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Cannabidiol use and effectiveness: real-world evidence from a Canadian medical cannabis clinic Open Access This article is licensed under a Creative Commons Attribution 4.0 International Public and medical interest in cannabidiol (CBD) has been rising, and CBD is now available from various sources. Research into the effects of low-dose CBD on outcomes like stress, anxiety, and sleep problems have been scarce, so we conducted an online survey of CBD users to better understand patterns of use, dose, and self-perceived effects of CBD. The sample consisted of 387 current or past-CBD users who answered a 20-question online survey. The survey was sent out to CBD users through email databases and social media. Participants reported basic demographics, CBD use patterns, reasons for use, and effects on anxiety, sleep, and stress. The sample (N = 387) consisted of 61.2% females, mostly between 25 and 54 years old (72.2%) and primarily based in the UK (77.4%). The top 4 reasons for using CBD were self-perceived anxiety (42.6%), sleep problems (42.5%), stress (37%), and general health and wellbeing (37%). Fifty-four per cent reported using less than 50 mg CBD daily, and 72.6% used CBD sublingually. Adjusted logistic models show females had lower odds than males of using CBD for general health and wellbeing [OR 0.45, 95% CI 0.30–0.72] and post-workout muscle-soreness [OR 0.46, 95%CI 0.24–0.91] but had higher odds of using CBD for self-perceived anxiety [OR 1.60, 95% CI 0.02–2.49] and insomnia [OR 1.87, 95% CI 1.13–3.11]. Older individuals had lower odds of using CBD for general health and wellbeing, stress, post-workout sore muscles, anxiety, skin conditions, focusing, and sleep but had higher odds of using CBD for pain. Respondents reported that CBD use was effective for stress, sleep problems, and anxiety in those who used the drug for those conditions. This survey indicated that CBD users take the drug to manage self-perceived anxiety, stress, sleep, and other symptoms, often in low doses, and these patterns vary by demographic characteristics. Further research is required to understand how low doses, representative of the general user, might impact mental health symptoms like stress, anxiety, and sleep problems. Cannabidiol in Anxiety and Sleep: A Large Case Series Cannabidiol (CBD) is one of many cannabinoid compounds found in cannabis. It does not appear to alter consciousness or trigger a “high.” A

Cannabidiol use and effectiveness: real-world evidence from a Canadian medical cannabis clinic

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Associated Data

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abstract

Background

Cannabidiol (CBD) is a primary component in the cannabis plant; however, in recent years, interest in CBD treatments has outpaced scientific research and regulatory advancement resulting in a confusing landscape of misinformation and unsubstantiated health claims. Within the limited results from randomized controlled trials, and lack of trust in product quality and known clinical guidelines and dosages, real-world evidence (RWE) from countries with robust regulatory frameworks may fill a critical need for patients and healthcare professionals. Despite growing evidence and interest, no real-world data (RWD) studies have yet investigated patients’ reports of CBD impact on symptom control in the common expression of pain, anxiety, depression, and poor wellbeing. The objective of this study is to assess the impact of CBD-rich treatment on symptom burden, as measured with a specific symptom assessment scale (ESAS-r).

Methods

This retrospective observational study examined pain, anxiety, depression symptoms, and wellbeing in 279 participants over 18 years old, prescribed with CBD-rich treatment at a network of clinics dedicated to medical cannabis in Quebec, Canada. Data were collected at baseline, 3 (FUP1), and 6 (FUP2) month after treatment initiation. Groups were formed based on symptom severity (mild vs moderate/severe) and based on changes to treatment plan at FUP1 (CBD vs THC:CBD). Two-way mixed ANOVAs were used to assess ESAS-r scores differences between groups and between visits.

Results

Conclusion

This retrospective observational study suggests CBD-rich treatment has a beneficial impact on pain, anxiety, and depression symptoms as well as overall wellbeing only for patients with moderate to severe symptoms; however, no observed effect on mild symptoms. The results of this study contribute to address the myths and misinformation about CBD treatment and demand further investigation.

Background

Cannabidiol (CBD) is one of the primary cannabinoids found in significant but variable concentrations in cannabinoid-based medicines (CBM). While structurally similar to Δ9-tetrahydrocannabinol (THC), CBD does not cause intoxication or euphoria (Russo 2017) and has showed considerable tolerability in humans with a low abuse potential (Chesney et al. 2020). This favorable safety profile has led to the recent mitigation of legal and regulatory barriers surrounding purified CBD products in several countries and recent increased interest in CBD treatments. While recent rulings clarified that CBD is not a drug under the 1961 United Nations as Single Convention on Narcotic Drugs, regulatory status in the USA remains extremely confusing. When derived from cannabis, CBD is a schedule 1 drug but when derived from “industrial hemp” plants it may be lawful federally (Corroon and Kight 2018; Corroon et al. 2020). In Canada, CBD is controlled under the Cannabis Act as are all cannabinoids, cannabis, and cannabis-derived products (Canada Go 2021). This regulatory status imparts restrictions and access obstacles for researchers.

CBD is widely touted as a panacea for a wide range of health problems and has been marketed as a dietary and “wellness” product (Russo 2017; Khalsa et al. 2020; Eisenstein 2019). CBD’s potential effects as an add-on therapy have been studied for social anxiety disorders, schizophrenia, non-motor symptoms in Parkinson’s disease, and substance use disorders (Bergamaschi et al. 2011; Crippa et al. 2019; McGuire et al. 2018; Millar et al. 2019; Prud’homme et al. 2015; Thiele et al. 2019; Leehey et al. 2020). However, the evidence of its effectiveness for indications other than drug-resistant pediatric epilepsy conditions remains very limited (Larsen and Shahinas 2020; Franco et al. 2020) and safety considerations such as drug-drug interactions associated with unsupervised use remain (Chesney et al. 2020; Freeman et al. 2019). Randomized controlled trials (RCTs) are limited in their rigorous design, population sample, and duration of observation making generalization of results and long-term data scarce. Therefore, real-world evidence (RWE) provides valuable insights and supplemental information about the use, safety, and effectiveness of CBD-based treatments (Graham et al. 2020).

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.

In this study, we investigated treatment with CBD-rich products within a dedicated clinical setting in Quebec, Canada, and the effects on a very common clinical symptom expression of pain and comorbid anxiety and depression symptoms, as well as the effect on overall wellbeing. We also examined the relevant clinical effects that were observed when CBD-rich treatments were replaced by THC:CBD-balanced products at subsequent follow-up visits.

Methods

Study population

This study is a retrospective examination of patients who were prescribed CBD-rich products by physicians at a clinic dedicated to CBM treatments operating at four locations across Quebec, Canada. All data are collected as part of standard clinical procedures during the initial visit and during 3 (FUP1) and 6 (FUP2) month follow-up visits and extracted from electronic medical records (EMR) (Prosk et al., 2021). All data were anonymized following extraction from the EMR and no identifiers linking to original data were maintained. A waiver of consent was required and approved by Advarra Ethics Committee, who also approved the study protocol, and by the provincial privacy commission (La commission daccès à linformation du Quebec).

Adult patients, at least 18 years of age, who were initially treated exclusively with CBD-rich products from 1 October 2017 to 31 May 2019 and for whom outcome scores and product information were recorded at FUP1 were included in this study. Patients were generally referred by primary-care physicians and specialists for an assessment on the suitability of medical cannabis to treat refractory symptoms. A complete medical history, including primary and secondary diagnoses, was collected at baseline visit. Medical cannabis treatment decisions are determined at the discretion of a clinic physician according to a standardized clinical procedure, including symptom identification, selection of product format, cannabinoid profile, and dosage based on existing evidence (MacCallum and Russo 2018; Cyr et al. 2018), but also to minimize risk of adverse effects. Patient and physician preference may also indicate initiation with products that have higher CBD and lower THC concentration in order to limit use of THC and its inherent potential adverse events. The follow-up visits serve to assess treatment compliance, safety, and effectiveness.

CBD-rich products in Canada

CBD-rich products are administered in various methods and formats, but most commonly as oral plant-derived extracts or oils and as inhaled dried flowers. In the Canadian medical cannabis program, CBD-rich cannabis oils contain approximately 0.5–1 mg of THC/mL and 20–25 mg of CBD/mL depending on the product manufacturer. Table ​ Table1 1 provides cannabinoid content and THC:CBD ratio for the three most common oil products (over 85% of patients) authorized at the clinic. Furthermore, product details in this study sample are described in Table ​ Table3. 3 . The clinic procedure dictates that all products with a ratio of CBD (mg) to THC (mg) higher than 10 are considered CBD-rich products.

Table 1

THC and CBD contents and associated THC:CBD ratio for the three most common oil products authorized at the clinic

CBD-rich products at baseline THC:CBD-balanced products at FUP1 THC-rich products at FUP1
Authorized dose range (in ml/intake) 0.1–2 0.05–3 0.2–1.5
Oil (mg/ml) THC CBD Ratio THC:CBD THC CBD Ratio THC:CBD THC CBD Ratio THC:CBD
Product 1 1.2 24 1:25 9.5 12 10:13 27.5 < 1 30:1
Product 2 1.3 30 1:30 15 15 15:15 18.5 0.7 20:1
Product 3 < 1 20 1:20 10 13.5 10:13 26.3 < 1 30:1

The data is categorized by product category: CBD-rich products, THC:CBD-balanced products, and THC-rich products

CBD cannabidiol, THC Δ9-tetrahydrocannabinol, SD standard deviation

Table 3

Details of the THC and CBD component of the CBD-rich, the THC:CBD 1:1, and the THC-rich formulations

CBD-rich products at baseline (n = 279) THC:CBD-balanced products at FUP1 (n = 104) THC-rich products at FUP1 (n = 12)
THC CBD THC CBD THC CBD
Oil products (in mg/ml) 0.1–2.0 2.0–52.0 0.6–30 2.5–39 1.25–45 0–18
Dried flower (in % w/w) 0.7 17.0 3.7–9 7.7–13.4 13–27 0–0.5
Average daily dose (mg) 0.5 11.47 19.65 26.32 54.28 10.80
Standard deviation (mg) 0.43 10.21 5.80 9.12 29.65 7.64
Maximum daily dose (mg) 6 156 60 78 90 54

Data comes from our sample of 279 patients

CBD cannabidiol, THC Δ9-tetrahydrocannabinol

Treatment adjustments occur at follow-up visits as a result of lack of effectiveness, presentation of adverse effects, or social or economic barriers. Adjustments may include a change of the recommended CBD-rich product, method of administration, dosage, or a change in product formulation such as the introduction of THC:CBD-balanced or THC-rich products. We investigated the change from CBD-rich to THC:CBD products during FUP1 by forming two groups based on their product adjustment at FUP1 (CBD-rich vs THC:CBD). Products at FUP1 reflect those recommended at the visit. Therefore, the adjusted treatment affects only the evaluation at FUP2.

