CONSORT flowchart of recruitment and enrollment for the open-label phase of clinical trial NCT02548559. COVID-19 indicates coronavirus disease 2019.
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Dahlgren MK, Sagar KA, Lambros AM, Smith RT, Gruber SA. Urinary Tetrahydrocannabinol After 4 Weeks of a Full-Spectrum, High-Cannabidiol Treatment in an Open-label Clinical Trial. JAMA Psychiatry. 2021;78(3):335–337. doi:10.1001/jamapsychiatry.2020.3567
Despite the growing popularity of cannabidiol (CBD) products, specifically those derived from legal industrial hemp sources,1 few studies have directly assessed whether the use of high-CBD products could yield positive results on urinary drug tests assessing cannabis use through the detection of Δ9-tetrahydrocannabinol (Δ9-THC) metabolites. A recent short-term administration study found that a single exposure to vaporized CBD-dominant cannabis flower (CBD, 10.5%; Δ9-THC, 0.39%), which the authors noted was similar to hemp, resulted in positive drug test results (>15 ng/mL) for 2 of 6 participants within 4 to 8 hours of administration.2 However, to our knowledge, no studies have examined drug test results in those consistently using full-spectrum (ie, Δ9-THC–containing) CBD products. Accordingly, as part of an open-label clinical trial (NCT02548559) examining the use of a full-spectrum high-CBD product for anxiety (with unpublished results as yet), we monitored THC urinary drug status.
This study was approved by the Partners Healthcare institutional review board, and all participants provided written informed consent. Study enrollment was conducted at McLean Hospital between June 2018 and February 2020. Participants were required to be 18 years or older, report at least moderate levels of anxiety assessed using well-validated measures,3,4 and test negative at baseline for 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THC-COOH), a major metabolite of Δ9-THC. Patients did not use cannabis and could not use any other cannabis/cannabinoid–based products throughout the 4-week trial. Women were required to have a negative pregnancy test result. Exclusion criteria included serious medical illness (eg, kidney or liver disease, neurological disorder). The open-label phase was capped at 15 participants to determine dosing and tolerability. The CONSORT guidelines were followed. A protocol is available in the Supplement.
The study product was formulated using a full-spectrum, high-CBD extract containing 9.97 mg/mL of CBD (1.04%) and 0.23 mg/mL of Δ9-THC (0.02%), as confirmed by ProVerde Laboratories. Patients self-administered 1 mL of the study product sublingually 3 times per day, for a targeted daily dose of approximately 30 mg of CBD and less than 1 mg of Δ9-THC. The actual dosage was quantified using outgoing vs incoming bottle weights, cross-referenced with weekly drug diaries. Urine drug assays (a 12-panel test, waived by the Clinical Laboratory Improvement Amendments5) assessed the presence of THC-COOH, which was confirmed via gas chromatography–mass spectrometry (Quest Diagnostics). Exploratory logistic regression analyses (SPSS version 25 [IBM]; α = .05, 2-tailed) assessed associations between THC-positive status, demographic variables, and creatinine, which is reflective of kidney function and hydration.
Of 15 patients enrolled (11 women [79%]; 12 White individuals [86%]), 1 discontinued participation because of use of another cannabinoid product; the remaining 14 patients completed all study procedures (Figure). The study drug was well tolerated; no serious adverse events were reported, and no patients reported psychoactivity. Patients used a mean (SD) of 3.48 (0.60) mL of the study product per day, equivalent to a mean (SD) of 34.73 (6.03) mg of CBD per day and 0.80 (0.14) mg of Δ9-THC per day. Results revealed that after 4 weeks, 7 participants (50%) tested positive for THC-COOH, while 7 tested negative. Gas chromatography–mass spectrometry results confirmed assay findings but indicated that the drug screen was often more sensitive than its stated lower limit of detection (50 ng/mL). Participants’ THC status was only significantly associated with creatinine levels (B, 1.92; P < .001; Table).
The results suggest that patients consistently using full-spectrum, hemp-derived products may have positive test results for THC-COOH on a urinary drug screen. Studies with larger sample sizes are needed to more thoroughly assess which variables (product use, body mass index, age, sex, race, medication use, etc) contribute to positive findings in only some individuals, particularly those with higher creatinine levels. Importantly, the study product contained 0.02% of Δ9-THC by weight; in the US, hemp-derived products can legally contain 0.30% or less of Δ9-THC by weight, more than 10 times the amount of Δ9-THC as the current study product.
Despite limitations in sample size and diversity, these findings have important public health implications. It is often assumed individuals using hemp-derived products will test negative for THC. Current results indicate this may not be true, especially if assays are more sensitive than advertised, underscoring the potential for adverse consequences, including loss of employment and legal or treatment ramifications, despite the legality of hemp-derived products.
Accepted for Publication: October 9, 2020.
Corresponding Author: Staci A. Gruber, PhD, Marijuana Investigations for Neuroscientific Discovery Program, McLean Hospital Imaging Center, 115 Mill St, Belmont, MA 02478 (email@example.com).
Published Online: November 4, 2020. doi:10.1001/jamapsychiatry.2020.3567
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Dahlgren MK et al. JAMA Psychiatry.
Author Contributions: Drs Dahlgren and Gruber had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Dahlgren and Sagar share first authorship.
Concept and design: Dahlgren, Gruber.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Sagar.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Dahlgren.
Obtained funding: Gruber.
Administrative, technical, or material support: Dahlgren, Smith, Gruber.
Supervision: All authors.
Other—regulatory support: Smith.
Conflict of Interest Disclosures: Drs Dahlgren, Sagar, Lambros, Smith, and Gruber reported grants from private donations to the MIND Program during the conduct of the study and grants from the National Institute on Drug Abuse, Foria/Praxis Ventures, and Charlotte's Web outside the submitted work. Dr Gruber also reported personal fees from Fenway Health and National Academy of Neuropsychology outside the submitted work. Dr Dahlgren also reported receiving the McLean Hospital Jonathan Edward Brooking Mental Health Research Fellowship outside the submitted work. No other disclosures were reported.
Funding/Support: Funding support for this project was provided by private donations to the Marijuana Investigations for Neuroscientific Discovery program at McLean Hospital. The cannabis extract base for the study drug was provided by the National Institute on Drug Abuse.
Role of the Funder/Sponsor: The funders and sponsor had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We thank Christopher Hudalla, PhD, ProVerde Laboratories, for his role in providing laboratory services and consultation, and Scott Lukas, PhD, McLean Hospital, for consultation with regulatory and compliance issues. Drs Hudalla and Lukas were not compensated for their contributions to this project.