Perspective: This article presents results that confirm previous clinical studies suggesting that cannabis may be an effective analgesic and potential opioid substitute. Participants reported improved pain, health, and fewer side effects as rationale for substituting. This article highlights how use duration and intentions for use affect reported treatment and substitution effects.

Chronic pain is common, costly, and challenging to treat. Many individuals with chronic pain have turned to cannabis as an alternative form of pain management. We report results from an ongoing, online survey of medical cannabis users with chronic pain nationwide about how cannabis affects pain management, health, and pain medication use. We also examined whether and how these parameters were affected by concomitant recreational use, and duration of use (novice: <1 year vs experienced: ≥1 year). There were 1,321 participants (59% female, 54% ≥50 years old) who completed the survey. Consistent with other observational studies, approximately 80% reported substituting cannabis for traditional pain medications (53% for opioids, 22% for benzodiazepines), citing fewer side effects and better symptom management as their rationale for doing so. Medical-only users were older (52 vs 47 years old; P < .0001), less likely to drink alcohol (66% vs 79%, P < .0001), and more likely to be currently taking opioids (21% vs 11%, P < .0001) than users with a combined recreational and medical history. Compared with novice users, experienced users were more likely to be male (64% vs 58%; P < .0001), take no concomitant pain medications (43% vs 30%), and report improved health (74% vs 67%; P = .004) with use. Given that chronic pain is the most common reason for obtaining a medical cannabis license, these results highlight clinically important differences among the changing population of medical cannabis users. More research is needed to better understand effective pain management regimens for medical cannabis users.

Chronic pain affects >100 million Americans, and costs an estimated $635 billion dollars per year in the United States alone.However, treating chronic pain is difficult, and many pharmacologic options only work in a subset of patients owing to inadequate pain relief or side effects that preclude use.In the context of the ongoing opioid crisis, which claimed approximately 42,000 lives in 2016,many individuals with chronic pain are seeking alternative medications for pain management. Cannabis is a promising analgesic for many chronic pain conditions, with recent meta-analyses of clinical trials suggesting that cannabis or cannabinoids may be effective for chronic pain management,although this effect was mostly seen in neuropathic pain.Nationwide, medical cannabis legislation is associated with 25% fewer opioid overdose deaths in states with medical cannabis laws compared with those without,with recent analyses suggesting that this effect is heavily driven by the presence of active medical cannabis dispensaries.Further, states with medical cannabis laws have consistent decreases in opioid prescribing compared with those without, with this effect again strongest in states with active dispensaries.

Medical marijuana laws may be associated with a decline in the number of prescriptions for Medicaid enrollees.

The effects of cannabis among adults with chronic pain and an overview of general harms: A systematic review.

In 2016, we found that medical cannabis users in Michigan with chronic pain reported 64% lower opioid consumption, fewer side effects, and improved quality of life after using cannabis.Other studies of medical cannabis users in the United States,Canada,and Israelhave found similar results, with users reporting improved pain, better quality of life, decreased opioid use, and in some cases, direct substitution of cannabis for opioids and other medications.Although the rationale for substitution has been explored in 2 smaller studiesthese studies have not focused on chronic pain. In addition, there are few reports of whether substitution patterns differ between subgroups of cannabis users. This finding is of special interest, given the rapidly changing cannabis landscape, in which there is increasing interest in cannabis among women and older individuals.

Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort.

Medical cannabis use is associated with decreased opiate medication use in a retrospective cross-sectional survey of patients with chronic pain.

In the present study, we build on this previous work, presenting results from an ongoing survey of medical cannabis patients throughout the United States. We queried whether medical cannabis patients substituted cannabis for other medications and their rationale for doing so, as well as whether pain or overall health had changed since using cannabis. We also examined differences between individuals who used cannabis solely for medical purposes versus those who used cannabis medically alone versus medically and recreationally, as well between individuals who had been using cannabis for <1 versus those who had been using cannabis for >1 year.