Outcomes

Patients age, sex, and diagnosis were recorded at baseline. Patients completed the ESAS-r (Edmonton Symptom Assessment System-revised version) at each visit. The ESAS-r is a self-administered scale, rating the severity of symptoms from 0 (absence of symptom) to 10 (worst possible severity) at the time of assessment (Hui and Bruera 2017). Symptoms evaluated include six physical- (pain, tiredness, nausea, drowsiness, lack of appetite, and shortness of breath), two emotional- (depression, anxiety), and one overall wellbeing-related symptoms. ESAS scores can be categorized as mild (score 0 to 3) moderate (score 4 to 6) or high (score 7 and above) (Butt et al. 2008) and the threshold for clinically significant improvement is a decrease of 1 point (Hui et al. 2015). Since pain and mental health issues represent the most common symptoms for patients and physicians seeking medical cannabis treatments, we investigated effects on pain, depression, and anxiety symptoms as well as overall wellbeing. For each symptom, two groups of patients were formed: moderate-severe severity group in which a baseline score of 4 or more was recorded and a mild severity group with baseline score of 0 to 3.

Analyses

Mean scores and standard deviation (SD), as well as percentage, where appropriate are presented for each variable. All analyses were performed on each ESAS-r symptom separately through the data analytics software R v4.0.2. An initial analysis compared the overall ESAS-r scores between each visit no matter the severity of the group, and looked at the role of product group (CBD/THC:CBD vs CBD/CBD group) (between-factor). Tukey HSD post hoc test was used to confirm where the differences occurred between groups.

To determine whether CBD-based treatments have different effectiveness based on the severity of patient symptoms, two-way mixed ANOVAs with severity group as between-factor and visit as a within-factor were conducted to assess the change in ESAS-r scores between visits. Paired t-tests were subsequently performed to assess the difference in mean scores within each severity group between baseline and FUP1. Significant p value was set at 0.05 and all analyses were two-tailed. Partial eta-squared (η 2 p) are reported to indicate magnitude of differences between groups.

Results

General

A total of 1095 patients were seen at the four clinic sites during the study period. Out of those, 715 were eligible for the study (at least 18 years old and initially treated exclusively with CBD-rich products). A total of 279 patients with ESAS-r scores and product information at FUP1 were analyzed (190 (68%) female, mean age = 61.1, SD = 16.6). The analyzed sample did not differ from the study-eligible group in terms of age, sex, or THC and CBD initial doses (all ps > 0.4). Table ​ Table2 2 outlines patient sample size and demographic information for each symptom and treatment group. Two hundred and ten (75%) patients were prescribed CBD-rich products to treat chronic pain, 19 (7%) for cancer-related symptoms, 21 (7.5%) to treat neurological disorders (Parkinson’s disease, multiple sclerosis, and drug-resistant epilepsy among others), 8 patients for inflammatory disease (arthritis), 10 for gastrointestinal disorders (Chron’s disease, inflammatory bowel syndrome, ulcerative colitis), 2 for anxiety, 1 for depression, 2 for headaches, and 6 unclassified. The chronic pain category included all medical indications for which pain was the main symptom such as but not limited to fibromyalgia, spinal stenosis, and chronic low back pain. Overall, 116 (41.6%) patients adjusted their prescription by adding THC at FUP1 (either to a THC:CBD-balanced combination or a THC-rich treatment). Two hundred and three (73%) patients had moderate/severe ESAS-r scores on at least 2 of the examined symptoms, 57 (20%) on three, and 75 (27%) on all four symptoms. Twenty-nine (10%) patients report no moderate/severe symptoms; these people may use CBD for other ESAS-r symptoms not examined here (shortness of breath, tiredness, nausea, drowsiness, appetite). There was no statistical difference on either age, sex, or THC and CBD initial doses between the patients who completed one FUP versus those who completed two FUP (all ps > 0.1).

Table 2

Demographic characteristics of 279 medical cannabis patients, by symptom group

Sample size (percentage) Number of female patients (percentage) Mean age (SD)
Overall sample 279 190 (68) 61.1 (16.6)
Moderate or severe pain symptom group 205 (73.5) 150 (73) 61.8 (15.9)
Moderate or severe anxiety symptom group 138 (48.5) 97 (70) 61.43 (16.3)
Moderate or severe depression symptom group 115 (41.2) 81 (70) 60.5 (15)
Moderate or severe wellbeing group 202 (72.4) 141 (70) 60.8 (16.1)
CBD/THC:CBD group 116 (41.6) 75 (65) 60.38 (14.4)

The symptom groups are mild and moderate or severe. The table presents the moderate or severe demographic characteristics. The CBD/THC:CBD group is composed of patients who added THC to their CBD-rich prescription during FUP1

CBD cannabidiol, THC Δ9-tetrahydrocannabinol, SD standard deviation

CBD-rich products characteristics

The baseline average daily doses for CBD and THC are presented in Table ​ Table3. 3 . The maximum initial CBD dose recorded (156 mg) was prescribed for the treatment of pain of one patient. The maximum THC dose recorded at FUP1 (90 mg) was prescribed for two patients for the treatment of pain.

Outcome of CBD treatment

Mean ESAS-r scores of pain, anxiety, depression symptoms, and overall wellbeing at baseline, FUP1, and FUP2 are described in Table ​ Table4 4 and Fig. ​ Fig.1 1 .

Table 4

Mean and standard deviation (SD) scores of ESAS-r scales for each severity group (mild or moderate/severe) and for each product group (CBD/CBD or CBD/THC:CBD)

Mean (SD) Pain Anxiety Depression Wellbeing
Baseline (sample size) 277 270 272 268
Overall sample 5.14 (2.57) 3.86 (3.19) 3.16 (3.08) 5.34 (2.61)
Mild severity group 1.69 (1.1) 0.99 (1.15) 0.87 (1.18) 1.86 (1.18)
Moderate or severe severity group 6.34 (1.7) 6.61 (1.78) 6.3 (1.86) 6.47 (1.83)
CBD/CBD group 5.03 (2.66) 3.80 (3.21) 2.99 (3.04) 5.28 (2.72)
CBD/THC:CBD group 5.28 (2.45) 3.95 (3.17) 3.40 (3.13) 5.42 (2.46)
FUP1 (sample size) 262 261 261 254
Overall Sample 4.37 (2.73) 2.93 (2.95) 2.33 (2.79) 4.45 (2.6)
Mild severity group 2.3 (2.4) 1.62 (2.08) 1.12 (1.78) 3.73 (2.75)
Moderate or severe severity group 5.04 (2.49) 4.15 (3.09) 3.77 (3.07) 4.72 (2.5)
CBD/CBD group 4.09 (2.67) 2.74 (2.87) 2.23 (2.71) 4.43 (2.6)
CBD/THC:CBD group 4.75 (2.78) 3.2 (3.05) 2.47 (2.9) 4.49 (2.63)
FUP2 (sample size) 101 99 102 97
Overall Sample 4.7 (2.7) 2.85 (3.01) 2.67 (3.02) 4.57 (2.47)
Mild severity group 2.18 (2.43) 1.32 (1.89) 1.52 (2.31) 3.82 (2.81)
Moderate or severe severity group 5.2 (2.47) 3.96 (3.19) 3.74 (3.26) 4.93 (2.23)
CBD/CBD group 4.55 (2.6) 2.44 (2.68) 2.44 (2.82) 4.76 (2.22)
CBD/THC:CBD group 4.88 (2.81) 3.08 (3.07) 2.94 (3.24) 4.36 (2.73)

The CBD/THC:CBD group is composed of patients who added THC to their CBD-rich prescription during FUP1. ESAS-r scores varied between 0 and 10 for all assessed symptoms and all visits except for the anxiety scale at FUP2 for which the maximum score was 9

CBD cannabidiol, FUP1 follow-up visit at 3 month, FUP2 follow-up visit at 6 month, THC Δ9-tetrahydrocannabinol

CBD-rich treatment effectiveness on pain, anxiety, depression symptoms, and on overall wellbeing in 279 patients. FUP1, follow-up visit at 3 month; FUP2, follow-up visit at 6 month. Mixed ANOVAs revealed a significant effect of visit on symptom reduction between baseline and FUP1 but not between FUP1 and FUP2

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.

CBD treatment impact according to symptom severity

From Table ​ Table2, 2 , moderate or severe scores at baseline were most common for pain (205 patients, 73.5%) and poor wellbeing (202 patients, 72.4%).

