Randomized Laboratory Study of Single-Dose Cannabis, Dronabinol, and Placebo in Patients With Schizophrenia and Cannabis Use Disorder

Abstract

Background and hypothesis: Up to 43% of people with schizophrenia have a lifetime cannabis use disorder (CUD). Tetrahydrocannabinol (THC) has been shown to exacerbate psychosis in a dose-dependent manner, but little research has assessed its effects on schizophrenia and co-occurring CUD (SCZ-CUD). In this double-dummy, placebo-controlled trial (total n = 130), we hypothesized that a modest dose of THC would worsen cognitive function but not psychosis.

Study design: Effects of single-dose oral THC (15 mg dronabinol) or smoked 3.5% THC cigarettes vs placebo in SCZ-CUD or CUD-only on positive and negative symptoms of schizophrenia (only for SCZ-CUD), cognition, and drug experiences assessed several hours after drug administration. SCZ-only and healthy control participants were also assessed.

Study results: Drug liking was higher in THC groups vs placebo. Neither smoked THC nor oral dronabinol predicted positive or negative symptom subscale scores 2 and 5 h, respectively, after drug exposure in SCZ-CUD participants. The oral dronabinol SCZ-CUD group, but not smoked THC SCZ-CUD group, performed worse than placebo on verbal learning (B = -9.89; 95% CI: -16.06, -3.18; P = .004) and attention (B = -0.61; 95% CI: -1.00, -0.23; P = .002). Every 10-point increment in serum THC + THCC ng/ml was associated with increased negative symptoms (0.40 points; 95% CI: 0.15, 0.65; P = .001; subscale ranges 7-49) and trends were observed for worse positive symptoms and performance in verbal learning, delayed recall, and working memory.

Conclusions: In people with SCZ-CUD, a modest single dose of oral THC was associated with worse cognitive functioning without symptom exacerbation several hours after administration, and a THC dose-response effect was seen for negative symptoms.

Keywords: THC; cannabis; cannabis use disorder; cognition; dronabinol; placebo; psychosis; randomized trial; schizophrenia.

Fig. 1.

Mean THC + THCC concentrations (ng/ml) over the second assessment day. Note: THC, (−)-trans-Δ⁹-tetrahydrocannabinol.

Fig. 2.

Drug experience ratings of mood and desirability. Panel 1: Sample of longitudinal mood ratings (0–100) by minutes (50–405) among SCZ-CUD drug exposure groups and SCZ-only participants. Panel 2: End-of-day drug desirability ratings. Note: CUD-only, cannabis use disorder only; SCZ-CUD, schizophrenia with cannabis use disorder.