lack of long-term data on cannabis and tobacco exposure that make it difficult to interpret findings.76 Cannabis and tobacco use were assessed only at the time of military conscription, and these exposures were related to subsequent risk of lung cancer over 40 years of follow-up.

Testicular cancer

A meta-analysis of 3 case-control studies (n=719 cases) found a small increase in the risk of testicular cancer among weekly cannabis users compared to those who never used (OR 1.92; 95% CI, 1.35 to 2.72).77 In sensitivity analyses, the increased risk was only seen among those with non-seminoma cancers and not in those with seminoma cancers. While the meta-analysis itself was methodologically strong, there were substantial methodologic weaknesses in each of the 3 included studies rendering the meta-analysis at high risk of bias. The smallest study did not control for all important confounders including tobacco use. Results were consistent in the 2 larger and methodologically stronger studies, but response rates were very low which may exacerbate issues with recall bias.

Transitional cell cancer

One small case-control study (n=52 cases) from 2 VA urology clinics assessed the risk of transitional cell carcinoma.78 While there was an increased risk of cancer seen with heavier cannabis use, the results are difficult to interpret because of significant methodologic flaws placing the study at high risk of bias.

Motor Vehicle Accidents

Overall, we found evidence suggesting an increased risk of collision associated with acute cannabis intoxication, but the magnitude and precision of increased risk are unclear.

A 2016 systematic review of cannabis intoxication and motor vehicle accidents pooled the findings of 21 multi-national observational studies that were published between 1982 and 2015, with a combined sample size of 239,739. The meta-analysis determined a statistically significant, moderate increase in collision risk associated with acute cannabis intoxication (OR 1.35; 95% CI, 1.15 to 1.61).79 In assessing study quality, the review authors examined the methods used to measure drug use (eg, self-report, or lab values from blood versus urine or saliva), crash severity, adjustment for alcohol use and other confounders, and whether the study evaluated a dose-response effect. Sub-analyses that grouped studies based on quality, design (case-control versus culpability studies), degree of adjustment for confounders, and crash severity (whether fatalities were involved) found pooled effects in the range of 1.07 to 1.81 using a random effects model, and 1.08 to 1.90 using meta-regression.

The review authors suggested that the pooled estimate may be complicated by factors affecting a user's decision to drive under the influence of cannabis. Experimental studies using simulated driving have reported that alcohol increases driving speed and risk-taking, while cannabis users tend to be aware of their impairment and drive slower and more cautiously in an effort to compensate.80,81 The pooled effect may underestimate the true risk of collision with acute cannabis intoxication, if users are more likely to drive when their level of impairment is low. Conversely, the pooled estimate may be inflated if cannabis users who choose to drive while intoxicated have a higher baseline risk independent of cannabis use, compared with cannabis users who choose not to drive after use.79

A study that sought to determine a threshold for serum concentration of THC associated with driving impairment found that serum concentrations below 10 ng/mL were not associated with elevated accident risk, based on limited epidemiological data.82 The authors of the study reported that based on experimental studies, THC serum concentration in the range of 7 to 10 ng/mL is comparable to a blood alcohol concentration of 0.05% on degree of impairment.82

Mental Health-Related Harms

Suicidal Behaviors

We found no evidence examining the effects of cannabis use on suicide risk in patients with chronic pain or PTSD.

A review and meta-analysis of epidemiological research from 1995 to 2015 found few studies on the effect of cannabis use and suicidality (suicide death, ideation, and attempt) among the general population including both adolescents and adults.83 Data were insufficient to comment on the effect of acute cannabis use and suicidality. However, the review found limited evidence suggesting significantly increased odds of suicide death (pooled OR 2.56; 95% CI, 1.25 to 5.27, 4 studies) with any cannabis use. In 6 studies each, any cannabis use was significantly associated with increased odds of suicide ideation (pooled OR 1.43; 95% CI, 1.13 to 1.83) and suicide attempt (pooled OR 2.23; 95% CI, 1.24 to 4.00). Further, heavy cannabis use was associated with significantly increased odds of suicide attempt (pooled OR 3.20; 95% CI, 1.72 to 5.94). Suicide ideation was noted to be increased among heavy cannabis users, though this was of borderline significance (OR 2.53; 95% CI, 1.00 to 6.39). Cannabis use was slightly more common among individuals who died from suicide who used non-overdose methods (11.6%) than among those who died from suicide related to overdose methods (9.2%) in general population studies. Limitations of this review included significant heterogeneity between studies with respect to measurement of cannabis exposure and control of risk factors, the use of observational studies (including case-series and cross-sectional), a small number of suicidality cases in studies, and research from a small number of geographical locations. An older review that included 7 studies on suicidal ideation or attempts (with 2 studies included in both reviews) found mixed results: 4 studies reported an association between cannabis use and increased risk of suicidal ideation, one study showed no association, and one school cohort study demonstrated reduced risk of attempts but increased risk of ideation.84