Clinical effect (difference of 1.3 to 2.5 points) observed in all symptoms for patients with moderate/severe symptoms between baseline and FUP1; however, there was no clinical effect for patients with mild symptoms (from − 0.3 to − 1.8) (Fig. ​ (Fig.2). 2 ). No clinical effect was observed in any symptoms between FUP1 and FUP2 for patients with moderate/severe symptoms (− 0.4 to 0.5) as well as for patients with mild symptoms (from − 0.7 to 0.4).

CBD-rich treatment effect according to symptom severity: mild or moderate/severe in 279 patients. FUP1, follow-up visit at 3 month; FUP2, follow-up visit at 6 month. a Mean ESAS-r scores for the pain symptom, b mean ESAS-r scores for the anxiety symptom, c mean ESAS-r scores for the depression symptom, and d mean ESAS-r scores for overall wellbeing. According to mixed ANOVAs, patients with moderate/severe symptoms reported symptom reduction whereas patients with mild symptoms reported symptom deterioration from baseline to FUP1. No effect was statistically significant between FUP1 and FUP2

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The ANOVA revealed that all main and interaction effects were significant at the 0.001 level with effect sizes large for severity (η 2 p = 0.29), medium for visit (η 2 p = 0.06), and small for the interaction (η 2 p = 0.03). Post hoc tests revealed a significant score difference between baseline and FUP1 and FUP2 (both ps < 0.05) but not between FUP1 and FUP2 (p = 0.98). Patients with moderate/severe symptoms on pain experienced important improvement at FUP1 (t(194) = 7.61, p < 0.001) whereas ESAS-r scores for patients with mild symptoms actually increased (t(64) = − 2.03, p < 0.05) (Fig. ​ (Fig.2 2 a).

Anxiety

There were significant effects of visit, severity group, and visit by group interaction (all ps < 0.001; η 2 p = 0.006, η 2 p = 0.4, η 2 p = 0.1, respectively). Post hoc tests revealed a significant score difference between baseline and FUP1 and FUP2 (both ps < 0.001) but not between FUP1 and FUP2 (p = 0.38). Although there was a large improvement for patients with moderate to severe anxiety symptoms (t(131) = 9.36, p < 0.001), the anxiety scores of patients with mild symptoms increased (t(119) = − 3.19, p < 0.01) from baseline to FUP1 (Fig. ​ (Fig.2 2 b).

Depression

The ANOVA showed main effects of visit, severity group (both ps < 0.001 with η 2 p = 0.04 and η 2 p = 0.4, respectively) and a significant group-by-visit interaction (F(2,620) = 34.47, p < 0.001; η 2 p = 0.1). Post hoc tests revealed a significant score difference between baseline and FUP1 and FUP2 (both ps < 0.01) but not between FUP1 and FUP2 (p = 0.85). Specifically, the scores of moderate/severe group decreased notably (t(110) = 9.56, p < 0.001) between baseline and FUP1 but the scores of the group with mild depression symptoms did not (p = 0.07) (Fig. ​ (Fig.2 2 c).

Wellbeing

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. ​ (Fig.2 2 d).

Discussion

This retrospective study explored the use of CBD-rich products in a medical cannabis clinical setting in Canada and associated effectiveness on a common symptom cluster presentation of pain, anxiety, depression, and poor sense of wellbeing, as measured by ESAS-r.

Patients treated with CBD-rich products were mainly women in their sixties, seeking predominantly chronic pain management.

Our findings show that overall effectiveness of CBD treatment is primarily by patients with moderate to severe symptoms. A deficiency in the endocannabinoid system (ECS) may provide a possible explanation for this result (Russo 2016). The ECS could be more deficient in patients with moderate/severe symptoms compared to mild symptoms leading to increased improvement in the first group. The absence of significant improvement for patients with mild symptoms at baseline may be explained by a smaller margin for symptom improvement. In such patients, CBD treatments may have been targeted to other clinical symptoms not assessed in the current study. There is a probable placebo effect; however, there were no differences in initial CBD doses between the severity groups. Furthermore, associated placebo effect would likely be decreased by FUP3M, also considering the significant treatment cost. The distinct beneficial impact of CBD treatment observed for patients with moderate-severe symptoms could elucidate discrepancies found in the literature.

RCTs on CBM and pain symptoms provide inconclusive results; however, several report that treatments of THC and CBD have some benefit for pain management (Häuser et al. 2018; Russo 2008; Prosk et al. 2020). Our results are largely novel as research on the effect of CBD on pain control is very limited (Boyaji et al. 2020). The reduction in reported anxiety may also contribute to the improvement in pain perception.

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).

The addition of THC to CBD during FUP1 did not produce any effect on ESAS-r scores at FUP2 in this analysis; however, the magnitude of the difference between groups is small. The examination of treatment regimen has been seldom addressed in the literature and further development is required to inform guidelines for prescription and refinement of clinical practice.

Furthermore, a significant discrepancy is observed between the recorded dosages of oral CBD in RCTs and dosages in real-world settings. The average daily CBD dosage authorized at our clinic (11.5 mg) is closer to other observational studies (Gulbransen et al. 2020) compared to what is seen in RCTs (up to 1000 mg for a single dose) (Larsen and Shahinas 2020). The presence of THC and other cannabinoids in CBD-rich products may affect the outcomes in this study. The majority of RCTs investigated single-dose administration of CBD making it difficult to compare observed treatment outcomes with chronic dosing clinical settings. Importantly, medical cannabis products are generally not covered by most insurers and patients rely on out-of-pocket payments. The cost of CBD remains very high globally, approximately $CAD 5–20 per 100 mg (Canada Go 2021; Eisenstein 2019; Canada 2020). Availability of reliable cannabinoid testing in certain international jurisdictions is also limited. The gap between effective doses demonstrated in RCTs and the actual affordable doses demonstrated by RWE mandate the need for a precise pricing and marketing strategy at the initiation of any drug development process.

Limitations

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.

The self-reported subjective assessment used may be biased by the patient’s positive expectation of treatment, which could lead to a possible placebo effect. This perceived effectiveness bias may also be increased by social and economic barriers. The current context of medical cannabis access, including social stigma, high cost, and lack of universal insurance coverage can increase the patient selection bias. Self-selection bias is increased by the significant patient interest in medical cannabis as these patients must be motivated to access the non-traditional medication system. This bias limits the generalizability of results but is common across international medical cannabis regimens and should not discount the observed results. The heterogeneity of the patient population with a variety of diagnoses and the diversity of medical cannabis preparations also affects the external validity of the study. However, clinical findings from within Canada’s controlled regulatory program do provide important models for international consideration. Future research is required in controlled clinical settings to examine these factors in order to provide a more complete account of CBD effectiveness.

Also, there was a large drop of sample size (53% loss) due to missing data. Additionally, there was an important loss to follow-up at the 6-month visit (FUP2) due to missed appointment and cost barriers, limiting the power of the findings. The total treatment cost has significant impact on treatment continuation. Improved patient retention and more robust, harmonized data collection methods will improve future observational studies and allow for long-term assessment. Collection of detailed, accurate product information is a challenge, especially with inhaled products (Corroon et al. 2020). There are opportunities for administration devices and other technology advancements to improve this limitation. Lastly, this study did not include safety data assessment, future studies should investigate safety considerations of CBD (Chesney et al. 2020). Collection of high-quality RWD will require improvements in patient retention, data monitoring, and more robust data collection methods within a controlled clinical setting.

Conclusion

This study on CBD-rich products demonstrates the potential of RWE for the advancement of medical cannabis research and practice guidelines, especially in a world where CBD use is exponentially increasing but scientific data are limited. It revealed that CBD-rich treatments have a beneficial impact on patients with self-reported moderate or severe symptoms of pain, anxiety, or depression and overall wellbeing but not in patients with mild symptoms. Further investigation is clearly required, but as of now the hyped, and often illegal, marketed claims of CBD as a wellness product are unsubstantiated. Our findings have important and novel implications to clinical practice, especially the examination of treatment plan adjustment during the first follow-up after initiation with CBD treatments. Improvements in access regimes, oversight, and clarification from regulatory agencies are also needed to improve the validity of RWE and assessment of the use of CBD-rich products.

Acknowledgements

The authors would like to thank the participants to this study. The authors would like to acknowledge Santé Cannabis co-founder Dr. Michael Dworkind and key clinical leaders Dr. Antonio Vigano, Dr. Howard Mitnick, Dr. Alain Watier, and Youri Drozd, clinical data assistant, for his contribution to data technical help.

Abbreviations

CBD Cannabidiol
CBM Cannabinoid-based medicines
EMR Electronic medical record
ESAS-r Edmonton Symptom Assessment System-revised version
FUP Follow-up visit
RWD Real-world data
RWE Real-world evidence
SD Standard deviation
THC Δ9-Tetrahydrocannabinol

Authors’ contributions

All authors contributed to conception and design, interpretation of data, manuscript writing, and final approval. LR and RG conducted the analysis of data. All authors agreed to be accountable for their own contributions. The author(s) read and approved the final manuscript.

Funding

This research was funded internally by Santé Cannabis clinic.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

A waiver of consent was required and approved by Advarra Ethics Committee, who also approved the study protocol, and by the provincial privacy commission (La commission d’accès à l’information du Quebec).

L.R.: Clinical research associate, employee at Santé Cannabis.

R.G.: Epidemiologic and statistic consultant for Santé Cannabis.

C.EH.: Director of Research and Innovation, employee at Santé Cannabis.

MF.A.: Associate Research Director of Santé Cannabis.

E.P.: President and co-founder of Santé Cannabis.