Histogram and quantile–quantile plots were used to assess normality of continuous variable distribution. Univariate and multiple logistic regression were used to calculate unadjusted odds ratios (OR) and adjusted ORs (AOR), respectively, for the odds of substituting and for meeting group categorization (eg, experienced vs novice, and medical vs MEDREC user). Relevant statistically significant confounding variables were controlled for in multiple logistic regression (eg, sex, age, relationship status, income, education, smoking, alcohol use). The Pearson χ 2 test was used to assess differences in proportions for categorical variables and are reported as frequency (percent). Between-group differences in continuous variables were assessed by independent samples t-tests, which included Levine's test for assessment of variances for equality; the Mann–Whitney U test was used as a nonparametric alternative for ordinal and highly skewed data. Continuous variables are reported as mean ± standard deviation or median ± standard error. All tests were 2-tailed and significance was set at P < .05. All analysis was performed using IBM SPSS 24 (SPSS, Inc, Armonk, NY).

Age was reported as a continuous variable and used to report group mean ages. Owing to the large range of ages and for consistency with previous research,age was converted to categorical groups. Also collected was annual household income, highest education level, relationship status, alcohol use, and smoking status. Concomitant pain medications were converted to a dichotomous (yes/no) for assessment as a covariate.

Comparing adults who use cannabis medically with those who use recreationally: Results from a national sample.

Participants were asked whether they had substituted cannabis for any drug classes of pain medication. Substitution rationale was assessed by asking participants to rank their most important reasons for substituting cannabis for medication.Participants could choose from the following: fewer adverse effects, fewer withdrawal effects, the ability to obtain cannabis versus (drug), greater social acceptance of cannabis, better symptom management with cannabis, and other. If other was selected as one of their choices, they were directed to a free text entry in which they could describe their substitution rationale.

Participants were asked about whether they had ever used cigarettes, and were invited to choose from options that included, “I never smoke and have never smoked,” “I used to smoke cigarettes, but I no longer do,” “I smoke cigarettes some days,” and “I smoke cigarettes every day.” For alcohol consumption, participants were asked “How often do you have a drink containing alcohol?” Response options included: never, monthly or less, 2 to 4 times a month, 2 to 3 times a week, and ≥4 times a week. Those who never drank were categorized on nondrinkers, and those who ever drank were categorized as drinkers.

Concomitant pain medications were assessed by asking participants to select all pain drug classes that they currently used, including opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs, serotonin norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), gabapentanoids, benzodiazepines, or other medications. If participants selected other, they were directed to a free text question in which they could type the name of the other medication.

Participants were asked about their cannabis use during the previous year and were given the following options: Did not use at all (n = 24 [2%]), recreationally only (n = 27 [2%]), medically only (designated MED; n = 715 [52%]), or a combination of medically and recreationally (designated MEDREC; n = 606 [44%]). Participants who selected used recreationally only (n = 27), who did not answer 1 of the 2 categorization questions (n = 2), or who selected did not use but failed to indicate how long ago they started medical cannabis (n = 23) were all excluded from analyses.

Participants were asked, “How long ago did you start using medical cannabis?” and were able to select: “less than 1 month ago; 1, 2, …11 months ago; 1, 2, …10 years ago; or more than 10 years ago.” Participants were divided into 2 groups, namely, 1) those who had used medical cannabis for <1 year (n = 489 [37%]) and 2) those who started medical cannabis ≥1 year ago (n = 832 [63%]). Those who reported starting medical cannabis use within the past year were labeled novice cannabis users and those who had used for a year or more were considered experienced users. These labels are used throughout this article for ease of reading.

The groupings of interest are described; in addition to these planned analyses, a post hoc analysis was performed and included an assessment of differences between those who substituted cannabis for a pain medication and those who did not.

