Reference
Tervo-Clemmens B, Schmitt W, Wheeler G, et al. Cannabis use and sleep quality in daily life: an electronic daily diary study of adults starting cannabis for health concerns. Drug Alcohol Depend. 2023;243:109760.
Key Takeaway
Daily cannabis effects can be monitored using a patient-completed survey. Sleep is positively affected by cannabis, but mood disorders (eg, anxiety, depression) and pain are not.
Design
Pragmatic, single-site, single-blinded clinical trial with randomized treatment
Participants
This study screened 1,224 individuals in the Greater Boston Area who were seeking a cannabis medical card for existing health concerns. Of these, 269 people enrolled, and 186 completed at least 1 baseline and 1 postbaseline visit. Two participants in the treatment group experienced delays in receiving their medical cannabis card, and they reported cannabis use prior to receipt of the card and, therefore, were excluded. Three participants who did not complete at least 10% of the daily record were also excluded. Thus, the final sample included 181 subjects.
All participants were already seeking a cannabis medical card for medical reasons.
The medical cannabis card treatment group consisted of 102 adults (68 female, 33 male, 1 nonbinary), and the waitlist control group consisted of 79 adults (50 female, male 29, 0 nonbinary). The participants were mostly of “Not Hispanic or Latino, White” ethnic/racial backgrounds. Average education was 16 years in both groups. Cannabis use per day ranged from 0 to 2.5 times in both groups.
Inclusion Criteria
Adults, aged 18 to 65 years, who were seeking a cannabis medical card for insomnia, pain, anxiety, and/or depression in the Greater Boston Area.
Exclusion Criteria
Chronic use disorder, cancer, psychosis, current substance disorder (except for mild-to-moderate alcohol use disorder and nicotine use disorder), and current cannabis use.
Intervention
The participants were randomized to receive a medical cannabis card (MCC) or assigned to the waitlist control group (WLC), where they agreed to wait 12 weeks before getting the card. Participants were stratified by sex, age, and their presenting problem, which included affective disorder (44 in MCC, 37 in WLC), insomnia (22 in MCC, 19 in WLC), and pain (36 in MCC, 0 in WLC). Investigators followed both groups for a 90-day period. The study occurred from June 2017 to August 2020.
Participants were to complete daily online self-reports of cannabis use and symptoms (sleep, mood, and pain).
The subjects were paid $2.00 US per survey completed each day and $6.00 for completing all seven days in a week, or up to $20.00 per week; investigators did not report the number of subjects paid and amount paid.
Study Parameters Assessed
Athens Insomnia Scale, Hospital Anxiety and Depression Scale, Brief Pain Inventory for worst pain, and daily self-reports for the previous 24 hours. Urinalysis for cannabinoids and their primary metabolites, and 15 other cannabinoids in urine via high-performance liquid chromatography with tandem mass spectrometry.
Primary Outcome
The primary outcome was to determine the feasibility of a self-reported longitudinal assessment of cannabis use for health conditions. The secondary outcome was to assess the association between cannabis use and sleep, mood, and pain symptoms across both short- (same-day) and long (90 days) timescales.
Key Findings
Median daily survey completion was 72 of 90 days with a mean of 66.21 days. The total number of completed daily surveys did not differ significantly between MCC and WLC. A positive correlation with daily completion was seen between age (P=0.001) and years of education (P=0.017). The treatment group reported cannabis use about half of the days in the daily diary.
Cannabis use increased significantly from baseline in treatment (P=0.007) but not in waitlist subjects (P=0.071). Cannabis metabolites in the urine were highly variable, so investigators noted only qualitative results, present or absent.
Sleep quality in the MCC group was better following days of cannabis use vs nonuse days (P<0.001), suggesting that long-term improvements were driven by use rather than the lasting effect of a single cannabis dose. The effect of cannabis on sleep quality varied significantly (P=0.026), depending on the presenting problem. Outcomes for self-reported sleep problems were positive (P=0.007), as were the outcomes for mood (P<0.001), but not for pain (P=0.623). There was no correlation between urine analysis and depressive symptoms or pain symptoms as the primary presenting problem. The sleep pattern suggested that long-term improvements were tied to an increase in cannabis use frequency, but details on amounts were absent.
Transparency
The clinical trial identifier is: NCT03224468. This study was designed and conducted by a group focused on treating addiction disorders and funded by the National Institute on Drug Abuse (NIH Award Number R01DA042043). The authors wrote, “The funder had no role in the design and conduct of the study…” Disclosures by the authors stated, “AEE has served as a consultant to Charles River Analytics (NIDA SBIR grant) and Karuna Pharmaceuticals (Chair Data Monitoring Board).” Other authors disclosed holdings in various pharmaceutical companies.