Santé Cannabis is a medical clinic, research, and training center dedicated to medical cannabis. The views expressed are those of the authors. This is a retrospective, observational study which took place at Santé Cannabis; therefore, the design and conduct of the study was executed by Santé Cannabis clinic staff. C.EH. and E.P. had a supporting role, in the retrospective protocol development. The authors had no role in the conduct of the study and collection of data. None of the authors are involved in the care of patients or in treatment decisions. The authors acted independently, and Santé Cannabis had no role in the analysis of the study, nor the writing of the manuscript or decision to publish. There is no financial gain for Santé Cannabis or for the authors to publish. The authors, while connected to Santé Cannabis, do not have a financial or professional incentive for the decision to publish.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Reasons for cannabidiol use: a cross-sectional study of CBD users, focusing on self-perceived stress, anxiety, and sleep problems

Public and medical interest in cannabidiol (CBD) has been rising, and CBD is now available from various sources. Research into the effects of low-dose CBD on outcomes like stress, anxiety, and sleep problems have been scarce, so we conducted an online survey of CBD users to better understand patterns of use, dose, and self-perceived effects of CBD.

Methods

The sample consisted of 387 current or past-CBD users who answered a 20-question online survey. The survey was sent out to CBD users through email databases and social media. Participants reported basic demographics, CBD use patterns, reasons for use, and effects on anxiety, sleep, and stress.

Results

The sample (N = 387) consisted of 61.2% females, mostly between 25 and 54 years old (72.2%) and primarily based in the UK (77.4%). The top 4 reasons for using CBD were self-perceived anxiety (42.6%), sleep problems (42.5%), stress (37%), and general health and wellbeing (37%). Fifty-four per cent reported using less than 50 mg CBD daily, and 72.6% used CBD sublingually. Adjusted logistic models show females had lower odds than males of using CBD for general health and wellbeing [OR 0.45, 95% CI 0.30–0.72] and post-workout muscle-soreness [OR 0.46, 95%CI 0.24–0.91] but had higher odds of using CBD for self-perceived anxiety [OR 1.60, 95% CI 0.02–2.49] and insomnia [OR 1.87, 95% CI 1.13–3.11]. Older individuals had lower odds of using CBD for general health and wellbeing, stress, post-workout sore muscles, anxiety, skin conditions, focusing, and sleep but had higher odds of using CBD for pain. Respondents reported that CBD use was effective for stress, sleep problems, and anxiety in those who used the drug for those conditions.

Conclusion

This survey indicated that CBD users take the drug to manage self-perceived anxiety, stress, sleep, and other symptoms, often in low doses, and these patterns vary by demographic characteristics. Further research is required to understand how low doses, representative of the general user, might impact mental health symptoms like stress, anxiety, and sleep problems.

Introduction

In the past years, cannabidiol (CBD), one amongst hundreds of naturally occurring phytocannabinoids found in the Cannabis sativa plant, has received a lot of attention from scientific communities, politicians, and mainstream media channels. CBD is the second most abundant cannabinoid in the Cannabis sativa plant after delta-9-tetrahydrocannabinol (THC), but unlike THC, CBD is not intoxicating (Pertwee 2008). In many countries, including the UK, there is unsanctioned availability of products containing CBD, from oils and capsules to chewing gums, mints, soft drinks, gummies, and intimate lubrication gels.

CBD has not demonstrated any potential for abuse or dependency and is considered well tolerated with a good safety profile, according to a report released by the World Health Organization (WHO) (Geneva CANNABIDIOL (CBD) n.d.). Since January 2019, the European Union (EU) has classified CBD as a novel food, implying that before 1997, consumption was insignificant. Each country has implemented the regulation of CBD differently. In the UK, The Food Standards Agency (FSA) recommends limiting the daily dose of CBD to 70 mg (Cannabidiol (CBD) n.d.). However, researchers have used doses up to 1200 mg without serious side-effects (Davies and Bhattacharyya 2019). Conversely, few clinical trials involving children with treatment-resistant epilepsy who received either 10 or 20 mg/kg of CBD (Epidiolex) for 12 weeks recorded side-effects, such as a reversible rise in liver enzymes (Devinsky et al. 2018a; Thiele et al. 2018).

The popularity of CBD can be partly explained by an increasing number of preclinical and clinical studies indicating a range of potential health benefits. However, mass media interest also plays a significant role. Studies suggest CBD might help with mental health symptoms and neurological conditions like experimentally induced anxiety (Zuardi et al. 1993), generalised social anxiety disorder (Bergamaschi et al. 2011), social phobia (de Faria et al. 2020), and conditions like PTSD (Elms et al. 2019; Shannon and Opila-Lehman 2016) schizophrenia (Zuardi et al. 2006; Leweke et al. 2012; Morgan and Curran 2008; Schubart et al. 2011), addiction (Hurd et al. 2019; Hindocha et al. 2018; Galaj et al. 2020), and epilepsy (Devinsky et al. 2017; Devinsky et al. 2018b; Cunha et al. 1980). These mental health disorders are often co-morbid and include other symptoms CBD might help with, e.g. sleep and impaired cognition. There is also data to suggest CBD could help treat neurodegenerative diseases like Alzheimer’s disease (Watt and Karl 2017; Fernández-Ruiz et al. 2013; Esposito et al. 2006), Parkinson’s disease (Fernández-Ruiz et al. 2013; García-Arencibia et al. 2007), and chronic pain conditions including fibromyalgia (Van De Donk et al. 2019), either alone or with THC (Rog et al. 2005; Berman et al. 2004; Wade et al. 2003; Svendsen et al. 2004; Notcutt et al. 2004). Additionally, in more than 30 countries, health authorities have approved CBD, under the name Epidiolex, to treat two severe forms of treatment-resistant childhood epilepsy (Dravet and Lennox-Gastaut syndrome) (Devinsky et al. 2016; Silvestro et al. 2019). Sativex, a sublingual spray containing an equal amount of THC and CBD, is also approved to treat multiple sclerosis in more than 30 countries (Keating 2017).

When used in high doses, somnolence is a primary adverse effect (Machado Bergamaschi et al. 2011). Patients in CBD clinical trials were more likely to experience sedation (OR 4.21, 95% CI 1.18–15.01) and somnolence (OR 2.23, 95% CI 1.07–4.64) in comparison to placebo (Chesney et al. 2020). Despite this preclinical and experimental research, there is a lack of human clinical trials to establish the efficacy and appropriate CBD indications fully. The effective dose for most of the above indications is still to be determined. In much of the research, high doses of CBD are used (between 300 and 1200 mg), whilst at the same time, globally, millions of CBD users are using low dose CBD. Thus, a disconnect exists between clinical research and the current state of the market.

A cross-sectional study of 2409 cannabidiol users from the USA found that the top three medical conditions reported were chronic pain, arthritis/joint pain, and anxiety, followed by depression and insomnia (Corroon and Phillips 2018). A recent survey carried out by Wheeler et al. of 340 young adults, some of whom were CBD users, found the top reasons to be stress relief, relaxation, and sleep improvement. They found edible CBD products to be the most prevalent (Wheeler et al. 2020). Another study of 400 CBD patients in New Zealand observed an increase in overall quality of life, a decrease in perceived pain, depression, and anxiety symptoms, as well as an increase in appetite and better sleep (Gulbransen et al. 2020).

A national survey indicated that in the UK, 8–11% of the adult population had tried CBD by June 2019 (Andrew et al. 2019). Studies of Google searches have shown considerable increases in CBD interest, with 6.4 million unique searchers in the USA in April 2019 (Leas et al. 2019). Yet it is clear that scientists, physicians, and governments were not prepared for the rapid surge in CBD use.

The regulatory confusion, along with recent media hype, has made it hard for most people to understand the true nature of CBD. Being classified as both a medicine and a supplement in some forms, whilst an illegal substance in others leads to consumer and patient confusion and potential frustration. Therefore, this study aimed to understand users’ consumption patterns regarding dose, route of administration, and reasons for using CBD. We hypothesised that out of all reasons for using CBD, the top three would be anxiety, sleep disturbances, and stress.

Methods

We developed an anonymous online questionnaire to collect CBD users’ self-reported characteristics, preferred method/s, and reason/s for using CBD. The survey was hosted on Survey Monkey Inc. (San Mateo, CA, USA). Data was collected between 10 January 2020 and 18 March 2020. The 20 questions were designed as multiple-choice questions with the option to choose either one or more answers. For some questions, respondents could write an alternative response if no option matched. We collected demographic information (age, sex, and location), CBD use patterns, reasons for use, other medication use, perceived effects, and side effects. The full questionnaire is provided in the supplementary materials.

To access actual CBD users, we collaborated with four different CBD brands and retailers (TheDrug.Store, OTO CBD, With Pollen and Grass & Co.), based in the UK, who sent out the survey to their email databases. The survey was sent out to 14,743 unique email addresses. Two thousand five hundred thirty-four were opened and 475 clicked through to the survey. We also shared the survey with CBD user groups on social media channels like Facebook and LinkedIn. We did not collect any personal data or IP addresses. Ethical approval was not required since this research investigated non-sensitive information using anonymous survey procedures with participants not defined as “vulnerable”. In addition, participation was deemed unlikely to induce undue psychological stress or anxiety based on ethics committee guidelines (UCL REC n.d.).

Statistical analysis

All analyses were conducted in SPSS version 24 (IBM Corporation, Armonk, NY). Valid percentages are reported rather than absolute values for descriptive statistics to account for missing data. We only report data on those reporting using CBD themselves equivalent to 90% of the respondents (e.g., not for veterinary use, not those who had not tried it, and those reporting on behalf of other users). An analysis of non-responders can be found in supplementary materials. We conducted logistic regression models to investigate associations between sex (males [reference category] and females), age (recoded to < 34 years old [reference category], between 35 and 54 years old, and 55+) and location (UK [reference category], other). For CBD use patterns, we used separate models to compare those who did and did not report their primary use of CBD for self-perceived anxiety, stress, and sleep whilst controlling for sex, age, and location. We dummy-coded “time of day” as each category versus all others. We report adjusted odds ratios with 95% confidence intervals and p values with a defined cut-off of 0.05.

