All average ESAS-r scores decreased between baseline and FUP1 and FUP2. This was further demonstrated by ANOVAs which revealed a significant effect of visit on mean ESAS-r scores for each symptom assessed (pain: F(2,634) = 4.9, p < 0.008; anxiety: F(2,624) = 8.36, p < 0.001, depression: F(2,629) = 5.36, p < 0.004; wellbeing: F(2,613) = 8.31, p < 0.001; all η 2 p between 0.008 and 0.02). In all assessed symptoms, no significant main effect of adding THC at FUP1, nor visit-by-product interaction, were observed (all ps > 0.2). Post hoc tests revealed ESAS-r mean scores significantly decreased between baseline and FUP1 (all ps < 0.003) for all symptoms, between baseline and FUP2 for anxiety and wellbeing (both ps < 0.03), but not between FUP1 and FUP2 for any symptoms (all ps > 0.5). This suggests statistical improvement recorded at FUP1 is still present at FUP2 in all symptoms independently from treatment adjustment at FUP1.
Limitations are common in real-world data (RWD), especially in retrospective studies. In this study, with no control group, no causality effect can be drawn between CBD-rich treatment and symptom improvement. Most patients treated with CBM present with multiple severe symptoms and the analyses presented here are limited to identify the treatment outcomes for such patients. Further studies can investigate the use of CBD to treat several symptoms simultaneously.
Discrepancies still exist regarding the anxiolytic effect of CBD. Some RCTs indicate an anxiolytic effect of CBD upon experimentally induced scenarios (Bergamaschi et al. 2011; Zuardi et al. 2017; Bhattacharyya et al. 2010; Skelley et al. 2020); however, these findings are difficult to replicate (Larsen and Shahinas 2020; Hundal et al. 2018; Crippa et al. 2012). This reinforces our findings that CBD may have a differential effect depending on anxiety severity. Regarding the effects of CBD on depression symptoms, further research is required to draw conclusions (Khalsa et al. 2020; Schier et al. 2014; Turna et al. 2017).
RWE from retrospective analyses and patient registries shows that CBMs are used for pain (chronic, neuropathic), mental health conditions, cancer-related symptoms (nausea, fatigue, weakness), HIV/AIDS, and neurological conditions (Bonn-Miller et al. 2014; Gulbransen et al. 2020; Lintzeris et al. 2020; Lucas and Walsh 2017; Sexton et al. 2016; Waissengrin et al. 2015). Symptom control is the primary reason for use of CBM, with most patients looking to address unalleviated symptoms, perceived symptom intensity, and burden on health-related quality of life independently of primary diagnosis (Sexton et al. 2016; Waissengrin et al. 2015; Baron et al. 2018; Purcell et al. 2019; Swift et al. 2005; Webb and Webb 2014). The Edmonton Symptom Assessment Scale-revised version (ESAS-r) is a validated scale to assess symptom burden developed for use in oncology and palliative care (Hui and Bruera 2017), it has relevance to medical cannabis care as patients are often treated for similar symptom management (Good et al. 2019; Pawasarat et al. 2020). Specifically, studies showed self-perceived improvement in ESAS-r emotional symptoms (anxiety and depression) scores following CBM treatment in oncology patients, while pain and wellbeing symptoms showed no improvement (Good et al. 2019; Pawasarat et al. 2020). Yet, RWE on CBD-rich products is scarce (Goodman et al. 2020; Shannon et al. 2019). In addition, although careful titration and treatment adjustment after initiation is critical to symptom improvement and adverse effects care, current literature has failed to address this issue.
From Table 2, moderate or severe scores at baseline were most common for pain (205 patients, 73.5%) and poor wellbeing (202 patients, 72.4%).
All average ESAS-r scores decreased between baseline and FUP1 (all ps < 0.003). The addition of delta-9-tetrahydrocannabinol (THC) during the first follow-up had no effect on symptom changes. Patients with moderate/severe symptoms experienced important improvement at FUP1 (all ps < 0.001), whereas scores on pain, anxiety, and wellbeing of those with mild symptoms actually increased. Differences in ESAS-r scores between FUP1 and FUP2 were not statistically different.
The ANOVA showed main effects of visit, severity group (both ps < 0.001 with η 2 p =0.04 and η 2 p =0.3 respectively) and a significant group-by-visit interaction (F(2,597) = 36.53, p < 0.001; η 2 p = 0.11). Post hoc tests revealed a significant main score difference between baseline and FUP1 and FUP2 (both ps < 0.01) but not between FUP1 and FUP2 (p = 0.89). Precisely, the scores of the group reporting good wellbeing increased (t(182) = 8.8, p < 0.001) whereas scores of patients with worst wellbeing notably decreased (t(59) = − 5.08, p < 0.001) between FUP1 and FUP2 (Fig. 2d).
Single-site, randomized, placebo-controlled, cross-over, within-subjects design.
Study sessions are 72 hours apart. Visits included pre-post assessments following ingestion of either placebo or CBD.
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