A total of 1,697 participants submitted responses. All submissions with missing demographic data were excluded (n = 322). Seven participants identified as transgender 7 (<1%) and were excluded from analysis owing to this extremely small sample size. Two subset analyses were conducted, where the population was split into 2 independent groups according to specific categorization (novice vs experienced cannabis users and medical only users vs combined medical and recreational users) based on responses to survey questions (described elsewhere in this article). Participants with missing responses to these grouping variables were excluded (n = 30) and discussed in detail elsewhere in this article. After all exclusions (n = 358, 21%), 1,321 participants were eligible for analysis.

Adults (≥18 years old) who use cannabis for chronic pain in states with legal medical or recreational cannabis were invited to participate in an anonymous, online survey through the Qualtrics (Provo, UT) survey platform. Multiple dispensaries and cannabis certification clinics throughout the country sent this link to their client databases, as well as sharing the study information on social media. Participants were asked questions about the conditions and/or symptoms for which they used cannabis, health and pain changes since starting cannabis, current pain medication use, whether they had substituted cannabis for prescription pain medications (eg, opioids), alcohol use (nondrinker vs drinker), tobacco use (never, former, and current smoker), and sociodemographic information such as age, income, education, and relationship status. In addition, participants answered other questionnaires on cannabis use (administration routes, dosing frequency, etc), pain severity, anxiety, depression, and other measures that will be reported elsewhere. All surveys and study procedures were approved as an exempt study by the Institutional Review Board at the University of Michigan Medical School under protocol HUM00079724. Participants freely consented to participate in the study, were not compensated for participating, and were able to drop out at any time.

Compared with MED users, MEDREC users reported using fewer concomitant medications, both overall and in multiple medication classes including opioids, benzodiazepines, NSAIDS, and gabapentanoids ( Table 3 ). There were no statistically significant differences between the number of medication substitutions between MED and MEDREC users (P = .16). After controlling for sex, age, relationship status, alcohol use, and smoking status, MED users were found to be 34% less likely to report substituting than MEDREC users (AOR = .66, 95% CI = .44-.98, P = .006). Compared with MED users, a significantly greater proportion of MEDREC users reported substituting overall (χ= 5.7; P = .017), as well as a greater proportion reporting substituting cannabis for opioids (57% vs 48%; P = .002) and gabapentanoids (17% vs 10%; P < .0001). A slightly higher proportion of MEDREC users reported a lot of improvement in their health (42% vs 37%; P = .007) compared with MED users, although the groups did not differ in changes in pain.

MEDREC users were significantly younger than nonrecreational users (46.9 ± 14.2 vs 52.3 ± 13.0 years; χ= 7.1, P < .0001; Table 4 ). The MEDREC group had a higher proportion of experienced users compared with the MED group (73.1% vs 54.4%; P < .0001). A significantly larger proportion of females were MED users compared with MEDREC users (64% vs 53%; χ= 20.2, P < .0001). Compared with males, females were 35% less likely to be MEDREC users: OR = .62 (95% CI = .47-.84, P < .0001); adjusted for age category and drinking status, and concomitant medication: AOR = .66 (95% CI = .48–.92, P = .001). Relationship status differed significantly (P < .0001), with MEDREC users reporting a lower rate of marriage (43% vs 55%); education (P = .22) and income (P = .15) did not differ. A significantly greater proportion of MEDREC users reported alcohol use (79% vs 66%; P < .0001) as well as a higher proportion of never smokers (37% vs 30%) that did not attain statistical significance (P = .054). Geographically, MED users were represented mainly by California (17.8%), Maine (17%), New Hampshire (13%), and Arizona (17%), whereas MEDREC users were predominately from California (24%) and Maine (19%).

The odds of substitution did not differ between novice and experienced users: (OR = 1.06, 95% CI = .73 - 1.52, P = .71) and (AOR = 1.05, 95% CI = .71 - 1.56, P = .74). However, among substitutors, experienced users reported a greater number of substitutions than novice users (mean ± standard deviation = 2.11 ± 1.43 vs 1.85 ± 1.43, respectively; P = .001). Experienced users reported a significantly higher rate of substitution for benzodiazepines (24% vs 17%; P = .001), NSAIDs (43% vs 37%; P = .02), and SSRIs (16% vs 8%; P < .0001) compared with novice users. As before, the top reasons for substitution for both groups were 1) fewer adverse side effects from cannabis and 2) better symptom management with cannabis than from (medication), for both groups and all medication classes.