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Results

The most significant findings were that many CBD users reported that CBD could improve sleep problems, stress, and anxiety and be used for general health and wellbeing. In the detailed results below, you can find the demographics of our survey population (Table 1), the CBD use patterns (Table 2), and logistic regression and OR’s for the different subgroups. The indications for CBD use are shown (Fig. 1), as well as how CBD affects sleep (Fig. 2), and other effects of CBD (Fig. 3). Using CBD for sleep was associated with taking it in the evening, and using CBD for anxiety or stress was associated with the sublingual route. Females had higher odds of using CBD for anxiety and men for post-workout. Details of the results can be found below.

Reasons for cannabidiol use amongst 397 adult cannabidiol users who were allowed to respond to more than one option leading to a total of 1622 responses. Y-axis represents percentage based on total responses

Perceived effects of cannabidiol on sleep amongst adult cannabidiol users responding to the question “how does cannabidiol affect your sleep?” Participants were allowed to select multiple options. Y-axis represents percentage of total responses (n = 522)

Other perceived benefits of cannabidiol amongst adult cannabidiol users. Respondents were asked what other benefits or effects they feel from using cannabidiol. Participants were allowed to select multiple options. X-axis is the percentage of total responses (n = 906)

Demographic characteristics

A total of 430 people started the survey, of whom 15 (3.48%) did not respond to any questions, and 28 (6.5%) reported they did not use CBD themselves (analysis of these non-users can be found in the supplementary materials). Non-CBD-users skipped most questions and had sociodemographic characteristics similar to those of CBD users. Three hundred eighty-seven (90%) reported using CBD themselves. The majority of users were females from the UK (see Table 1). In regards to other medication use, there were a total of 467 responses. 39.4% of respondents reported not taking any other medication, 14.7% “painkillers”, and 14.7% “other” (40% anxiolytics and antidepressants). No other medication was reported by more than 10% of responses.

Logistic regression on location purchased (CBD shop or other) found that those who lived outside of the UK (aOR 2.286, [95% CI 1.35–3.86], p = 0.002) and males (aOR 1.75, [95% CI 1.06–2.88], p = 0.02) had greater odds of purchasing CBD from an “other” location. Each of the primary disorders was included in the model individually, and did not significantly alter the model and were not associated with location purchased.

CBD use patterns

The majority of users take CBD sublingually for 3–6 months (see Table 2). Those 35–54 years old (aOR 1.67 [95% CI 1.02–2.72], p = 0.04) and those 55+ (aOR 2.01, [95% CI 1.11–3.64], p = 0.02) had greater odds of using CBD daily in comparison to less than daily. There were no associations with self-perceived anxiety, stress, or sleep improvement. Females had lower odds of using CBD for greater than 1 year versus less than 1 year (aOR 0.54, [95% CI 0.38–0.88], p = 0.013) suggesting females had used CBD for less time. No associations emerged for self-perceived anxiety, stress, or sleep. There were no sex or age associations for the frequency of use, duration of use, or number of times per day. Females had a greater odds of responding that they take CBD when they need it versus males (aOR 1.79, [95% CI 1.036–3.095], p = 0.037). However, no other associations with age and sex on time of day emerged.

Compared with people not using CBD for anxiety, those who did self-medicate used CBD multiple times a day (aOR 3.44, [95% CI 1.70, 7.00], p = 0.001). Moreover, compared with those not using CBD for self-perceived stress, those who were self-medicating also used CBD multiple times a day (aOR 1.97, [95% CI 1.034–3.77], p = 0.039). Those using CBD for sleep improvement had greater odds of using CBD in the evening (aOR 3.02, [95% CI 1.86, 4.93], p ≤ 0.001) and lower odds of using CBD in the morning (aOR 0.157, [95% CI 0.07–0.38], p ≤ 0.001). Those using CBD for self-perceived anxiety had lower odds of using CBD in the evening (aOR 0.56, [95% CI 0.14–0.45], p ≤ 0.001). No associations emerged between those who did and did not use CBD for self-perceived stress on the time of day they used CBD.

CBD dose and route of administration

Route of administration did not vary by sex. There were lower odds of those aged 55+ of vaping CBD (aOR 0.176, [95% CI 0.04–0.80], p = 0.025) as well as lower odds of those aged 35–55 (aOR 0.245, [95% CI 0.10–0.59], p = 0.002) and 55+ (aOR 0.115, [95% CI 0.025–0.520], p = 0.005) in comparison to 18–34 years old for drinking CBD. Self-reported anxiety (aOR 1.78, [95% CI 1.08–2.92], p = 0.023) and those using CBD for sleep improvement (aOR 1.945, [95% CI 1.152–3.285], p = 0.013) were associated with the sublingual route. Stress was not associated with route of administration.

Reasons for use of CBD

42.6% endorsed using CBD for self-perceived anxiety, followed by 37.5% for stress, 37% for general health and wellbeing, and 37% for improving sleep (see Fig. 1). 24.6% reported use for self-perceived insomnia. Overall, 42.5% of respondents said they were using CBD for some sleep issue, either to improve sleep or for self-perceived insomnia. In the supplementary materials (see Table 2), we show reasons for use broken down by sex, age, and location.

In adjusted logistic models, more males (47.4%) were using CBD for general health and wellbeing than females (30.7%; aOR 0.464, [95% CI 0.30–0.72], p = 0.001). More females were using CBD for self-perceived anxiety (47.9%) than males (34.2%; aOR 1.595, [95% CI 1.021, 2.49], p = 0.04), and for self-perceived insomnia (females 28.6%, males 17.8%; aOR 1.871, [95% CI 1.125–3.112], p = 0.015). More males (14.1%) than females (7.1%) were using CBD for post-workout sore muscles (aOR 0.462, [95% CI 0.236–0.905], p = 0.024).

Self-perceived anxiety

One hundred sixty-five of 387 (42.6%) endorsed using CBD for self-perceived anxiety. In response to the question “how does CBD affect your anxiety levels”, participants responded that they felt less anxious (141/163 (86.5%)), followed by “no difference (I still suffer from the same degree of anxiety)” (21/163; 12.8%), and one person (0.6%) noted greater anxiety. Moreover, participants were asked how often they thought about problems when they were supposed to be relaxing, compared with before they started taking CBD. We found that just 96/163 (58.9%) of respondents thought about their problems less than before, followed by “it hasn’t changed (I still think a lot about problems” (55/163; 33.7%), followed by “it hasn’t changed (I did not think about problems a lot before)” (11/163; 6.7%), followed by (1/163; 0.6%) of respondents reporting thinking about problems more than before.

Amongst those who reported experiencing anxiety, adjusted logistic models comparing those who responded that CBD reduces their self-perceived anxiety with those who responded that they still suffer from anxiety found no associations with age, sex, or location. Similar results emerged for “thinking about problems”.

Self-perceived stress

One hundred forty-five of 387 (37.5%) of respondents endorsed the use of CBD for self-perceived stress. Amongst those using CBD for stress, in response to the question “how does CBD affect your stress level”, participants responded that they felt less stressed (130/141; 92.2% followed by it does not affect my stress levels (I still feel stressed) (11/141; 7.8%). No respondent said that it increased their stress level. Adjusted logistic models comparing those who responded that CBD reduces their stress versus those who responded that they still have stress found no associations with age, sex, or location.

Self-perceived sleep problems

As we initially designed the study to address sleep, we asked detailed questions regarding this. Improving sleep (125/387; 32.3%) and self-perceived insomnia (95/387; 24.5%) were the fourth and fifth-ranked endorsed reasons for using CBD, overall 42.5% endorsed sleep as a reason for use. Respondents said that CBD helped them sleep (see Fig. 2). As we restricted this analysis to respondents who selected using CBD for sleep improvement, there was considerable overlap between using CBD for sleep improvement and self-perceived insomnia. Regarding questions about the time it takes to fall asleep, 48.2%(73/124;) said CBD led them to fall asleep faster, followed by 29/124 (23.4%) who said it did not make a difference and still have a hard time falling asleep, followed by 22/124 (17.7%) who said it did not make a difference because they did not have a problem falling asleep beforehand. Age, sex, and location were not associated with the speed of falling asleep.

Other reported benefits

We asked participants to report on other effects they experience. From a total of 960 responses, the most prevalent effect was calm (21.3%), followed by decreased pain (19.5%) (see Fig. 3). One per cent reported feeling euphoric/high. In examining the “other” responses, 27/960 (9.3%) reported that they did not feel any benefits from the use of CBD.

Sex was associated with sexual enhancement where males reported experiencing more sexual enhancement (9.9%) than females (2.9%) (aOR 0.274, [95% CI 0.11–0.70], p = 0.007). There were no other associations between sex and other CBD benefits. Those aged 55+ (23.1%; aOR 3.8, [95% CI 1.63–8.87], p = 0.002) and those aged 35–54 years old (16.8%; aOR 2.72, [95% CI 1.258–5.876], p = 0.011) reported taking less of their other medications in comparison to those aged under 34 years old (9.9%). Those ages 55+ reported experiencing more “no positive experiences” (14.3%) in comparison to those under 34 (2.7%; aOR 5.31, [95% CI 1.45–19.41], p = 0.012).

CBD side-effects

A total of 388 responses were made, of whom 277/388 (71%) were logged as not experiencing any side-effects. Dry mouth was experienced by 44/388 (11%), and 13/288 (3%) experienced fatigue. All other side-effects were reported less than 2% (e.g. dizziness, nausea, upset stomach, rapid heartbeat, diarrhoea, headache, anxiety, psychotic symptoms, sexual problems, trouble concentrating). No respondents reported vomiting, fainting, liver problems (raised liver enzymes in blood test), or seizures. Adjusted logistic models show no associations of age, of sex with “no side effects” or fatigue. Location of the participants was associated with dry mouth, those who lived outside of the UK had greater odds of experiencing dry mouth (aOR 2.44, [95% CI 1.25–4.75], p = 0.009). No other side-effects were analysed due to the small number of respondents citing other side-effects.

