Cannabis containing equivalent concentrations of delta‐9‐tetrahydrocannabinol (THC) and cannabidiol (CBD) induces less state anxiety than THC‐dominant cannabis
Nadia R. P. W. Hutten, T. R. Arkell, F. Vinckenbosch, J. Schepers, R. C. Kevin, E. L. Theunissen, K. P. C. Kuypers, I. S. McGregor, J. G. Ramaekers
Psychopharmacology, 2022, 239, 3731–3741
Doi : 10.1007/s00213-022-06248-9
Abstract
Rationale : Delta-9-tetrahydrocannabinol (THC), an active component of cannabis, can cause anxiety in some users during intoxication. Cannabidiol (CBD), another constituent of cannabis, has anxiolytic properties suggesting that cannabis products containing CBD in addition to THC may produce less anxiety than THC-only products. Findings to date around this issue have been inconclusive and could conceivably depend on moderating factors such as baseline anxiety levels in users.
Objective : The present study examined whether anxiety following single doses of vaporised THC, CBD and THC/CBD might be explained by state and trait anxiety levels at baseline.
Methods : A placebo-controlled, randomised, within-subjects study including 26 healthy recreational cannabis users tested the effects of vaporised THC-dominant cannabis (13.75 mg THC), CBD-dominant cannabis (13.75 mg CBD), THC/CBD-equivalent cannabis (13.75 mg THC/13.75 mg CBD) and placebo cannabis on anxiety. Self-rated trait anxiety was assessed with the State-Trait Anxiety Inventory (STAI). State levels of anxiety were objectively assessed with a computer-based emotional Stroop task (EST) and subjectively rated with the STAI-state questionnaire and a visual analogue scale.
Results : Both THC and THC/CBD significantly increased self-rated state anxiety compared to placebo. State anxiety after THC/CBD was significantly lower than after THC alone. THC-induced anxiety was independent of anxiety at baseline. When baseline anxiety was low, CBD completely counteracted THC-induced anxiety; however, when baseline anxiety was high, CBD did not counteract THC-induced anxiety. There were no effects of any treatment condition on the EST.
Conclusion : Overall,the study demonstrated that theTHC/CBD-equivalent cannabis induces less state anxiety than THC-dominant cannabis.
Keywords : Delta-9-tetrahydrocannabinol · Cannabidiol · Anxiety · Healthy
Introduction
With the growing trend to legalise or decriminalise recreational and medical use of cannabis, the prevalence of cannabis consumption is expected to increase (Hall and Lynskey 2016; Han et al. 2018). The potency of recreational cannabis products has risen substantially in Europe and the USA over the past decade, as shown by higher levels of their psychoactive substance delta-9-tetrahydrocannabinol (THC) (Chandra et al. 2019). THC is mainly used recreationally to induce a subjective feeling of high (Curran et al. 2002), but it may also produce undesired feelings such as anxiety (Arkell et al. 2019; Bhattacharyya et al. 2010; D’Souza et al. 2004; Hunault et al. 2014; Karschner et al. 2011; Zuardi et al. 1982). Also, medical formulations of THC have been associated with anxiety in patients suffering from HIV wasting disease (Inc. 2017).
The anxiolytic properties of the non-intoxicating can- nabis compound, cannabidiol (CBD), have shown to be promising in reducing symptoms in social anxiety disorder, generalised anxiety disorder, panic disorder and post-traumatic stress disorder in preclinical and clinical studies (Berger et al. 2020; Blessing et al. 2015; Masataka 2019; Skelley et al. 2020). Preclinical studies suggest that CBD has anxiolytic effects under high-stress conditions (i.e. foot shock prior to a light–dark emergence test) but not under low-stress conditions (i.e. light–dark emergence test or open field test) (Rock et al. 2017; Todd and Arnold 2016). Human studies have also indicated anxiolytic properties of CBD and reported reductions in stress-induced anxiety in healthy volunteers (de Souza Crippa et al. 2004; Linares et al. 2018; Zuardi et al. 2017b; Zuardi et al. 1993) and patients with Parkinson’s disease (de Faria et al. 2020).
Nabiximols, a plant-based medication containing THC and CBD in a ratio of 1:1, ranging from 2.7 mg THC/2.5 mg CBD to 32.4 mg THC/30 mg CBD oromucosal, is currently prescribed to relieve symptoms of multiple sclerosis and cancer-related pain (Krcevski‐Skvarc et al. 2018). A THC/CBD ratio of 1:1 is believed to provide the best balance between therapeutic effects and adverse effects, such as anxiety (Rob- son 2014). However, some patients using nabiximols still experienced THC-induced anxiety despite the presence of CBD in their formulation (Barnes 2006; Syed et al. 2014). Notably, the anxiolytic effects of CBD tend to occur at a much higher dose (300 mg orally) (Masataka 2019; Zuardi et al. 2017b) than would be delivered with therapeutic doses of nabiximols (e.g. 2.5–30 mg oromucosal) (GW Pharma Ltd. 2022). Also, clinical studies in healthy volunteers have reported only a minimal impact of CBD on THC-induced anxiety with THC to CBD ratios of 1:1 and 1:2 when vapor- ised (13.75 mg THC/13.75 CBD), consumed orally (0.5 mg/ kg THC/1.0 mg/kg CBD) or after oromucosal use (5.4 mg THC/5.0 mg CBD and 16.2 mg THC/15.0 mg CBD) (Arkell et al. 2019; Zuardi et al. 1982; Karschner et al. 2011). These findings might indicate that other factors play a role in the anxiogenic or anxiolytic effects of THC/CBD.
Potential factors moderating CBD and THC effects on anxiety include both state and trait anxiety prior to canna- bis intake. In preclinical studies, high levels of state anxiety, induced by the presence of an explicit stressor, may determine the anxiolytic effects of CBD (Rock et al. 2017). However, it is unknown whether baseline state anxiety also affects THC and THC/CBD-induced anxiety in humans. In addition, high trait anxiety is positively associated with increased selective attention towards anxiety-related stimuli, i.e. words or pictures (Mathews et al. 1997). This increased bias towards anxiety-related stimuli might also play a role in the increased state anxiety after THC inhalation. In line with this, those who score high on trait anxiety might experience greater relief of anxiety symptoms when treated with CBD. Furthermore, while CBD appears only to produce anxiolytic effects in individuals with high states of anxiety (Freeman et al. 2019; Szkudlarek et al. 2019), CBD might only counteract high levels of THC-induced anxiety. Therefore, it is interesting to explore whether those who experience heightened anxiety after THC inhalation display lower anxiety levels after combined inhalation of THC and CBD.
The present study contain secondary, exploratory analyses of the anxiety data collected presented in a randomised controlled trial investigating THC and CBD effects on cognition and driving performance (Arkell et al. 2020). The current study compared the effects of inhaled CBD, THC and THC/CBD on anxiety (presented in Arkell et al. 2020) and further examined whether these effects depend upon moderating factors such as baseline state and trait anxiety levels. Furthermore, we aimed to explore whether individuals who experience high THC-induced anxiety levels display a more substantial reduction in anxiety symptoms when CBD is co-administered.
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