Cannabidiol (CBD)-what we know and what we don’t
Cannabidiol (CBD) is often covered in the media, and you may see it touted as an add-in booster to your post-workout smoothie or morning coffee. You can even buy a CBD-infused sports bra. But what exactly is CBD? And why is it so popular?
How is cannabidiol different from marijuana, cannabis and hemp?
CBD, or cannabidiol, is the second most prevalent active ingredient in cannabis (marijuana). While CBD is an essential component of medical marijuana, it is derived directly from the hemp plant, a cousin of marijuana, or manufactured in a laboratory. One of hundreds of components in marijuana, CBD does not cause a “high” by itself. According to a report from the World Health Organization, “In humans, CBD exhibits no effects indicative of any abuse or dependence potential…. To date, there is no evidence of public health related problems associated with the use of pure CBD.”
Is cannabidiol legal?
CBD is readily obtainable in most parts of the United States, though its exact legal status has been in flux. All 50 states have laws legalizing CBD with varying degrees of restriction. In December 2015, the FDA eased the regulatory requirements to allow researchers to conduct CBD trials. In 2018, the Farm Bill made hemp legal in the United States, making it virtually impossible to keep CBD illegal – that would be like making oranges legal, but keeping orange juice illegal.
The Farm Bill removed all hemp-derived products, including CBD, from the Controlled Substances Act, which criminalizes the possession of drugs. In essence, this means that CBD is legal if it comes from hemp, but not if it comes from cannabis (marijuana) – even though it is the exact same molecule. Currently, many people obtain CBD online without a medical marijuana license, which is legal in most states.
The evidence for cannabidiol health benefits
CBD has been touted for a wide variety of health issues, but the strongest scientific evidence is for its effectiveness in treating some of the cruelest childhood epilepsy syndromes, such as Dravet syndrome and Lennox-Gastaut syndrome (LGS), which typically don’t respond to antiseizure medications. In numerous studies, CBD was able to reduce the number of seizures, and, in some cases, stop them altogether. Epidiolex, which contains CBD, is the first cannabis-derived medicine approved by the FDA for these conditions.
Animal studies, and self-reports or research in humans, suggest CBD may also help with:
Studies and clinical trials are exploring the common report that CBD can reduce anxiety.
- Insomnia. Studies suggest that CBD may help with both falling asleep and staying asleep.
- Chronic pain. Further human studies are needed to substantiate claims that CBD helps control pain. One animal study from the European Journal of Pain suggests CBD could help lower pain and inflammation due to arthritis when applied to skin. Other research identifies how CBD may inhibit inflammatory and neuropathic pain, which are difficult treat.
- Addiction. CBD can help lower cravings for tobacco and heroin under certain conditions, according to some research in humans. Animal models of addiction suggest it may also help lessen cravings for alcohol, cannabis, opiates, and stimulants.
Is CBD safe?
Side effects of CBD include nausea, fatigue and irritability. CBD can increase the level of blood thinning and other medicines in your blood by competing for the liver enzymes that break down these drugs. Grapefruit has a similar effect with certain medicines.
People taking high doses of CBD may show abnormalities in liver related blood tests. Many non-prescription drugs, such as acetaminophen (Tylenol), have this same effect. So, you should let your doctor know if you are regularly using CBD.
A significant safety concern with CBD is that it is primarily marketed and sold as a supplement, not a medication. Currently, the FDA does not regulate the safety and purity of dietary supplements. So, you cannot be sure that the product you buy has active ingredients at the dose listed on the label. In addition, the product may contain other unknown elements. We also don’t know the most effective therapeutic dose of CBD for any particular medical condition.
How can CBD be taken?
CBD comes in many forms, including oils, extracts, capsules, patches, vapes, and topical preparations for use on skin. If you’re hoping to reduce inflammation and relieve muscle and joint pain, a topical CBD-infused oil, lotion or cream – or even a bath bomb — may be the best option. Alternatively, a CBC patch or a tincture or spray designed to be placed under the tongue allows CBD to directly enter the bloodstream.
Outside of the US, the prescription drug Sativex, which uses CBD as an active ingredient, is approved for muscle spasticity associated with multiple sclerosis and for cancer pain. Within the US, Epidiolex is approved for certain types of epilepsy and tuberous sclerosis.
The bottom line on cannabidiol
Some CBD manufacturers have come under government scrutiny for wild, indefensible claims, such that CBD is a cure-all for cancer or COVID-19, which it is not. We need more research but CBD may prove to be a helpful, relatively non-toxic option for managing anxiety, insomnia, and chronic pain. Without sufficient high-quality evidence in human studies, we can’t pinpoint effective doses, and because CBD currently is typically available as an unregulated supplement, it’s hard to know exactly what you are getting.