A significantly greater proportion of experienced users reported no concomitant pain medication use (43% vs 30%; P < .0001; Table 3 ). Novice users reported a significantly higher rate of concomitant opioids (22% vs 13%; P < .0001), benzodiazepines (17% vs 10%; P < .0001), gabapentanoids (16% vs 10%; P < .0001), NSAIDs (35% vs 28%; P = .02), and SNRIs (14% vs 7%; P < .0001) compared with experienced users. A significantly greater proportion of experienced users reported their health had improved since they had started medical cannabis (74% vs 67%; P = .004), although changes in pain (P = .74) did not differ significantly between groups.

A significantly greater proportion of novice users were female than experienced users (64% vs 58%; P = .005; Table 4 ). Groups differed significantly in relationship status (P = .023), but did not differ by age (P = .409), education (P = .06), or income (P = .64). There were no differences in alcohol or tobacco consumption between groups (P = .28 and P = .18, respectively). Novice users were represented mostly by California (15%), Pennsylvania (17%), and New Hampshire (17%), and experienced users were represented by California (24%) and Maine (25%).

Participants who reported substituting were significantly younger (49.4 ± 13.6 years vs 52.1 ± 14.8 years; P = .004), and more likely to be female (61% vs 54%; P = .025) than nonsubstituting users. Females were 30% more likely to report substituting than males, although not significantly so (adjusted for: age, alcohol use, concomitant medication; AOR = 1.30, 95% CI = .88–1.94, P = .085). A significantly greater proportion of nonsubstituting cannabis users reported concomitant medication use (52% vs 34%; P < .0001). Since starting cannabis use medically, a significantly greater proportion of substitutors reported that pain had decreased either a little or a lot (χ 2 = 12.4, P = .002) and that their health had improved either a little or a lot (χ 2 = 8.7, P = .012), compared with nonsubstituting users.

Substituting participants were asked to report how their medication consumption changed since they began using cannabis medically. A high rate of users reported complete cessation of medication since initiating cannabis use: opioids (72%), benzodiazepines (68%), NSAIDs (44%), gabapentanoids (74%), disease-modifying antirheumatic drugs (80%), SNRIs (78%), and SSRIs (80%). No more than 3% of substituting users in each medication class reported their medication use had increased either a little or a lot except DMARDs (5%) ( Fig 1 ). The top reasons for medication substitution across medication classes were 1) fewer adverse effects from cannabis and 2) better symptom management with cannabis. Participants also reported significant improvements in pain ( Fig 2 ) and health ( Fig 3 ), with 88% reporting that their pain had improved a lot or a little, and 71% reporting that their health had improved a lot or a little since starting cannabis.

Participants reported current concomitant pain medications ( Table 3 ): opioid analgesics (16%), benzodiazepines (13%), NSAIDs (31%), gabapentanoids (12%), disease-modifying antirheumatic drugs (3%), SNRIs (9%), SSRIs (12%), and other medications (16%, free-text entry). Of the participants, 38% reported no concomitant medication use. Eighty percent reported substituting cannabis for other medications, with a mean (standard deviation) of 2.0 ± 1.4 substitutions (range = 0–7, n = 2,136 total substitutions) per user. Among substitutors, females reported a significantly greater number of medication substitutions than males (t = 2.3, P = .02).

