Urinary Tetrahydrocannabinol After 4 Weeks of a Full-Spectrum, High-Cannabidiol Treatment in an Open-label Clinical Trial

This cohort study examines whether consumption of a high-cannabidiol product resulted in detectable amounts of Δ9-tetrahydrocannabinol metabolites in the urine samples of participants.

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of an open-label clinical trial (NCT02548559) examining the use of a full-spectrum high-CBD product for anxiety (with unpublished results as yet), we monitored THC urinary drug status.
Methods | 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-Δ 9 -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 Amendments 5 ) assessed the presence of THC-COOH, which was confirmed via gas chromatographymass 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.
Results | 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).
Discussion | 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.  ) are omitted to protect privacy and confidentiality. None of these variables had a significant association with urinary THC-COOH status. b Participants are arranged in ascending order by the mean amount of product used. 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.

Conflict of Interest
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.

Functional Magnetic Resonance Imaging-Guided Personalization of Transcranial Magnetic Stimulation Treatment for Depression
Antidepressant outcomes to repetitive transcranial magnetic stimulation (rTMS) are better when stimulation is serendipitously delivered to sites of the dorsolateral prefrontal cortex (DLPFC) showing negative (anticorrelated) functional connectivity with the subgenual cingulate cortex (SGC). 1-3 This sug- Functional connectivity (FC) was computed between the subgenual cingulate cortex and each vertex comprising the dorsolateral prefrontal cortex using each individual's own resting-state functional magnetic resonance imaging scan. Vertices most anticorrelated with the subgenual cingulate cortex were spatially clustered, and the center of the largest cluster was defined as the personalized target coordinate. Change in depression symptoms at 3 weeks was assessed compared with baseline using the Montgomery-Asberg Depression Rating Scale (MADRS). B, We anticipated that closer proximity between clinically applied and functional magnetic resonance imaging-personalized targets would lead to improved treatment response. This is a cartoon example only. C, Personalized stimulation targets (gray spheres) varied considerably across the spatial extent of the dorsolateral prefrontal cortex. D, Closer proximity between clinically applied and personalized targets associated with better clinical response.