If you decide to try CBD, make sure you are getting it from a reputable source. And talk with your doctor to make sure that it won’t affect any other medicines you take.
How To Use CBD To Help Alleviate Anxiety
Dr. Bindiya Gandhi is an integrative medicine physician with expertise in functional and holistic medicine based in Atlanta, Georgia.
Commissions we earn from partner links on this page do not affect our opinions or evaluations. Our editorial content is based on thorough research and guidance from the Forbes Health Advisory Board.
Table of Contents
- CBD for Anxiety
- How to Use CBD for Anxiety
- CBD Dosage for Anxiety
- Potential Risks and Side Effects
While delta-9-tetrahydrocannabinol (THC) can have a bad rap for being intoxicating and anxiety-inducing, cannabidiol (CBD) can actually be used to relieve anxiety. Research supports this benefit, with several studies reinforcing the positive effects CBD can have on various anxiety conditions. In fact, 51% of U.S. adults who use CBD do so to help alleviate their anxiety, according to a recent Forbes Health survey of 2,000 U.S. adults conducted by OnePoll.
CBD isn’t yet legally cleared as an anxiolytic, or anxiety relief medication. Therefore, it’s up to you—and, ideally, a doctor who specializes in cannabis administration—to determine whether CBD is a safe treatment for your anxiety.
Here’s what the science says regarding CBD’s anxiolytic properties, along with experts’ dosage guidelines and advice on how to take CBD safely.
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CBD for Anxiety
The Food and Drug Administration (FDA) has yet to approve any CBD-based medications for anxiety. However, many studies indicate the substance can be an effective anxiolytic.
CBD for Generalized Anxiety
In 2011, a small trial-tested CBD on participants with generalized social anxiety disorder (SAD) and healthy control patients undergoing a simulated public speaking test (SPST), which is a common anxiety testing method  Bergamaschi MM, Queiroz RH, Chagas MH, et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology. 2011;36(6):1219-1226. . Compared to a placebo, CBD significantly reduced anxiety and discomfort in the participants with SAD. In fact, their reduced anxiety levels were comparable to those of the control participants.
Eight years later, a 2019 test compared the efficacy of three CBD doses (150 milligrams, 300 milligrams and 600 milligrams) and a placebo in men taking an SPST  Linares IM, Zuardi AW, Pereira LC, et al. Cannabidiol presents an inverted U-shaped dose-response curve in a simulated public speaking test. Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999). 2019;41(1):9-14. . Compared to a placebo, 300 milligrams of CBD significantly reduced participants’ anxiety during the speech, but the 150-milligram and 600-milligram doses did not. These results highlight how dosage can be highly variable and that more CBD isn’t necessarily more effective.
Meanwhile, another 2019 study tested CBD in much lower doses than most other clinical studies—some participants consumed 25 milligrams a day while others consumed 50 milligrams or 75 milligrams a day  Shannon S, Lewis N, Lee H, Hughes S. Cannabidiol in Anxiety and Sleep: A Large Case Series. Perm J. 2019;23:18-041. . Researchers thought higher doses might be too expensive for participants to maintain in their normal lives and that low doses would still prove effective. Indeed, anxiety decreased within the first month for most participants and remained low. Sleep quality also improved, although it fluctuated more than anxiety. Only three patients reported side effects.
CBD for Anxiety and Depression
In 2020, researchers tested the effects of CBD oil at varying doses across 397 patients with a variety of ailments  Gulbransen G, Xu W, Arroll B. Cannabidiol prescription in clinical practice: an audit on the first 400 patients in New Zealand. BJGP Open. 2020;4(1):bjgpopen20X101010. . Participants with non-cancer pain or mental health-related symptoms experienced significant improvement in anxiety and depression, as well as in their abilities to complete their usual activities. The use of CBD oil suggested significant pain relief in these groups as well.
CBD for PTSD and Phobia Therapy
A small 2019 study of 11 patients found that, when consumed orally and administered alongside routine psychiatric care, CBD decreased patients’ posttraumatic stress disorder (PTSD) symptom severity  Elms L, Shannon S, Hughes S, Lewis N. Cannabidiol in the Treatment of Post-Traumatic Stress Disorder: A Case Series. J Altern Complement Med. 2019;25(4):392-397. .