This study population included 1,321 medical cannabis users (59% female) with a mean age of 50 ± 14 years ( Table 1 ). The sample had greatest representation from California (20%), Maine (18%), Arizona (10%), and New Hampshire (9%). Nearly all participants (86%) reported having an associate's degree, some college or higher; one-half (49%) were married, and 62% reported an annual household income of 1 year ago. Participants also reported using cannabis for a large number of pain-related symptoms and mood disorders (n = 4,876 of 5,449 conditions/symptoms listed), which are detailed in Table 2 . These include broad symptoms (eg, chronic pain), specific diagnoses (eg, rheumatoid arthritis), chronic pain conditions that fall under the definition of chronic overlapping pain conditions (eg, fibromyalgia), and mood disorders that are often comorbid with pain (eg, anxiety). More than one-half of the sample population reported using cannabis for anxiety (52%).

NOTE. Although the entire population identified as having chronic pain of some kind, reported are the chronic pain conditions, symptoms, and mood disorders in the study population. The percentages add up to far greater than 100%, because participants reported using cannabis to manage or treat on average 4.5 conditions or symptoms.

Discussion

5 Boehnke KF

Litinas E

Clauw DJ Medical cannabis use is associated with decreased opiate medication use in a retrospective cross-sectional survey of patients with chronic pain. 25 Lucas P

Walsh Z Medical cannabis access, use, and substitution for prescription opioids and other substances: A survey of authorized medical cannabis patients. 14 Corroon Jr., JM

Mischley LK

Sexton M Cannabis as a substitute for prescription drugs - a cross-sectional study. , 34 Piper BJ

DeKeuster RM

Beals ML

Cobb CM

Burchman CA

Perkinson L

Lynn ST

Nichols SD

Abess AT Substitution of medical cannabis for pharmaceutical agents for pain, anxiety, and sleep. , 38 Reiman A

Welty M

Solomon P Cannabis as a substitute for opioid-based pain medication: Patient self-report. , 39 Sexton M

Cuttler C

Finnell JS

Mischley LK A cross-sectional survey of medical cannabis users: Patterns of use and perceived efficacy. , 41 Troutt WD

DiDonato MD Medical cannabis in Arizona: Patient characteristics, perceptions, and impressions of medical cannabis legalization. 38 Reiman A

Welty M

Solomon P Cannabis as a substitute for opioid-based pain medication: Patient self-report. 33 Piper BJ

Beals ML

Abess AT

Nichols SD

Martin MW

Cobb CM

DeKeuster RM Chronic pain patients' perspectives of medical cannabis. Consistent with our previous report,but with a much larger sample size (n = 1,321 vs n = 185), we found that medical cannabis users with chronic pain reported substituting cannabis for opioids and other pain medications, as well as reporting decreased pain and improved health after using cannabis. The 2 most common reasons for substitution were improved symptom management and fewer adverse side effects. These findings closely replicate findings in Canada, where Lucas et alreported that 63% of 270 medical cannabis users substituted cannabis for prescription drugs, including opioids (32%) and benzodiazepines (16%) for similar reasons. Although other studies did not capture substitution rationale, their results have been remarkably consistent.For example, 97% (n = 841) of medical cannabis users in California reported decreasing opioid consumptionand 77% of medical cannabis users with pain reporting reduced opioid use since starting medical cannabis.

1 Abuhasira R

Schleider LB

Mechoulam R

Novack V Epidemiological characteristics, safety and efficacy of medical cannabis in the elderly. , 3 Bar-Lev Schleider L

Mechoulam R

Lederman V

Hilou M

Lencovsky O

Betzalel O

Shbiro L

Novack V Prospective analysis of safety and efficacy of medical cannabis in large unselected population of patients with cancer. , 18 Haroutounian S

Ratz Y

Ginosar Y

Furmanov K

Saifi F

Meidan R

Davidson E The effect of medicinal cannabis on pain and quality-of-life outcomes in chronic pain: A prospective open-label study. 18 Haroutounian S

Ratz Y

Ginosar Y

Furmanov K

Saifi F

Meidan R

Davidson E The effect of medicinal cannabis on pain and quality-of-life outcomes in chronic pain: A prospective open-label study. 3 Bar-Lev Schleider L

