Guanfacine Attenuates Adverse Effects of Dronabinol (THC) on Working Memory in Adolescent-Onset Heavy Cannabis Users: A Pilot Study

Abstract

The cannabinoid-1 receptor (CB1R) agonist Δ9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, adversely effects working memory performance in humans. The α2A-adrenoceptor (AR) agonist guanfacine improves working memory performance in humans. The authors aimed to determine the effects of short-term (6 days) treatment with guanfacine on adverse cognitive effects produced by THC. Employing a double-blind, placebo-controlled crossover design, the cognitive, subjective, and cardiovascular effects produced by oral THC (20 mg) administration were determined twice in the same cannabis users: once after treatment with placebo and once after treatment with guanfacine (3 mg/day). Compared with performance at baseline, THC negatively affected accuracy on spatial working memory trials while participants were maintained on placebo (p=0.012) but not guanfacine (p=0.497); compared with placebo, accuracy was significantly (p=0.003, Cohen's d=-0.640) improved while individuals were treated with guanfacine. Similarly, compared with baseline, THC increased omission errors on an attentional task while participants were maintained on placebo (p=0.017) but not on guanfacine (p=0.709); compared with placebo, there were significantly (p=0.034, Cohen's d=0.838) fewer omissions while individuals were maintained on guanfacine. Although THC increased visual analog scores of subjective effects and heart rate, these increases were similar during treatment with placebo and guanfacine. THC did not significantly affect performance of a recognition memory task or blood pressure while individuals were maintained on either treatment. Although preliminary, these results suggest that guanfacine warrants further testing as a potential treatment for cannabis-induced cognitive deficits.

The effects of cannabinoid 1 receptor compounds on memory: a meta-analysis and systematic review across species

“…Future studies are needed to identify if the endocannabinoid system may modulate other aspects of memory such as episodic, semantic, and procedural memory. Our finding that chronic THC had no effect on spatial or non-spatial memory performance is consistent with findings from human literature showing that THC has no effect on memory performance when administered chronically (Mathai et al 2018). However, future studies are needed to investigate the chronic effects of THC in placebo-controlled trials in order for this to be quantitatively investigated.…”

“…This finding was not influenced by rodent species, sex, paradigm, drug administration timing, dose, age or the compound used. While further studies are needed to investigate the chronic effects of THC in humans, a single study found that THC (10–20 mg) had no effect on verbal memory performance in humans when administered chronically for 7 days (Mathai et al 2018).…”

Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species

“…Recent studies suggest that guanfacine may also be useful in addressing addiction to cannabis. Guanfacine treatment was shown to reduce the cognitive impairment induced by THC ( Mathai et al, 2018 ), and new data suggest that it may be helpful in treating cannabis addiction ( Dakwar et al, 2020 ), although there are mixed results regarding its effects on withdrawal symptoms ( Haney et al, 2019 , Holst et al, 2019 ). As cannabis use in adolescents is a risk factor for subsequent schizophrenia ( Hasan et al, 2020 ), guanfacine treatment may also be protective in the prodrome to mental illness in high risk adolescents who are cannabis users.…”

Bioligands Acting on the Cannabinoid Receptor CB1 for the Treatment of Withdrawal Syndrome Caused by Cannabis sativa

“…Daily administration of the compound significantly reduced irritability, produced small but significant decreases in blood pressure and heart rate, however was well tolerated, producing no sedation, dizziness, or altered food intake observed with lofexidine. Due to these results, guanfacine hydrochloride stands out as one of the first non-cannabinoid agonists to reduce cannabis abstinence-related irritability [64,70].…”