Abstract
Numerous existing full-spectrum cannabis extract products have been used in clinical trials for the treatment of various diseases. Despite their efficacy, the clinical use of some of these full-spectrum cannabis extracts is limited by behavioral side effects such as cognitive dysfunction and impaired motor skills. To better understand what constitutes cannabis-induced behavioral effects, our objective was to identify a novel panel of blood-based metabolites that are predictive, diagnostic, and/or prognostic of behavioral effects.At 8 weeks of age, male rats were randomly assigned to groups and were gavage fed with full-spectrum cannabis extract (tetrahydrocannabinol/cannabidiol (THC/CBD) along with all other cannabis compounds, 15 mg/kg), broad-spectrum cannabis extract (CBD along with all other cannabis compounds, 15 mg/kg), or vehicle oil. Four hours after being gavage fed, behavioral assessments were determined using the open field test and the elevated plus maze. Following these assessments, serum was collected from all rats and the serum metabolites were identified and quantified by LC–MS/MS and 1H NMR spectroscopy.We found that only rats treated with full-spectrum cannabis extract exhibited behavioral changes. Compared to vehicle-treated and broad-spectrum extract–treated rats, full-spectrum extract–treated rats demonstrated higher serum concentrations of the amino acid phenylalanine and long-chain acylcarnitines, as well as lower serum concentrations of butyric acid and lysophosphatidylcholines. This unique metabolomic fingerprint in response to cannabis extract administration is linked to behavioral effects and may represent a biomarker profile of cannabis-induced behavioral changes. If validated, this work may allow a metabolomics-based decision tree that would aid in the rapid diagnosis of cannabis-induced behavioral changes including cognitive impairment.
Highlights
Cannabis has been used for centuries due to its medicinal benefits (Maayah et al, 2020b)
Given that there is no evidence that the simple presence of cannabis impairs behavior (Brubacher et al, 2019), the dosage of the fullspectrum cannabis extract we used in our rat model was selected from studies in rodents to provide the highest achievable concentration of THC in humans (Huestis, 2007)
We conclude that consistent with other studies (Misner and Sullivan, 1999; Maayah and Dyck, 2020), THC is the primary component of cannabis that is responsible for behavioral changes (Misner and Sullivan, 1999)
Summary
Cannabis has been used for centuries due to its medicinal benefits (Maayah et al, 2020b). Cannabis-related behavioral effects often involve reduced motor skills and coordination, which can eventually affect an individual’s overall quality of life (Misner and Sullivan, 1999; Maayah and Dyck, 2020) even for tasks like impairing the ability to drive (Hartman and Huestis, 2013; Lee et al, 2021). Given that many cannabinoids are present in cannabis and a number of these can induce behavioral changes (Montone et al, 2020), a test designed to measure THC levels in biological fluid samples may be misleading as these levels may not be truly indicative of cognitive dysfunction or impairment in motor skills (Brubacher et al, 2019). There remains a crucial need to identify tests that can help in the detection of full-spectrum cannabis–related behavioral effects and devise a real-time decision tree that would have an impact on different aspects of a user’s day-to-day activities like the ability to operate a motor vehicle
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