Mechoulam R

Lederman V

Hilou M

Lencovsky O

Betzalel O

Shbiro L

Novack V Prospective analysis of safety and efficacy of medical cannabis in large unselected population of patients with cancer. 1 Abuhasira R

Schleider LB

Mechoulam R

Novack V Epidemiological characteristics, safety and efficacy of medical cannabis in the elderly. 16 Farrar JT

Young Jr., JP

LaMoreaux L

Werth JL

Poole RM Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. 42 Vigil JM

Stith SS

Adams IM

Reeve AP Associations between medical cannabis and prescription opioid use in chronic pain patients: A preliminary cohort study. Longitudinal studies in Israel and New Mexico further our findings of cannabis being opioid sparing and reducing pain. In Israel, 3 recent open-label studies followed cannabis users for 6 months in clinical settings.In the first, 176 participants using cannabis for intractable chronic pain reported significantly decreased pain and pain interference, and 32 of 73 had discontinued opioids at 6 months.In the second, of 344 elderly individuals with cancer who used opioids at baseline, 36% discontinued use and 9.9% decreased their dosage.In the third, conducted among 901 elderly individuals with mixed conditions, 114 discontinued opioid use and 29 reduced their dosage.Participants reported a median 4-point decrease in pain on a 0- to 10-point visual analog scale, exceeding the typical 2-point threshold for clinically significant improvement.This pattern of discontinuing or decreasing opioid use was also reported among habitual opioid users with chronic pain in New Mexico who enrolled in the state medical cannabis program.

The current study and the consistent nature of these observational findings provide additional nuance to the ongoing debate about cannabis's analgesic value for chronic pain, as well as a potential substitute for opioids or other drugs. Indeed, they add granularity to the ecological associations between medical cannabis laws and opioid overdose decreases, highlighting a specific behavioral mechanism (intentionally substituting cannabis for opioids and other medications) that may be driving these statewide trends. Further, the noted differences between the subgroups (novice vs experienced, MEDREC vs MED) suggest distinct demographic and behavioral patterns that may reflect the changing nature of cannabis use nationwide, at least among users with chronic pain.

33 Piper BJ

Beals ML

Abess AT

Nichols SD

Martin MW

Cobb CM

DeKeuster RM Chronic pain patients' perspectives of medical cannabis. 14 Corroon Jr., JM

Mischley LK

Sexton M Cannabis as a substitute for prescription drugs - a cross-sectional study. , 38 Reiman A

Welty M

Solomon P Cannabis as a substitute for opioid-based pain medication: Patient self-report. , 41 Troutt WD

DiDonato MD Medical cannabis in Arizona: Patient characteristics, perceptions, and impressions of medical cannabis legalization. 11 Clauw DJ Fibromyalgia: A clinical review. , 22 Institute of Medicine. Relieving pain in America: A blueprint for transforming prevention, care, education, and research. Washington, DC: The National Academies Press, 2011 23 Keyhani S

Steigerwald S

Ishida J

Vali M

Cerda M

Hasin D

Dollinger C

Yoo SR

Cohen BE Risks and benefits of marijuana use: A national survey of U.S. adults. , 28 Malani P, Singer D, Solway E, Kirch M, Clark S: Older adults’ perspectives on medical marijuana. University of Michigan National Poll on Healthy Aging. April 2018. Available at: http://hdl.handle.net/2027.42/143211 24 Lin LA

Ilgen MA

Jannausch M

Bohnert KM Comparing adults who use cannabis medically with those who use recreationally: Results from a national sample. 24 Lin LA

Ilgen MA

Jannausch M

Bohnert KM Comparing adults who use cannabis medically with those who use recreationally: Results from a national sample. Our sample population had a higher proportion of females (59%) and older adults (54% over the age of 50). With the exception of the study in New England,our sample population is quite different from other U.S. studies on substitution, in which the populations were generally male and younger.These differences likely reflect the focus of this study on chronic pain, which affects women and the elderly at a higher rate than other populations.It may also reflect the changing demographics of medical cannabis users. As more states have legalized cannabis over time, perceptions of cannabis safety and its medical value have increased, and more seniors are interested in cannabis as a potential pain management tool when recommended by doctors.In our sample, MED users tended to be older and female compared with MEDREC users. This finding is consistent with a recent analysis of a national sample, although that study aggregated users by medical use versus recreational use, rather than medical versus combined medical and recreational use.Respondents who used cannabis medically in the national sample also had lower past year alcohol abuse,similar to our study in which participants who used cannabis medically alone were more likely to not drink alcohol at all.