Discussion

This study aimed to investigate CBD use patterns in the general population regarding the route of administration, dose, and indications for use. We found that the main indications for using CBD were self-perceived anxiety, stress, general health and wellbeing, sleep, and pain.

User characteristics and reason for use

More than half of the users were using a daily dose below 50 mg via a sublingual route of administration. Most were using CBD daily, sometimes multiple times per day. We found that respondents who use CBD for self-perceived anxiety and stress tend to use it several times per day, whilst respondents endorsing using CBD for sleep take it in the evening, indicating that user patterns vary according to the symptoms. A recent review suggests half-life is between 1.4 and 10.9 h after oromucosal spray and 2–5 days after chronic oral administration (Iffland and Grotenhermen 2017). In the light of these findings, it may be that people are dosing CBD several times per day to maintain stable plasma levels throughout the day if managing symptoms of stress and anxiety, whilst only using CBD at night if managing sleep problems.

We found that 69.7% of users had been using CBD for less than 1 year. Moreover, only 4.1% had used CBD for more than 5 years, reflecting both that it is a fairly new phenomenon and an increasing interest in CBD in the UK, compared with the USA. A similar American survey reported that 34.6% had used CBD for less than 1 year and 53.2% more than 5 years (Corroon and Phillips 2018). At the time of writing, CBD is legal in all but three, out of fifty, American states, and many of these allow the products to contain THC. In the UK and Europe, non-prescription CBD products are not allowed to contain any THC (< 0.01%). These differences might create a divergence between European vs American consumers’ experiences, and stresses the urgency for internal and external regulation, and education about cannabinoids in Europe.

We found age and sex differences in the reason for CBD use. Most of the sample was female, but males had greater odds of using CBD for general health and wellbeing and post-workout for sore muscles. In contrast, females were more likely to use CBD for self-perceived anxiety and insomnia, reflecting the higher prevalence of both symptoms amongst women (McLean et al. 2011; Li et al. 2002). We also found more females using CBD for fibromyalgia, possibly reflecting the much higher prevalence of fibromyalgia amongst women (Yunus 2002). A recent study compared the subjective effects of 100 mg oral versus vaporised and smoked CBD and found that women reported experiencing more subjective effects of CBD than men (Spindle et al. 2020), which may reflect why women were using CBD for more chronic symptomology. There were also significant age differences, with more people under 34 years old using CBD for general health and wellbeing than older age groups, which might be explained in part by the fact that disease burden generally increases with age. More young people use CBD to reduce self-perceived stress and anxiety, aligning with studies finding young people are more troubled by symptoms of anxiety than older people (Brenes et al. 2008).

In the present study, we found that the largest proportion of respondents used CBD to help with mental health symptoms like perceived anxiety, stress, and sleep problems. This finding aligns with a previous CBD survey that found that anxiety and insomnia were amongst the top 6 reasons for using CBD (Corroon and Phillips 2018). However, Corroon et al. found that the two main reasons for using CBD was arthritis/joint pain and chronic pain, whereas these ranked number six and seven amongst reasons from our respondents. This result may reflect the younger demographics of our sample compared with Corroon et al.

With few variations, the reasons for use in our study were somewhat similar to the results from another study of 400 patients in New Zealand, who were all prescribed sublingual CBD oil with doses ranging from 40 to 300 mg/day (Gulbransen et al. 2020). This study found that the patients had an increase in overall quality of life, including improved sleep and decreased self-perceived anxiety levels and reduced pain scores.

Route of administration, dosing, and side-effects

Younger respondents were more likely to use novel routes of administration, e.g., vaping or drinking. This trend correlates with data showing that more people have tried vaping (in general) amongst younger age groups (Vaping and e-cigarette use by age U.S 2018). Only 9.3% reported vaping CBD in our sample, compared with 19% in the study by Corroon et al. (Corroon and Phillips 2018). The fast onset of vaporised CBD might explain why inhaled CBD is popular for self-perceived anxiety and stress.

Corroon et al. found a more even distribution between various application methods with the most popular being sublingual CBD (23% vs 72,6% in our study sample). Our approach of recruiting respondents through email databases of non-vape CBD brands may explain why the sublingual administration route is much more frequent in our study than in the American survey.

The bioavailability of CBD varies by route of administration (Millar et al. 2019), but is generally low, between 10 and 31% (Millar et al. 2018). Oral routes have the lowest bioavailability due to first-pass metabolism, whilst inhaled routes have the highest bioavailability (Ohlsson et al. 1986). The bioavailability of sublingual CBD is between 13 and 19% (Mechoulam et al. 2002), and greater than the oral route, thus exerting effects at much lower doses, making it more efficient for users. Investigating plasma levels of low-dose sublingual CBD users, and correlating them to the subjective experience, might give important insights into the optimal dose for treating these low-level mental health problems like self-perceived stress, anxiety, and sleep problems.

Most people were using less than 100 mg (72.9%) per day. Due to the high price and the lack of medical supervision, it is not surprising that non-medical CBD users are taking much lower doses than those used in clinical studies, and those prescribed for specific medical conditions (Davies and Bhattacharyya 2019; Szaflarski et al. 2018). It is important to highlight that 16.8% reported using more than 100 mg per day, and 10.2% did not know how much CBD they were using. The use of high doses CBD is concerning in light of the current FSA recommendation of restricting the dose to 70 mg CBD per day (Cannabidiol (CBD) n.d.), and it stresses the importance of better public information and communication and improved packaging and guidance from brands to consumers.

Amongst our study sample, almost 11% experienced having a dry mouth, most likely indicating levels of THC in the product, as this is a common side effect of THC rather than CBD (Darling and Arendorf 1993; LaFrance et al. 2020). People living outside of the UK had higher odds of experiencing a dry mouth, which might be explained by the different legislation regarding permitted THC content and CBD quality between countries. This differentiation leads to some concerns about product safety, consistency, and ultimately trust amongst CBD consumers. A recent study of 29 CBD products showed that only 11% contained within 10% of the advertised CBD concentration, 55% of the products had traces of controlled substances such as THC (Liebling et al. 2020). There is still a need for external and internal control within the CBD industry to ensure consumer safety is prioritised.

CBD and self-perceived stress

37.5% of respondents reported using CBD for perceived stress, with 92.2% reporting reduced stress levels, making it the third-highest ranking reason for CBD use amongst our sample. Yet, no studies are looking directly at how CBD affects perceived stress levels. This might in part be because stress, apart from post-traumatic stress disorder, is not classified as a disease according to international disease classification (WHO | Burn-out an “occupational phenomenon”: International Classification of Diseases 2019). With more than 12.8 million working days lost because of work-related stress, anxiety, or depression in the UK (Hse 2019), the relationship between CBD and stress is an area of interest for further research. A recent study surveying social media for comments about perceived therapeutic effects of CBD products revealed that the most frequently discussed symptoms, which are not addressed in the research literature, are indeed stress and nausea (Tran and Kavuluru 2020).

CBD and self-perceived anxiety

Self-perceived anxiety was the top-ranked reason for the use of CBD with 42.6% reporting they take CBD for this reason. Of these, 86.5% reported they felt less anxiety. There are biologically plausible reasons for the use of CBD in anxiety. Pharmacological research suggests CBD is a partial 5-HT1a receptor agonist which supports anxiolytic and stress-reducing properties (Russo et al. 2005; Resstel et al. 2009), the activation of which has been associated with anxiolytic, antidepressant, and antipsychotic effects (Zuardi et al. 1993; Bergamaschi et al. 2011; de Faria et al. 2020; Vilazodone for major depressive disorder | MDedge Psychiatry n.d.; Newman-Tancredi and Kleven 2011). CBD also modulates specifically configured GABAA receptors that may be relevant to anxiolytic effects (Bakas et al. 2017; Deshpande et al. 2011). CBD is anxiolytic under experimental conditions in animals, healthy humans and in those with generalised social anxiety disorder (de Faria et al. 2020; Elms et al. 2019; Newman-Tancredi and Kleven 2011) although large clinical trials have not been conducted. Crippa et al. administered an oral dose of 400 mg CBD or placebo, in a double-blind procedure. They found it significantly lowered feelings of anxiety, accompanying changes in limbic areas, in subjects with social anxiety disorder (SAD) (Crippa et al. 2011). Similar results were seen in a small randomised trial using a public speaking test with 600 mg CBD vs placebo (Bergamaschi et al. 2011).

CBD and self-perceived sleep problems

In our survey, sleep was the second-highest-ranking reason for CBD use. We found that 42.5% used CBD to help with sleep, which is higher than for previously published data on adult CBD users, where it was the fifth-highest reason (Corroon and Phillips 2018). It is well-known that a lack of sleep can cause a variety of physical and mental health effects including raised levels of cortisol(Leproult et al. 1997), anxiety (Babson et al. 2010), and mood disturbances (Brazeau et al. 2010), and both short and long duration of sleep is a significant predictor of death (Cappuccio et al. 2010). A recent controlled study of 300 mg CBD found no effect on any sleep indices (Linares et al. 2018), whilst observational and cross-sectional studies showed improvement in sleep outcomes (Corroon and Phillips 2018; Gulbransen et al. 2020). Preclinical studies have shown mixed results with some doses showing an increase in total sleep time (Chagas et al. 2013) and another study indicating that CBD causes increased wakefulness (Murillo-Rodríguez et al. 2006). Thus, the research on CBD and sleep thus far is mixed. However, as sedation and somnolence are regarded as common adverse effects of CBD in a meta-analysis of clinical trials where high doses are used (Chesney et al. 2020), it may not be surprising that CBD at low doses improved sleep quality and duration.

