Safety and pharmacokinetics of varying doses of cannabidiol (CBD) and cbd/tetrahydrocannabinol (THC) combination oral tablet formulation in recreational users: A randomized double-blind

Background: Medical marijuana use has increased with more states legalizing marijuana to treat various medical and neurological disorders, including chronic pain‐related illnesses, Posttraumatic Stress Disorder (PTSD) as well as epilepsy, multiple sclerosis, and cancer. Recent data show increased use of Cannabidiol (CBD)‐derived products to treat a myriad of diseases and conditions due to its non‐psychoactive nature. However, there is heterogeneity in local and regionally produced cannabis composition, dose, route, and overall drug formulations, and more importantly, significant ambiguity regarding the specific pharmacokinetics and pharmacodynamics as well as information on specific therapeutic doses for specific conditions. In this Phase I, randomized, double‐blind, cross‐over study we assessed the safety and PK/PD profile of acute 5 single doses of natural oral tablets of two doses of cannabidiol (CBD) (40 mg, 100 mg), and three CBD/delta‐9‐tetrahydrocannabinol (THC) combination doses (CBD40mg/THC10mg, CBD40mg /THC20mg and CBD100mg/ THC30 mg) and matching placebo (PBO) in six separate sessions, conducted one week apart in healthy adult men and women who are current recreational cannabis users, with a focus on pain and anxiety symptoms and alteration in stress responses. Methods: Eight subjects (5 male, 3 female; mean age 28.2 years) were randomized to receive a single dose of 40 mg CBD alone (CBD40), 100 mg CBD alone (CBD100), or combination 40 mg CBD/10 mg THC (CBD40/THC10), 40 mg CBD/20mg THC (CBD40/THC20), and 100 CBD/ 30 mg THC (CBD100/THC30), or placebo on separate sessions one week apart over six weeks. Repeated serum samples were collected and analyzed by liquid chromatography/mass spectrometry (LC‐MS/MS) for THC and CBD. Linear Mixed Effect (LME) models were utilized to assess repeated Within Subject Dose effects across repeated sampling over time, as well as peak (Tmax) levels. Results: A significant main effect of Dose was observed for THC (F = 6.02; p =<.0001) and for CBD (F =4.76; p =.0004) rises relative to baseline over time. THC serum concentration were significantly increased relative to baseline compared to placebo for CBD40/THC20 (p =.01) and CBD100/THC30 (p =.0001) but not at the CBD40/THC10 (p =.14) dose. Statistically significant increases were also observed at CBD40/THC20 (p =.01) and CBD100/THC30 (p = .0001) compared to CBD 40 mg alone dose. Compared to CBD100 alone serum THC was increased at CBD40/THC20 (p =.03) and for CBD100/THC30 (p =.0001). Also, the CBD100/THC30 dose showed an increase in serum THC compared to CBD40/THC10 (p = .01) and but trended for CBD40/THC20 (p =.08) respectively. CBD serum levels were significantly higher compared to placebo at CBD100 alone (p = .001) and at CBD100/THC30 (p = .0001). Higher serum CBD concentrations were seen at CBD100 (p =.01) and CBD100/THC30 (p= .002) compared to CBD40 alone. Lastly, higher CBD serum levels was observed at 100mg/30mg (p =.02) compared to 40mg/20mg. There was no significant effect observed for CBD40 alone compared to CBD40/THC10 for serum THC (p = .11) or serum CBD (p =.12). Peak serum THC concentrations for each dose were as followed, placebo (.228ng/mL; p =.73), CBD 40mg (.11ng/mL; p =.87), CBD 100mg (.49ng/mL; p =.46), CBD40/ THC10 (1.52ng/mL; p= .03) CBD40/THC20 (2.42ng/mL; p =.0006), and CBD100/THC30 (3.97ng/mL; p= <.0001). CBD peak serum concentration for each dose were as followed, placebo (.90ng/mL; p= .56), CBD 40mg (2.55ng/mL; p =.11), CBD 100mg (7.07ng/mL; p= .0001), 40mg/10mg (5.31ng/mL; p =.002) 40mg/20mg (4.04ng/mL; p =.01), and 100mg/30mg (8.0ng/mL; p =<.0001). All doses were well‐tolerated, and no serious adverse events were reported. Conclusions: The 40mg CBD /20mg THC and 100mg CBD/30mg THC doses elicited the greatest serum levels for THC, while the 100mg CBD alone and 100mg CBD/30mg THC doses produced the highest CBD response. Implications for pain and anxiety symptoms and stress responses will also be discussed.