12 Compton WM

Han B

Jones CM

Blanco C

Hughes A Marijuana use and use disorders in adults in the USA, 2002-14: Analysis of annual cross-sectional surveys. Our findings that MED users were both more likely to report substituting cannabis for pain medications and to currently take multiple concomitant medications suggest several potentially overlapping interpretations. These include: 1) intentional medical use and harm reduction by deliberately trying to improve health outcomes, as reflected in the substitution rationale; 2) the potential for polysubstance abuse (adding cannabis to several other medications), 3) higher medication requirements among MED users owing to more serious medical issues, reflecting an inability to stop taking certain medication classes, and 4) MED users are likely to be new to cannabis, so they have not had as much time to taper other medications. With regard to experience with cannabis, novice users were more likely than experienced users to be female and to take concomitant medications. This finding is consistent with trends of higher historical rates of recreational cannabis use among men than women,suggesting that women may be a new and growing group of medicinal cannabis users. The higher concomitant medication use also makes intuitive sense, because it likely takes time to figure out a successful dosing regimen that would allow individuals to taper off medications. Although future longitudinal studies will help to parse out these differences, our reported association between medication substitutions and improved pain and health suggests that, within our cohort, many medical cannabis users with chronic pain are finding better pain management outcomes with cannabis than traditional pain medications.

43 Volkow ND

Baler RD

Compton WM

Weiss SR Adverse health effects of marijuana use. , 44 Volkow ND

Swanson JM

Evins AE

DeLisi LE

Meier MH

Gonzalez R

Bloomfield MAP

Curran HV

Baler R Effects of cannabis use on human behavior, including cognition, motivation, and psychosis: A review. 32 Olfson M

Wall MM

Liu SM

Blanco C Cannabis use and risk of prescription opioid use disorder in the United States. 9 Campbell G

Hall WD

Peacock A

Lintzeris N

Bruno R

Larance B

Nielsen S

Cohen M

Chan G

Mattick RP

Blyth F

Shanahan M

Dobbins T

Farrell M

Degenhardt L Effect of cannabis use in people with chronic non-cancer pain prescribed opioids: Findings from a 4-year prospective cohort study. 24 Lin LA

Ilgen MA

Jannausch M

Bohnert KM Comparing adults who use cannabis medically with those who use recreationally: Results from a national sample. 36 Available at: Procon.org. 31 legal medical marijuana states and DC. 2018. Accessed October 22, 2018 23 Keyhani S

Steigerwald S

Ishida J

Vali M

Cerda M

Hasin D

Dollinger C

Yoo SR

Cohen BE Risks and benefits of marijuana use: A national survey of U.S. adults. 27 MacCallum CA

Russo EB Practical considerations in medical cannabis administration and dosing. 37 Available at: Procon.org. Number of legal medical marijuana patients. 2018. Accessed October 22, 2018 15 Dowell D