Given the low quality of CBD available on the market, it may be that these individuals were not taking CBD, or that CBD is not efficacious in sleep, so many individuals report better sleep by virtue of the placebo effect, fuelled by marketing (Haney 2020). Another reason may be that CBD is acting on other aspects of stress and anxiety that indirectly reduce sleep problems. Still, in this survey, participants directly attributed improved sleep to CBD. This points to the need for RCTs, as the effect of expectations (i.e. the result of the placebo effect), particularly with compounds advertised as cure-alls (Haney 2020). Suggesting that the placebo effect may contribute to the purported impact of CBD does not reject the potential medical value of CBD, but it does mean we must be wary of the results of observational studies (Haney 2020).

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Strengths and limitations

Our measures were retrospective self-reported symptoms, rather than contemporaneous reports or object assessments, and thus prone to recall bias. This approach may lead to over- or under-estimation of benefits and harms. In reporting anxiety symptoms, it should be noted that many anxiety measures are self-reported, and scales are often an accurate measure of anxiety. Stress itself is not often measured, but scales assessing self-reported stress are reliable (Morgan et al. 2014). Regarding sleep problems, our measures do not accurately correspond with objective measures of sleep such as actigraphy (Girschik et al. 2012), which has implications in the epidemiology of sleep, including in the present study. Future research should use validated measures of anxiety, stress, and sleep. However, it should be noted we included responses to gain an insight where CBD may not help, with about 20% responding that CBD did not help with sleep or anxiety and about 10% saying CBD did not help with stress. There is also a risk of selection biases regarding our recruitment method from email databases of current users and social media recruiting. As we had a self-selected sample, we do not represent the general population or even the overall population of CBD users. It is more likely that respondents with a positive experience have responded to this survey, and continue to use CBD. Still, users with a negative experience may have stopped using CBD and therefore were not reached by this survey, which might further contribute to the selection biases.

Conclusion

The survey demonstrated that CBD is used for a wide range of physical and mental health symptoms and improved general health and wellbeing. A majority of the sample surveyed in this study found that CBD helped their symptoms, and they often used doses below 50 mg. Out of the four most common symptoms, three were related to mental health. Self-perceived stress, anxiety, and sleep problems constitute some of society’s biggest health problems, but we lack adequate treatment options. Further research is needed into whether CBD can efficiently and safely help treat these symptoms.

Availability of data and materials

The datasets used and analysed during the current study are available from the corresponding author on reasonable request.

Cannabidiol in Anxiety and Sleep: A Large Case Series

Cannabidiol (CBD) is one of many cannabinoid compounds found in cannabis. It does not appear to alter consciousness or trigger a “high.” A recent surge in scientific publications has found preclinical and clinical evidence documenting value for CBD in some neuropsychiatric disorders, including epilepsy, anxiety, and schizophrenia. Evidence points toward a calming effect for CBD in the central nervous system. Interest in CBD as a treatment of a wide range of disorders has exploded, yet few clinical studies of CBD exist in the psychiatric literature.

Objective

To determine whether CBD helps improve sleep and/or anxiety in a clinical population.

Design

A large retrospective case series at a psychiatric clinic involving clinical application of CBD for anxiety and sleep complaints as an adjunct to usual treatment. The retrospective chart review included monthly documentation of anxiety and sleep quality in 103 adult patients.

Main Outcome Measures

Sleep and anxiety scores, using validated instruments, at baseline and after CBD treatment.

Results

The final sample consisted of 72 adults presenting with primary concerns of anxiety (n = 47) or poor sleep (n = 25). Anxiety scores decreased within the first month in 57 patients (79.2%) and remained decreased during the study duration. Sleep scores improved within the first month in 48 patients (66.7%) but fluctuated over time. In this chart review, CBD was well tolerated in all but 3 patients.

Conclusion

Cannabidiol may hold benefit for anxiety-related disorders. Controlled clinical studies are needed.

INTRODUCTION

The Cannabis plant has been cultivated and used for its medicinal and industrial benefits dating back to ancient times. Cannabis sativa and Cannabis indica are the 2 main species.1 The Cannabis plant contains more than 80 different chemicals known as cannabinoids. The most abundant cannabinoid, tetrahydrocannabinol (THC), is well known for its psychoactive properties, whereas cannabidiol (CBD) is the second-most abundant and is nonpsychoactive. Different strains of the plant are grown containing varying amounts of THC and CBD. Hemp plants are grown for their fibers and high levels of CBD that can be extracted to make oil, but marijuana plants grown for recreational use have higher concentrations of THC compared with CBD.2 Industrial hemp must contain less than 0.3% THC to be considered legal, and it is from this plant that CBD oil is extracted.3

Many different cultures have used the Cannabis plant to treat a plethora of ailments. Practitioners in ancient China targeted malaria, menstrual symptoms, gout, and constipation. During medieval times, cannabis was used for pain, epilepsy, nausea, and vomiting, and in Western medicine it was commonly used as an analgesic.4,5 In the US, physicians prescribed Cannabis sativa for a multitude of illnesses until restrictions were put in place in the 1930s and then finally stopped using it in 1970 when the federal government listed marijuana as a Schedule I substance, claiming it an illegal substance with no medical value. California was the first state to go against the federal ban and legalize medical marijuana in 1996.6 As of June 2018, 9 states and Washington, DC, have legalized recreational marijuana, and 30 states and Washington, DC, allow for use of medical marijuana.7 The purpose of the present study is to describe the effects of CBD on anxiety and sleep among patients in a clinic presenting with anxiety or sleep as a primary concern.

CBD has demonstrated preliminary efficacy for a range of physical and mental health care problems. In the decade before 2012, there were only 9 published studies on the use of cannabinoids for medicinal treatment of pain; since then, 30 articles have been published on this topic, according to a PubMed search conducted in December 2017. Most notable was a study conducted at the University of California, San Diego’s Center for Medicinal Cannabis Research that showed cannabis cigarettes reduced pain by 34% to 40% compared with placebo (17% to 20% decrease in pain).8 In particular, CBD appears to hold benefits for a wide range of neurologic disorders, including decreasing major seizures. A recent large, well-controlled study of pediatric epilepsy documented a beneficial effect of CBD in reducing seizure frequency by more than 50%.9 In addition to endorphin release, the “runner’s high” experience after exercise has been shown to be induced in part by anandamide acting on CB1 receptors, eliciting anxiolytic effects on the body.10 The activity of CBD at 5-HT1A receptors may drive its neuroprotective, antidepressive, and anxiolytic benefits, although the mechanism of action by which CBD decreases anxiety is still unclear.11 CBD was shown to be helpful for decreasing anxiety through a simulated public speaking test at doses of 300 mg to 600 mg in single-dose studies.12–14 Other studies suggest lower doses of 10 mg/kg having a more anxiolytic effect than higher doses of 100 mg/kg in rats.15 A crossover study comparing CBD with nitrazepam found that high-dose CBD at 160 mg increased the duration of sleep.16 Another crossover study showed that plasma cortisol levels decreased more significantly when given oral CBD, 300 to 600 mg, but these patients experienced a sedative effect.17 The higher doses of CBD that studies suggest are therapeutic for anxiety, insomnia, and epilepsy may also increase mental sedation.16 Administration of CBD via different routes and long-term use of 10 mg/d to 400 mg/d did not create a toxic effect on patients. Doses up to 1500 mg/d have been well tolerated in the literature.18 Most of the research done has been in animal models and has shown potential benefit, but clinical data from randomized controlled experiments remain limited.

Finally, the most notable benefit of cannabis as a form of treatment is safety. There have been no reports of lethal overdose with either of the cannabinoids and, outside of concerns over abuse, major complications are very limited.19 Current research indicates that cannabis has a low overall risk with short-term use, but more research is needed to clarify possible long-term risks and harms.

Given the promising biochemical, physiologic, and preclinical data on CBD, a remarkable lack of randomized clinical trials and other formal clinical studies exist in the psychiatric arena. The present study describes a series of patients using CBD for treatment of anxiety or sleep disturbances in a clinical practice setting. Given the paucity of data in this area, clinical observations can be quite useful to advance the knowledge base and to offer questions for further investigation. This study aimed to determine whether CBD is helpful for improving sleep and/or anxiety in a clinical population. Given the novel nature of this treatment, our study also focused on tolerability and safety concerns. As a part of the evolving legal status of cannabis, our investigation also looked at patient acceptance.

METHODS

Design and Procedures

A retrospective chart review was conducted of adult psychiatric patients treated with CBD for anxiety or sleep as an adjunct to treatment as usual at a large psychiatric outpatient clinic. Any current psychiatric patient with a diagnosis by a mental health professional (psychiatrist, psychiatric nurse practitioner, or physician assistant) of a sleep or anxiety disorder was considered. Diagnosis was made by clinical evaluation followed by baseline psychologic measures. These measures were repeated monthly. Comorbid psychiatric illnesses were not a basis for exclusion. Accordingly, other psychiatric medications were administered as per routine patient care. Selection for the case series was contingent on informed consent to be treated with CBD for 1 of these 2 disorders and at least 1 month of active treatment with CBD. Patients treated with CBD were provided with psychiatric care and medications as usual. Most patients continued to receive their psychiatric medications. The patient population mirrored the clinic population at large with the exception that it was younger.

Nearly all patients were given CBD 25 mg/d in capsule form. If anxiety complaints predominated, the dosing was every morning, after breakfast. If sleep complaints predominated, the dosing was every evening, after dinner. A handful of patients were given CBD 50 mg/d or 75 mg/d. One patient with a trauma history and schizoaffective disorder received a CBD dosage that was gradually increased to 175 mg/d.