Mania

We found no evidence examining the effects of cannabis on the risk of mania among persons with PTSD or chronic pain.

One systematic review that included 6 prospective studies of other populations (mean follow-up 3.9 years) found support for an association between cannabis use and exacerbation or incidence of manic symptoms.85 Among patients with known bipolar disorder, 3 studies demonstrated significant associations between cannabis use and fraction of time with mania or mania score/symptoms during follow-up, though meta-analysis was not undertaken. Further, a meta-analysis of 2 prospective community studies demonstrated an association between cannabis use and new-onset mania symptoms among those without a diagnosis of bipolar disorder (pooled OR 2.97; 95% CI, 1.80 to 4.90) with low heterogeneity between studies. The strength of the findings is limited by the small number of included studies in this review.

Psychosis

One systematic review84 and 7 studies86-92 provided evidence related to psychotic symptoms associated with cannabis use. Overall, studies consistently showed a relationship between cannabis use and the development of psychotic symptoms, though the magnitude of risk is uncertain. In addition, experimental studies have found acute, transient psychotic symptoms within hours of use. The Moore et al (2007) review also included studies that showed an increased risk of psychotic spectrum disorder among cannabis users. Given that many of the studies are observational, it is difficult to determine whether cannabis directly contributed to the development of psychotic symptoms or whether its use was simply more common among individuals with a preexisting tendency towards these symptoms. The possibility that cannabis contributes directly to symptom development is supported but not proven by biologic plausibility, evidence of a dose-response relationship, and the results of prospective cohort studies, described in the following sections.

Psychotic symptoms

Four studies included only participants with no psychotic symptoms at baseline.86-88,92 Time to follow-up ranged from 12 to 36 months; 2 of the 4 studies examined linear trends across frequencies, and the other 2 comparing higher to lower frequencies of use. All 4 studies found that participants who had ever used cannabis had an increased likelihood of any psychotic outcome (eg, symptoms, psychotic disorder) compared to participants who had never used. The studies also found that frequency of use correlated with the likelihood of a psychotic outcome.

Two articles provided data from the Early Developmental Stages of Psychopathology (EDSP) study, a prospective cohort study (medium risk of bias) of randomly selected adolescents and young adults aged 14 to 24 at baseline (N=3,021; mean age 18.3 years).86,87 Findings from these studies indicate that at the second (T2) and third time point (T3), using cannabis more than 5 times since the previous assessment (3.5 years between baseline and T2, and 4.9 years between T2 and T3) was associated with positive symptoms (OR 2.10; 95% CI, 1.61 to 2.75) and the co-occurrence of both positive and negative symptoms (OR 2.05; 95% CI, 1.18 to 3.59), but not negative/disorganized symptoms alone (OR 1.12; 95% CI, 0.91 to 1.39).87 Among those reporting no cannabis use at baseline, cannabis use between baseline and T2 increased the risk for psychotic symptoms between T2 and T3 (adjusted OR 1.9; 95% CI, 1.1 to 3.1; P = .02). Among those reporting cannabis use at baseline, continued use at T2 was associated with psychotic symptoms at both T2 and T3 (adjusted OR 2.0, 1.0 to 3.8; P = .037).86 In addition, a case-control study of 280 individuals presenting with a first episode of psychosis and 174 healthy controls found that after adjusting for confounders, there was no significant difference between groups in ever having used cannabis, or the duration of use. However, those experiencing a first episode of psychosis were more likely to use cannabis daily (adjusted OR 6.4; 95% CI, 3.2 to 28.6), and were more likely to use sinsemilla (adjusted OR 6.8; 95% CI, 2.6 to 25.4).92