Haegerich TM

Chou R CDC guideline for prescribing opioids for chronic pain–United States, 2016. We acknowledge the importance of approaching our substitution findings with caution, both because cannabis use carries numerous health risks (eg, respiratory issues from smoking, cognitive issues, impaired driving)and because substitution trends have been contended. Olfson et alexamined longitudinal data on cannabis and opioid use from the National Epidemiologic Survey on Alcohol and Related Conditions, which conducted surveys from 2001 to 2002 (wave 1) and follow-up between 2004 and 2005 (wave 2). Cannabis use at wave 1 was associated with a 2.62 higher odds of nonmedical opioid use, as well as a 2.18 higher odds of opioid use disorder at wave 2. Nonmedical opioid use was amplified among individuals with pain. Similarly, a recent longitudinal study of individuals with chronic pain who were prescribed opioids in Australia also found that cannabis use was associated with more pain severity, pain interference, and anxiety, as well as no evidence of cannabis substitution for opioids.Unfortunately, these studies were lacking in several critical ways. They did not distinguish between medical and recreational cannabis use—an important distinction, given that medical and recreational users exhibit different drug use characteristics, with medical users reporting lower prevalence of drug and alcohol use/abuse (excluding cannabis).Further, the medical cannabis landscape in these studies is incongruent with the current cannabis environment, because medical cannabis was only recently legalized in Australia, and U.S. laws have changed substantially since the National Epidemiologic Survey on Alcohol and Related Conditions was conducted in 2005. Twenty-two additional states have legalized medical cannabis, and 9 have legalized recreational cannabis.There are a wide variety of available cannabis products,increasing education opportunities for physicians and patients,and a much larger patient base (estimated to be >2.1 million),as well as the ongoing opioid crisis, which has placed stricter guidelines on opioid prescribing practicesand led patients to seek alternatives. All that said, as with any analgesic, it is likely that cannabis is not appropriate to use in some individuals owing to the risk of addiction and abuse, as well as because it is not always effective for pain management. Determining which populations are most at risk as well as those who stand to benefit the most from cannabinoid therapies remains an important and ongoing research topic.

20 Hurd YL

Yoon M

Manini AF

Hernandez S

Olmedo R

Ostman M

Jutras-Aswad D Early phase in the development of cannabidiol as a treatment for addiction: Opioid relapse takes initial center stage. 29 Nielsen S

Sabioni P

Trigo JM

Ware MA

Betz-Stablein BD

Murnion B

Lintzeris N

Khor KE

Farrell M

Smith A

Le Foll B Opioid-sparing effect of cannabinoids: A systematic review and meta-analysis. 13 Cooper ZD

Bedi G

Ramesh D

Balter R

Comer SD

Haney M Impact of co-administration of oxycodone and smoked cannabis on analgesia and abuse liability. A logical next step would be to examine whether these substitution findings hold up in clinical trials, which would more rigorously test their validity. Unfortunately, to our knowledge no trials have been conducted that directly examine cannabis as an opioid substitute, although preclinical and a small, double-blind study suggested that cannabidiol may attenuate craving.A recent systematic review also reported that preclinical (but not human) studies consistently showed synergistic analgesic effects between tetrahydrocannabinol and opioids.Since that review was published, a clinical trial in healthy individuals showed that combining subanalgesic doses of oxycodone with smoked cannabis increased pain thresholds and pain tolerance.This finding suggests that individuals using cannabis with opioids may be able to lower their opioid dosage to achieve the same analgesic effect and represents a potential mechanism for how individuals are finding similar pain relief while lowering their opioid dose.

40 National Academies of Sciences, Engineering, and Medicine

The health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research. Washington, (DC): National Academies Press. 31 O'Neil ME

Nugent SM

Morasco BJ

Freeman M

Low A

Kondo K

Zakher B

Elven C

Motu M

Paynter R Benefits and harms of plant-based cannabis for posttraumatic stress disorder. It is also possible that participants are using cannabis to manage affective aspects of chronic pain or opioid tapering—such as anxiety or pain-related distress—that lead to perceptions of improved symptom management. Indeed, many participants in our survey frequently reported that they were using cannabis to manage anxiety, depression, and post-traumatic stress disorder. Although there is little peer-reviewed evidence suggesting that cannabis is useful for these mood disorders (with some studies suggesting that cannabis use may worsen anxiety and depression among individuals with chronic pain),there are currently multiple ongoing clinical trials to better understand cannabis's potential therapeutic value in this context.