¹Yale University School of Medicine, Psychiatry, New Haven, United States, ²Yale University School of Medicine, Psychiatry and Yale Stress Center, New Haven, Connecticut, United States, ³University of California at Irvine, Anatomy and Neurobiology, Irivine, CA, United States

Background: Cannabis-based compounds as therapeutics for various pain-related illnesses are being explored. However, uncertainty remains regarding effective formulations for specific symptoms, optimal dosing of specific cannabinoids and the risk of misuse. This project previously evaluated specific CBD and CBD+THC therapeutic dose ranges to target acute and chronic pain, as well as associated symptoms of anxiety and sleep disturbance.

Aims & Objectives: The current preliminary study assessed whether two combination doses of CBD and THC ( CBD40/THC10 mg or CBD100/THC30 mg) versus placebo over 7 days reduced acute pain and anxiety and also changes in chronic pain over the 7-days of treatment and over 2-week follow-up and also assessed plasma levels of the endocannabinoids 2-AG and anandamide.

Method: Twenty-four patients with chronic pain from musculo-skeletal disorder, multiple sclerosis or opioid use disorder were randomly assigned to 7-day b.i.d. dosing of CBD40/THC10 or CBD100/THC30 or placebo in a parallel group design. We utilized the Yale Pain Stress Test (YPST) adapted from Cold Pressor Test (CPT) with three repeated pain-stress and no pain-stress trials per condition to assess acute pain and anxiety implemented on day 1 and day 7 of treatment to assess acute pain and anxiety and 2-AG and anandamide levels (by LCMS-MS) and also assessed real world pain, anxiety and sleep daily during the 7-day dosing (study days) and over a 2-week follow-up period. Linear Mixed Effect (LME) models were utilized to assess medDose X Day X repeated time effects for YPST subjective pain and anxiety, and 2-AG and anandamide and daily pain and sleep ratings.

Results: Comparing chronic 7-day b.i.d. dosing of placebo versus CBD40/THC10 and CBD100/THC30 doses showed MedDose X YPST day effect (F[2,342]=6.07, p<.003) for acute pain with increases for placebo and CBD100/THC30 doses but not the CBD40/TH10 dose. Similarly, YPST acute anxiety showed MedDose X Day effect (F[6,155]=3.09, p<.04) with significant increases in anxiety on both day 1 and 7 for placebo and CBD100/THC30 but not the CBD40/THC10 dose. Daily ratings of pain showed significant and sustain reductions in pain for the CBD40/THC10 dose from baseline to study period and during follow-up (p’s<.001) but increases in pain (p’s<.01) after initial drop in pain from baseline to study period (p’s<.001) for the placebo and the CBD100/THC30 doses. Notably, sleep ratings showed significant improvements from baseline to study period (p<.05) and follow-up period (p<.001) only for the CBD40/THC10 and not for placebo not the CBD100/THC30 doses. MedDose X Day interactions were observed for 2-AG (Χ²[2] = 7.12, p < .03) and for anandamide (Χ²[2] = 7.66, p < .02). Elevations in 2-AG levels by day 7 for CBD40/THC10 dose compared to placebo (p<.055) and CBD100/THC30 (p<.009) were observed, but lower anandamide levels were observed with placebo (p<.05) and nonsignificant increases in anandamide for the CBD40/THC10 dose. All doses were well-tolerated, and no serious adverse events were reported.

Discussion & Conclusions: Current positive findings of the combined CBD40/THC10 dose for provoked and daily pain, anxiety and sleep disturbances suggests further evaluation of this formulation as a novel therapeutic for chronic pain, anxiety, and sleep disturbances.