One cohort study (N=591) with a low risk of bias examined the relationship between frequency of use in adolescence and psychotic symptoms over a 30 year period. In the multivariate model, the frequency of use in adolescence (casual use: OR 1.80; 95% CI, 1.24 to 2.59; P = .002; regular use: OR 2.60; 95% CI, 1.59 to 4.23; P < .001) was a significant predictor of ‘schizotypal signs’ (eg, feeling lonely even when with people, never feeling close to another person). There was no significant relationship between cannabis use and schizophrenia nuclear symptoms (eg, thought insertion, thought broadcasting, thought control, hearing voices).88

Acute cannabis-induced psychosis

Three studies examined the relationship between cannabis use and acute psychotic symptoms.89-91 In one (moderate risk of bias) study, a double-blind cross-over RCT of 16 healthy cannabis-naïve women (mean age 23.56 years), comparing oral cannabis extract to placebo, one participant experienced psychotic symptoms (ie, “severe” somatic concern, anxiety, tension, depressive mood, suspiciousness, hallucinatory behavior, motor retardation, and “extremely severe” unusual thought contents) 3 hours after cannabis intake. Symptoms decreased without pharmacological intervention.89 The second (low risk of bias) study compared THC plus CBD to THC plus placebo (N=48). Clinically significant positive symptoms (ie, an increase in Positive and Negative Syndrome Scale [PANSS] positive scores of 3 or more points), were more common with THC plus placebo (11 of 26 cases) compared to THC plus CBD (3 of 22 cases), (χ2=4.74, P < .05), and individuals in the THC plus placebo group experienced greater paranoia (t=2.28, P < .05).91 The third was a (high risk of bias) case-control study comparing 140 cannabis users to 144 non-users on psychotic symptoms (ie, delusory thinking, perceptual distortion, cognitive disorganization, anhedonia, mania, and paranoia). Cannabis users were evaluated immediately after use, as well as 3 to 4 days later. Univariate results indicate more psychotic symptoms in the cannabis group (F1,282 = 80.1, P < .005), with greater effects immediately after use.90

Cognitive Effects

One systematic review provides moderate-strength evidence that active, long-term cannabis use is associated with small negative effects on all domains of cognitive function, but insufficient evidence of long-term cognitive effects in past users.93 The review first synthesized the literature on non-acute (ie, residual and long-term combined) cognitive effects of cannabis use, reporting that the 33 included studies (with a combined total of 1,010 cannabis users compared to 839 controls) suggested that there is a small, non-acute effect of cannabis use on global cognitive functioning and on each of the 8 domains of cognitive functioning reported in the papers, which included abstraction/executive, attention, forgetting/retrieval, learning, motor, perceptual-motor, simple reaction time, and verbal/language domains. The authors then conducted a subgroup analysis of only 13 studies (with a combined total of 388 cannabis users and 387 controls) which examined cognitive functioning after at least 25 days of abstaining from cannabis use, described as long-term use. They reported that in this subgroup of studies examining long-term effects, there was not a statistically significant effect on global cognitive functioning, nor on any of the 8 reported cognitive domains.93

Schreiner and colleagues' systematic review93 documents consistent evidence supporting non-acute (ie, combined findings from both residual and long-term effects studies) cognitive effects of cannabis from the 33 studies included in their review, though these data are not specific to chronic pain or PTSD populations. Therefore, the strength of evidence for residual effects of cannabis use is rated as moderate. The magnitude of these non-acute effects is small overall, but because the studies all reported average cognitive impairment and not the percent of study participants with clinically significant cognitive impairment, it is not possible to provide an estimate for the range of severity of cognitive impairment experienced by the cannabis users in these studies.

The long-term effects of cannabis use on cognitive functioning are less clear, and the systematic review by Schreiner and colleagues suggests that cannabis use might not result in long-term cognitive impairment. This sub-analysis, however, was based on a relatively small sample from 13 studies with a very broad range of time since last cannabis use (ranging from an average of 25 days to an average of over 3 years). The amount of prior cannabis use reported in these studies also varied greatly, ranging from an average of weekly use to an average of using cannabis multiple times per day. This heterogeneity among the 13 included studies makes generalizations about amount and frequency of cannabis use associated with cognitive impairment impossible and could be at least part of the reason for the lack of consistent findings across studies. Most of the cognitive domains reported in these studies had inconsistent results within or across studies or more consistent but non-significant trends indicating the presence of at least mild long-term cognitive impairment. This suggests that, in at least some cognitive domains, a larger sample might yield findings of significant associations between cannabis use and cognitive impairment that is present after at least 25 days after abstinence. The evidence for a lack of long-term cognitive impairment associated with cannabis use reported in the Schreiner et al review, therefore, is rated as insufficient strength of evidence.