Practice Implications
In a separate paper, these investigators found that some medical cannabis users developed cannabis use disorder (CUD), based on the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders. These results were 3% to 10% at 2 weeks, 5% to 13% at 4 weeks, and 3% to 19% at 12 weeks, with the greatest incidence of CUD among those seeking cannabis for depression and anxiety, but much less so in those using cannabis for pain or insomnia.1
Urine in the above study was provided by 97 subjects (67.01% female), with 256 samples meeting criteria for analysis. Subjects were light users, less than monthly at baseline. After treatment, 39% to 47% used cannabis 3 to 4 days per week; 15% to 20% used it 5 to 6 days per week; and 29% to 54% used cannabis daily. Cannabis metabolites were found in 220 samples (85.9%). In cannabidiol (CBD)–dominant and CBD–tetrahydrocannabinol (THC) products (which had equal amounts of CBD and THC), no CBD was found in 30.3% and 37% of urine samples, respectively. THC was present in 78.8% of samples from subjects using a CBD-dominant product. In THC-dominant or THC-CBD products, no THC metabolites were found in 10.9% and 35.2%, respectively.2
Vaping was the most common method of administration in the trial subjects, but 19.7% of urine samples yielded no cannabis metabolites. CBD was most often found in the urine of participants who used it orally or smoked, and THC was most often found in the urine of those who used it orally or smoked. Vaped-product users yielded little or no cannabis metabolites. These findings parallel those from California and Washington where over half of the cannabis products were apparently incorrectly labeled.3
The urine outcomes from this trial are concerning.
A comparison of this paper to others from this group suggests there may be benefit for some subjects with anxiety, but not for depressed subjects. However, most of their reporting combines data from anxiety and depression into mood disorder or depressive disorders, and these results were not significantly beneficial. This study was designed and conducted by a group focused on treating addiction disorders and funded by the National Institute on Drug Abuse.
This study highlights the risk of patients obtaining cannabis or a cannabis medical license and using it with little to no medical supervision. In Canada, CBD is by prescription only through an MD or a nurse practitioner working under a prescribing medical doctor. In my clinical experience these patients are followed and counseled, or they cannot renew their medical cannabis license. In Canada, THC is available over the counter and individuals are free to access and use these products and quantities as they desire if they meet the legal minimum age requirement.
The urine outcomes from this trial are concerning. Did the products these subjects medically obtain not actually contain cannabis, or were the testing methods used by this research group faulty? The EMIT d.a.u. (enzyme multiplied immunoassay technique for drugs of abuse) screening test has a sensitivity limit of 20 ng/mL of urine and a 100% true negative in unadulterated samples with false positives of 3%. Gas chromatography–mass spectrometry yields virtually 100% accuracy in cannabis detection.4 The drug abuse screening test (DAST) is a 2-part urine test for THC, where THC of 50 ng/mL or more is detectable. THC can linger about 10 days to 4 weeks depending on level of use.5 Dronabinol, cannabidiol (CBD), and plant sources will also give positive results.5 Saliva tests can detect exposure 24 to 72 hours after use; hair tests can detect up to 90 days after use, while blood tests detect only for 3 to 4 hours. Urine levels are highest 0.6 to 7.4 hours after smoking.5
This trial aimed to assess if cannabis users would accurately complete an online survey using their own personal devices daily. That process was successful in this trial. A secondary outcome was the effect of medically obtained cannabis on insomnia, pain, anxiety, and depression; only insomnia was improved. Serious weaknesses of this trial were the type and strength of cannabis the subjects obtained (never assessed or tested), the method of cannabis administration (oral, smoked, vaped, but not controlled) by clinical condition (never assessed), the absence of monitoring to achieve or assess clinical effectiveness, and the poor detection of cannabis metabolites in the urine of these subjects, which prevented correlation of reported use with urine metabolite levels. Their publications focus on the development of cannabis use disorder in depressed (and perhaps anxious) subjects, and their conclusions are that no data support clinical use of cannabis. In fact, as one reads the paper from front to back, anxiety became subsumed under depression without an explanation of why or if they are even equivalent medical conditions.
My review of the literature found that THC can reduce anxiety at low doses and increase it at high doses, while CBD decreased anxiety at all doses.6 There is a risk of abuse in some individuals.6 A Canadian study found that anxiety decreased over 1 to 3 months, and at 2 years; the change in depression was smaller.7 The researchers appear to have an anti-addiction bias, and this seems to have crept into the interpretation of their results. The lack of control over the sourcing and administration of the cannabis likely contributed to the absence of correlation with urine testing.
Summary
Patients given a cannabis medical card can track their daily use on their personal devices over a 12-week period. Cannabis use can lead to significant sleep improvements, but the formulation of the cannabis in the study was unknown, the dose of the cannabis was unknown, and use level did not correlate to urine testing in this trial. Increasing cannabis use may or may not lead to cannabis use disorder. This was not objectively tested in this trial or in the authors’ other papers, but it was a conclusion in the primary publication of this study.1