Often CBD was employed as a method to avoid or to reduce psychiatric medications. The CBD selection and dosing reflected the individual practitioner’s clinical preference. Informed consent was obtained for each patient who was treated and considered for this study. Monthly visits included clinical evaluation and documentation of patients’ anxiety and sleep status using validated measures. CBD was added to care, dropped from care, or refused as per individual patient and practitioner preference. The Western Institutional Review Board, Puyallup, WA, approved this retrospective chart review.

Setting and Sample

Wholeness Center is a large mental health clinic in Fort Collins, CO, that focuses on integrative medicine and psychiatry. Practitioners from a range of disciplines (psychiatry, naturopathy, acupuncture, neurofeedback, yoga, etc) work together in a collaborative and cross-disciplinary environment. CBD had been widely incorporated into clinical care at Wholeness Center a few years before this study, on the basis of existing research and patient experience.

The sampling frame consisted of 103 adult patients who were consecutively treated with CBD at our psychiatric outpatient clinic. Eighty-two (79.6%) of the 103 adult patients had a documented anxiety or sleep disorder diagnosis. Patients with sole or primary diagnoses of schizophrenia, posttraumatic stress disorder, and agitated depression were excluded. Ten patients were further excluded because they had only 1 documented visit, with no follow-up assessment. The final sample consisted of 72 adult patients presenting with primary concerns of anxiety (65.3%; n = 47) or poor sleep (34.7%; n = 25) and who had at least 1 follow-up visit after CBD was prescribed.

Main Outcome Measures

Sleep and anxiety were the targets of this descriptive report. Sleep concerns were tracked at monthly visits using the Pittsburg Sleep Quality Index. Anxiety levels were monitored at monthly visits using the Hamilton Anxiety Rating Scale. Both scales are nonproprietary. The Hamilton Anxiety Rating Scale is a widely used and validated anxiety measure with 14 individual questions. It was first used in 1959 and covers a wide range of anxiety-related concerns. The score ranges from 0 to 56. A score under 17 indicates mild anxiety, and a score above 25 indicates severe anxiety. The Pittsburg Sleep Quality Index is a self-report measure that assesses the quality of sleep during a 1-month period. It consists of 19 items that have been found to be reliable and valid in the assessment of a range of sleep-related problems. Each item is rated 0 to 3 and yields a total score from 0 to 21. A higher number indicates more sleep-related concerns. A score of 5 or greater indicates a “poor sleeper.”

Side effects and tolerability of CBD treatment were assessed through spontaneous patient self-reports and were documented in case records. Any other spontaneous comments or complaints of patients were also documented in case records and included in this analysis.

Data Analysis

Deidentified patient data were evaluated using descriptive statistics and plotted graphically for visual analysis and interpretation of trends.

RESULTS

The average age for patients with anxiety was 34 years (range = 18–70 years) and age 36.5 years for patients with sleep disorders (range = 18–72 years). Most patients with an anxiety diagnosis were men (59.6%, 28/47), whereas more sleep-disordered patients were women (64.0%, 16/25). All 72 patients completed sleep and anxiety assessments at the onset of CBD treatment and at the first monthly follow-up. By the second monthly follow-up, 41 patients (56.9%) remained on CBD treatment and completed assessments; 27 patients (37.5%) remained on CBD treatment at the third monthly assessment.

Table 1 provides means and standard deviations for sleep and anxiety scores at baseline and during the follow-up period for adults taking CBD. Figure 1 graphically displays the trend in anxiety and sleep scores over the study period. On average, anxiety and sleep improved for most patients, and these improvements were sustained over time. At the first monthly assessment after the start of CBD treatment, 79.2% (57/72) and 66.7% (48/72) of all patients experienced an improvement in anxiety and sleep, respectively; 15.3% (11/72) and 25.0% (18/72) experienced worsening symptoms in anxiety and sleep, respectively. Two months after the start of CBD treatment, 78.1% (32/41) and 56.1% (23/41) of patients reported improvement in anxiety and sleep, respectively, compared with the prior monthly visit; again, 19.5% (8/41) and 26.8% (11/41), respectively, reported worsening problems as compared with the prior month.

These results demonstrated a more sustained response to anxiety than for sleep over time. Patient records displayed a larger decrease in anxiety scores than in sleep scores. The sleep scores demonstrated mild improvement. The anxiety scores decreased within the first month and then remained decreased during the study duration.

CBD was well tolerated, with few patients reporting side effects. Two patients discontinued treatment within the first week because of fatigue. Three patients noted mild sedation initially that appeared to abate in the first few weeks. One patient with a developmental disorder (aged 21 years) had to be taken off the CBD regimen because of increased sexually inappropriate behavior. The CBD was held, and the behavior disappeared. The behavior reappeared on redosing 2 weeks later, and the CBD regimen was formally discontinued. The treating psychiatrist thought this was related to disinhibition because the patient’s anxiety responded dramatically. One patient noted dry eyes. Reasons for patients not following-up at later assessment points are largely unknown but are probably because of standard attrition experienced in usual clinical practice. There was no evidence to suggest patients discontinued care because of tolerability concerns. The attrition rates were similar in nature and size to those found in routinely scheduled visits in this clinic.

The treatment with CBD was in general well accepted, as judged by the clinicians’ and patients’ responses. Four patients declined CBD treatment because of religious or ethical concerns about the relation to cannabis. Nearly all patients easily provided informed consent once the nature of the treatment was explained. Most patients appreciated the opportunity to try something natural and avoid further or initial psychiatric medication use.

DISCUSSION

In an outpatient psychiatric population, sleep scores displayed no sustained improvements during the 3-month study. Anxiety scores decreased fairly rapidly, and this decrease was sustained during the study period. These results are consistent with the existing preclinical and clinical data on CBD. CBD was well accepted and well tolerated in our patients. Side effects were minimal (mainly fatigue) and may be related to dosing.

The doses used in this study (25 mg/d to 175 mg/d) were much lower than those reported in some of the clinical literature (300 mg/d to 600 mg/d)12–14,17 for 2 reasons. The first is that in our experience lower doses appear to elicit an adequate clinical response. Second, the current retail cost of CBD would make the use of 600 mg/d cost prohibitive.

Study Limitations

These results must be interpreted cautiously because this was a naturalistic study, all patients were receiving open-label treatment, and there was no comparison group. Concurrent psychiatric medications were employed as in routine clinical care. This is both a limitation and strength, as very few publications exist in this population. Other researchers have noted that the large societal notoriety about cannabis and medical marijuana probably contributes to a larger-than-normal placebo effect.20 Any study that explores efficacy in this therapy probably will struggle with a potentially inflated placebo effect that will make these determinations more difficult. Likewise, the clinical population in this case series is skewed younger than typical for our clinic, and future studies could explore the possible selection bias inherent in this treatment option. Most patients were also taking psychiatric medications and receiving other mental health services, such as counseling, which limits the ability to make any causal links to CBD treatment. Clinical attrition is evident in the dataset. The reason for this might be related to CBD ingestion or not, so the overall component remains unclear. Furthermore, patients at our clinic often express a desire to reduce or to avoid use of psychiatric medications, which may contribute to an enhanced placebo effect or additional bias. The length of clinical monitoring may help to decrease this concern. However, the clinical data in this analysis show a trend toward clinically significant relief of anxiety upon the start of CBD treatment.

Legality of Cannabidiol

The legality of CBD is not clear. Like the issues surrounding the legality of cannabis in general, CBD presents the clinician with a confusing state vs federal legal quandary, and this keeps the issue in question. CBD is legal in the 33 states that have legalized medical or recreational use of marijuana and in 17 other states that have legalized some form of CBD, according to the National Organization for the Reform of Marijuana Laws (NORML).21 But like marijuana, it is still not legal at the federal level. The federal government has announced that it is not focused on this compound in terms of enforcement or interdiction.22 However, CBD is interpreted by the Drug Enforcement Administration, Food and Drug Administration, and Congress to be a Schedule I substance, and therefore it is illegal in all 50 states.23 Pragmatically, CBD is widely available on the Internet, with sales expected to reach $1 billion by 2020. Pending federal legislation to redefine the legal status of cannabis would clarify this complex issue. Canada’s move to legalize cannabis in October 2018 further highlights the need for a speedy resolution to this question.24

CONCLUSION

Formal studies on efficacy and dose finding are much needed. Some urgency exists, given the explosion of lay interest in this topic and the rush to market these compounds. Current understanding of the physiology and neurologic pathways points to a benefit with anxiety-related issues. The results of our clinical report support the existing scientific evidence. In our study, we saw no evidence of a safety issue that would limit future studies. In this evaluation, CBD appears to be better tolerated than routine psychiatric medications. Furthermore, CBD displays promise as a tool for reducing anxiety in clinical populations, but given the open-label and nonrandomized nature of this large case series, all results must be interpreted very cautiously. Randomized and controlled trials are needed to provide definitive clinical guidance.

Acknowledgments

CV Sciences Inc, Las Vegas, NV, provided cannabidiol products for the study. CV Sciences was not involved in the data collection, data interpretation, preparation of the report, or decision to submit the report for publication. No other financial support was provided. The authors would like to express their deep appreciation to the staff and clinicians at Wholeness Center for their professionalism.

Kathleen Louden, ELS, of Louden Health Communications provided editorial assistance.

Footnotes

Disclosure Statement

Dr Shannon has published several professional books on integrative mental health. Dr Shannon is a Principal Investigator for a Phase 3 study of 3,4-methylenedioxy-methamphetamine (MDMA)-assisted psychotherapy for severe posttraumatic stress disorder and receives compensation for his clinical work from the Multidisciplinary Association for Psychedelic Studies, Santa Cruz, CA. The other authors have no conflicts of interests to disclose.

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