Cannabis Use Disorder (CUD)

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)94 and the 10th Revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10)95 both require multiple symptoms of significant psychiatric distress, social impairment, and adverse consequences associated with cannabis use for an individual to be diagnosed with CUD. While we did not find studies reporting prevalence estimates of CUD in the population of Veterans with PTSD, Bonn-Miller et al (2012) report that the prevalence of PTSD among Veterans with CUD was 29.05% in fiscal year 2012.96

We did not find any articles comparing rates of CUD in chronic pain or PTSD populations to other populations.

A recent large national prospective cohort study found high prevalence of CUD (36%) among those reporting cannabis use in the past year (N = 1279).97 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. Cannabis use was also associated with increased odds of other substance use disorders (any substance use disorder: odds ratio [OR], 6.2; 95% CI, 4.1-9.4; any alcohol use disorder: OR, 2.7; 95% CI, 1.9-3.8.

Other studies of CUD provide potentially relevant cross-sectional data. For example, one non-VA study using structured diagnostic interviews found that the prevalence of cannabis misuse and dependence were 2.4% and 0.9%, respectively, in a primary care sample (though the proportion of patients who used cannabis was unknown).98 Another cross-sectional study by Hefner and colleagues (2015) examined rates of CUD in a sample of over 1.3 million Veterans with chronic non-cancer pain, comparing rates of CUD among groups of Veterans based on the number of opioid prescriptions for non-cancer pain.99 They found that 1.98% of Veterans with chronic non-cancer pain who were not prescribed opioids had a CUD diagnosis compared to 2.83% of those with 1 to 2 opioid prescriptions in one year, 3.44% with 3 to 10 opioid prescriptions, 3.28% with 11 to 19 opioid prescriptions, and 3.92% of Veterans with 20 or more opioid prescriptions in one year who were diagnosed with CUD.

Bonn-Miller et al (2015) studied 104 Veterans who had CUD and were attempting to stop using cannabis.100 They reported that PTSD was associated with higher baseline rates of cannabis use and a slower decrease in cannabis use during the first 4 weeks following a quit attempt. Walsh and colleagues (2014) found that cannabis dependence was not associated with trauma exposure, but was associated with a greater number of PTSD symptoms in a sample of 1317 Jewish Israeli individuals.101 Finally, Kevorkian and colleagues (2015) examined data from the National Epidemiologic Survey on Alcohol and Related Conditions (N=34,396).102 They reported that while trauma exposure during one's lifetime was only very minimally associated with CUD (OR 0.997; 95% CI, 0.996 to 0.999), among trauma-exposed, cannabis-using individuals, PTSD was significantly associated with increased likelihood of CUD (OR 1.217; 95% CI, 1.214 to 1.220).

CUD may also impact response to PTSD treatment, though CUD has not been well-studied in general in PTSD populations. Bonn-Miller et al reported in 2013 that among Veterans who were enrolling in a VA, all-male, inpatient, intensive PTSD treatment program, those who had CUD experienced less improvement in PTSD symptoms during the course of treatment than those who did not have CUD upon enrollment.103 This relationship was observed for overall PTSD symptoms as well as avoidance/numbing and hyperarousal symptom clusters, though group differences were non-significant for re-experiencing symptoms. These analyses included statistical adjustment for covariates including age, combat exposure, and depression symptoms as well as alcohol, amphetamine, cocaine, opioid, and sedative use disorders.

Emerging Harms

Infectious Diseases

Several case reports have suggested an association between smoking cannabis and invasive pulmonary aspergillosis in immunocompromised individuals.104-106 In an older study, investigators randomly selected 28 individuals with a history of cannabis smoking, 21 of whom were asymptomatic, 6 of whom had bronchitis symptoms after smoking, and 1 of whom was diagnosed with pulmonary aspergillosis.107 Serum precipitins against Aspergillus antigens were significantly more common among individuals with a cannabis smoking history compared to age-matched controls. Most cannabis cigarette samples provided by the participants had Aspergillus species detected in culture, and there was passage of fungal spores demonstrated through most of the samples.