Other studies suggest CBD can reduce PTSD symptoms when consumed with THC  Bitencourt RM, Takahashi RN. Cannabidiol as a Therapeutic Alternative for Post-traumatic Stress Disorder: From Bench Research to Confirmation in Human Trials. Front Neurosci. 2018;12:502. . When taken together, the two compounds create what’s known as the “entourage effect,” where THC enhances the effects of CBD as CBD tempers the effects of THC, resulting in a more well-rounded experience  Ferber SG, Namdar D, Hen-Shoval D, et al. The “Entourage Effect”. Terpenes Coupled with Cannabinoids for the Treatment of Mood Disorders and Anxiety Disorders. Curr Neuropharmacol. 2020;18(2):87-96. .
Some studies also suggest CBD can enhance the effects of exposure therapy—which assists patients in dissociating certain cues with a fear response—and cognitive behavioral therapy  Das RK, Kamboj SK, Ramadas M, et al. Cannabidiol enhances consolidation of explicit fear extinction in humans. Psychopharmacology (Berl). 2013;226(4):781-792.  Blessing EM, Steenkamp MM, Manzanares J, Marmar CR. Cannabidiol as a Potential Treatment for Anxiety Disorders. Neurotherapeutics. 2015;12(4):825-836. .
How to Use CBD for Anxiety
Without clear FDA guidance, optimal CBD use for anxiety varies from person to person. You may find one method works better for you over another. You can consume CBD in the following forms:
- Oils and tinctures, which come in dropper bottles and are consumed by mouth
- Gummies, which are chewable, sweet and often fruit-flavored
- Sprays, which come in bottles with a nozzle to be sprayed in the mouth
- Capsules, softgels or tablets, which are taken individually by mouth like a pill
- Vapes, which heat CBD oil without igniting it, resulting in an inhalable vapor
- Flowers, which are dried hemp plants that are typically ignited and smoked
- Creams and gels, which introduce CBD topically (through the skin) as a more localized treatment
You may have to try different forms to determine what works best in addressing your anxiety. For instance, when it comes to the absorption of CBD in your bloodstream, vaping and smoking are more effective than edibles like gummies.
CBD Dosage for Anxiety
You also have to find the right CBD dosage for your anxiety. Experts suggest starting small and working your way up depending on how your body reacts.
Many clinical trials jump right to testing high doses. Successful doses evaluated for anxiety relief specifically include:
- 600 milligrams in patients with SAD in a speech simulation  Bergamaschi MM, Queiroz RH, Chagas MH, et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology. 2011;36(6):1219-1226.
- 300 milligrams in male patients in a speech simulation  Linares IM, Zuardi AW, Pereira LC, et al. Cannabidiol presents an inverted U-shaped dose-response curve in a simulated public speaking test. Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999). 2019;41(1):9-14.
However, other trials suggest much lower doses are also quite effective in treating anxiety.
- 25 to 75 milligrams for generalized anxiety and/or sleep problems  Shannon S, Lewis N, Lee H, Hughes S. Cannabidiol in Anxiety and Sleep: A Large Case Series. Perm J. 2019;23:18-041.
- 33 to 49 milligrams a day for PTSD, in addition to routine psychiatric treatment  Elms L, Shannon S, Hughes S, Lewis N. Cannabidiol in the Treatment of Post-Traumatic Stress Disorder: A Case Series. J Altern Complement Med. 2019;25(4):392-397.
Another study involving hundreds of patients noted success with doses from 40 milligrams to 300 milligrams a day, further supporting the idea that CBD dosage varies significantly, depending on a person’s symptoms and physiology.
Potential Risks and Side Effects
The World Health Organization deems CBD a safe and generally well-tolerated substance. Studies report very few adverse effects, if any.
However, taking CBD while on other medications may pose a risk, as these substances may interact and cause unwanted effects, such as weight gain, drowsiness, upset stomach and change in appetite.
Cheryl Bugailiskis, M.D., a cannabis specialist at Heally, a telehealth platform for alternative medicine, also warns people with preexisting liver injuries and people taking medications that can cause liver injuries should practice caution when using CBD.
Cannabidiol use and effectiveness: real-world evidence from a Canadian medical cannabis clinic
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).
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.
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.
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.
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 d’accès à l’information 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 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 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
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.
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.
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.
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 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).
CBD-rich products characteristics
The baseline average daily doses for CBD and THC are presented in Table 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.
Table 3 Details of the THC and CBD component of the CBD-rich, the THC:CBD 1:1, and the THC-rich formulations
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 4 and Fig. 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)
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 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. 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
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. 2a).
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. 2c).
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 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.
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.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.