Do withdrawal-like symptoms mediate increased marijuana smoking in individuals treated with venlafaxine-XR?

Abstract

Background and aims: Cannabis-dependent participants with depressive disorder are less likely to achieve abstinence with venlafaxine-XR (VEN-XR) treatment. Individuals on VEN-XR reported more severe withdrawal, despite not reducing their smoking behavior. We hypothesized that withdrawal-like symptoms, likely medication side effects, led to continued marijuana smoking in this group.

Methods: We conducted a secondary analysis using Marijuana Withdrawal Checklist (MWC) scores and urine THC to test whether severity of withdrawal-like symptoms mediates the relationship between VEN-XR treatment and continued marijuana smoking. We included 103 participants (VEN-XR=51, Placebo=52). Marijuana use was dichotomized into smoking (THC>100 ng/ml) and non-smoking (THC ≤ 100 ng/ml) weeks. MWC scores were obtained weekly. We used three models in a regression based mediation analysis.

Results: The estimated risk of smoking marijuana was greater for individuals on VEN-XR in weeks 7-9, even when controlling for MWC scores (week 7 Risk Difference (RD)=0.11, p=0.034; week 8 RD=0.20, p=0.014), and higher scores mediated this effect. In weeks 10 and 11, the estimated effect was stronger (week 10 RD=0.03, p=0.380; week 11 RD=0.07, p=0.504), and worse withdrawal-like symptoms more fully accounted for continued marijuana smoking in the VEN-XR group, according to the models.

Conclusions: Individuals treated with VEN-XR had more severe withdrawal-like symptoms, which mediated their continued marijuana smoking. Noradrenergic agents, such as VEN-XR, may negatively impact treatment outcomes in cannabis-dependent patients attempting to reduce or stop their use.

Keywords: Cannabis; Cannabis Withdrawal; Marijuana; Marijuana Withdrawal; Treatment; Venlafaxine.

Fig. 1

Mediation analysis. a_t = The estimated effect of treatment with VEN-XR on marijuana withdrawal. b_t = The estimated effect of marijuana withdrawal on marijuana smoking when treatment with VEN-XR is included in the model. c_t= The total estimated effect of treatment with VEN-XR on marijuana smoking when marijuana withdrawal is not included in the model. c_t′= The direct estimated effect of treatment with VEN-XR on marijuana smoking when marijuana withdrawal is included in the model.

Fig. 2

Observed proportion of positive urine toxicologies over the weeks in the study by treatment arm.

Fig. 3

Observed withdrawal symptoms averaged by treatment group (VEN-XR, n = 51; PBO, n = 52) and week. *Significant differences were found between treatment arms in the later weeks of the study (specifically, at weeks 7–12).