Cannabis has been implicated as a possible contributing factor in tuberculosis clusters through the shared use of a cannabis water pipe,108 13841 or through the practice of “hotboxing.”109

Cannabinoid Hyperemesis Syndrome

Recently, a number of case series have described a syndrome of at times severe cyclic vomiting associated with chronic cannabis use called the cannabinoid hyperemesis syndrome.110-116 The largest case series included 98 patients from a single institution.117 The authors performed an institution-wide review of medical records of patients with recurrent vomiting, without an associated etiology, and known preceding cannabis use. All patients were younger than 50 years old and 95% had used at least once weekly; 68% of the patients had used cannabis for over 2 years. Most patients (86%) had abdominal pain as well. Information about the effect of hot water was available in 57 patients: 91% of these patients reported relief of symptoms with hot showers. Long-term follow-up was only available in 10 patients, so it is uncertain how many patients ultimately abstained from use and how often this resolved the symptoms. Earlier case series reported that most patients who discontinued use recovered.112

Complications from Intravenous Use of Cannabis

The intravenous marijuana syndrome is an acute illness following the injection of boiled cannabis preparations. The syndrome was last described in a synthesis of 25 case reports in 1986. In most cases, patients had a febrile illness with tachycardia, hypotension, gastrointestinal symptoms, and myalgias.118 The pathogenesis of the syndrome is unknown. A minority of patients had used cotton to strain the preparation prior to use suggesting some similarity to “cotton fever” that has been described in heroin users. Alternatively, it is possible that very high doses of cannabis itself could have contributed.

Aggression and Violence

Two studies investigated the effect of cannabis use on aggression and found mixed results. A retrospective study of clinical files from 4 public psychiatric outpatient facilities in Italy that included patients treated for 6 months continuously (N=1,582; 49% male, 41% with mood disorder and 27% with psychotic disorder) found cannabis use to be a risk factor for violent behavior, regardless of psychiatric disorder, sex, and age.119 The combination of a mental disorder and cannabis use was present in significantly more patients with violent behavior (3.9%) versus those with non-violent behavior (0.2%; OR 19.2; 95% CI, 4.4 to 118.6). Also, mental health patients who used cannabis were significantly more likely to engage in both violence towards others (OR 10.2; 95% CI, 3.8 to 27.5) and violence towards themselves (OR 5.7; 95% CI, 2.4 to 13.5). In particular, the probability of suicide increased more than 17 times (OR 17.6; 95% CI, 3.5 to 87.7) and the probability of attempted suicide tripled (OR 3.4; 95% CI, 1.5 to 9.4) among cannabis users versus non-users. Notably, cannabis use was significantly associated with being male, a family history of violent behavior, precarious employment, poor compliance with treatment, and undergoing psychotherapy, and there was a significant correlation between violent behavior and a positive family history for both substance misuse and violent behavior, suggesting that factors other than cannabis use are implicated in violent behavior.

A second study of 30 undergraduate males who received intense provocation following ingestion of either low (0.1 mg/kg), medium (0.25 mg/kg), or high (0.4 mg/kg) doses of THC found that the low-dose group tended to respond with more aggression than the high-dose group.120 Participants in this study were randomly allocated to their THC dosing and asked to select a shock intensity to be administered to an opponent during a competition. In the absence of provocative stimulation, in which participants were not aware of their opponents' aggressive intentions (based on opponents' choice of shock level to be administered to the participant), there was no difference in shock intensity given by participants by THC dose. In the presence of provocative stimulation, participants in the low-dose group were significantly more likely to escalate shock intensity and use extremely high shock settings to retaliate against aggressive opponents compared with those in moderate and high THC dose groups (P < .05 for both). These findings suggest that aggression is not associated with cannabis use.

Miscellaneous

There are emerging issues related to newer methods of cannabis use that clinicians may encounter. “Dabbing” refers to vaporization and inhalation of butane hash oil which has THC concentrations that typically far exceed that seen in the cannabis flower. In a survey study, “dab” users (N=357) reported more trouble with tolerance and withdrawal than what they had experienced using flower cannabis.121 Edible cannabis use has become more common in recent years, especially in states in which cannabis has been legalized for recreational or medical purposes.122 A recent case series described 5 patients hospitalized with acute psychosis after ingestion of edible cannabis.123 The patients described ingesting multiple portions in part because of the delay in onset of effect seen with edible cannabis, thus ingesting a much larger dose of THC than recommended.

A recently published (after our search dates ended) follow-up to a New Zealand birth cohort study found that cannabis use was associated with the development of periodontal disease by early midlife after adjusting for tobacco use.124 They found no association with intermediate health outcome measures such as lipids, hemoglobin A1c, and measures of inflammation. However, nearly two-thirds of cannabis users also used tobacco, and there were relatively few people who used cannabis heavily.

KEY QUESTION 4. What are important areas of ongoing research and current evidence gaps in research on cannabis for chronic pain or PTSD, and how could they be addressed by future research?

Summary of Findings

Chronic Pain

We identified 10 ongoing RCTs examining the effectiveness of cannabis for a variety of chronic pain conditions (Table 7), including several populations included in this report (3 studies for cancer pain and 2 studies for neuropathic pain), as well as conditions for which there is currently very little or no evidence (osteoarthritis, sickle cell disease, low back pain, and ulcerative colitis). While there are several ongoing observational studies on the benefits and/or harms of cannabis, we found no studies looking specifically at chronic pain populations that would meet our inclusion criteria.

Table 7. Ongoing Studies of Cannabis for Chronic Pain.

Table 7

Ongoing Studies of Cannabis for Chronic Pain.

Most of the ongoing trials are relatively small, with 6 including fewer than 100 patients (mean 46 participants). However, 2 industry-funded placebo-controlled trials investigating nabiximols include roughly 400 patients each, and another parallel RCT compares vaporized cannabis to dronabinol (synthetic THC) and placebo in 120 adults. In addition to assessing pain, 5 trials will assess quality of life and/or functional status outcomes, 5 trials will look for mental health outcomes such as mood and depression, and 4 trials will examine cognitive outcomes, a harm on which there is very little current evidence in chronic pain populations. The follow-up duration for these trials is relatively short, ranging from 1 to 10 weeks (median 5 weeks).

Similar to the published studies included in this report, the most commonly used cannabis products in these ongoing trials are vaporized (3 studies) or smoked (3 studies) cannabis with known THC and/or CBD content, or nabiximols oromucosal spray (2 studies). One of these trials is a crossover RCT investigating 6 different vaporized cannabis products with varying THC and CBD content in 40 adults with painful osteoarthritis of the knee (NCT02324777). This trial may provide some evidence as to the most effective cannabis formulations or potencies; however, as a relatively small trial (40 patients) with only one day of exposure for each of the formulations, conclusions about their effectiveness will be limited. We found only one other study planning to compare different potencies of cannabis (NIH project number 5R01DA030424-03).

PTSD

There are 2 recently initiated studies on the benefits and harms of cannabis for PTSD using an RCT design that should add to the body of evidence (Table 8). The Colorado Department of Public Health and Environment has funded a “triple-blind cross-over placebo-controlled” trial to determine the effects of smoking 4 different types of cannabis with varying THC and CBD content on PTSD symptoms in Veterans (Bonn-Miller, NCT02759185). The anticipated completion date of the trial is April 2019. Second, Eades et al are conducting a study sponsored by Tilray and the University of British Columbia (NCT02517424). This study is a cross-over RCT of 42 adults with PTSD who will be administered differing amounts of THC and CBD (High/Low, High/High, and Low/Low) to compare PTSD outcomes as well as other mental and physical health outcomes.

Table 8. Ongoing Studies of Cannabis for PTSD.

Table 8

Ongoing Studies of Cannabis for PTSD.

There are also multiple ongoing studies of cannabis and PTSD that are not RCTs, or that investigate cannabis-related outcomes but do not specifically test the effectiveness of cannabis for reducing PTSD symptoms. For example, a VA-funded trial is described as investigating the impact of cognitive behavioral therapy for insomnia on cannabis cessation. Bonn-Miller and colleagues are investigating how cannabis use impacts PTSD and sleep in an unfunded observational study of 150 Veterans. Finally, another study funded by The Colorado Department of Public Health and Environment is assessing 150 individuals with PTSD to determine if recent medical or recreational cannabis use versus no cannabis use in the past 6 months is associated with differential trajectories of PTSD symptoms over the course of a year. Table 8 provides a summary of ongoing studies related to benefits and harms of cannabis for PTSD.