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Cbd oil for pain management research

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.

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).

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 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.

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 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).

Anxiety

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. 2c).

Wellbeing

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.

Availability of data and materials

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

A Balanced Approach for Cannabidiol Use in Chronic Pain

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Abstract

Cannabidiol (CBD), the major non-psychoactive constituent of Cannabis sativa L., has gained traction as a potential treatment for intractable chronic pain in many conditions. Clinical evidence suggests that CBD provides therapeutic benefit in certain forms of epilepsy and imparts analgesia in certain conditions, and improves quality of life. CBD continues to be Schedule I or V on the list of controlled substances of the Drug Enforcement Agency of the United States. However, preparations labeled CBD are available publicly in stores and on the streets. However, use of CBD does not always resolve pain. CBD purchased freely entails the risk of adulteration by potentially hazardous chemicals. As well, CBD use by pregnant women is rising and poses a major health-hazard for future generations. In this mini-review, we present balanced and unbiased pre-clinical and clinical findings for the beneficial effects of CBD treatment on chronic pain and its deleterious effects on prenatal development.

Introduction

Cannabis and its components are being widely used for chronic pain, especially given the multifaceted and persistent nature of chronic pain in many conditions (Kalant, 2001). Cannabidiol (CBD), one of the major phytocannabinoids, has gained significant attraction because it is devoid of the psychoactive effects associated with tetrahydrocannabinol (THC), another major constituent of cannabis (Leweke et al., 2012). With the recent rescheduling (Schedule V) of CBD as Epidiolex for the treatment of Dravet and Lennox-Gastaut syndromes there has been a major shift in the view of these ancient molecules for their medicinal potential (Laux et al., 2019). Preclinical and clinical studies have indicated a potential benefit of CBD use in chronic pain associated with multiple conditions (Wade et al., 2003). However, increasing access to cannabis derived products especially CBD partly because of their approval for recreational and medicinal use in the United States poses risks with inadvertant side-effects from overuse, contamination with adulterants in preparation or harsh chemicals in the plant cultivation, and its teratogenicity in the offspring of users (Bonn-Miller et al., 2017; Young-Wolff et al., 2017; Rubin, 2019). In this mini-review we will evaluate literature discussing CBD use in treating intractable pain and the potential hazards of its overuse and/or misuse (see Figure 1 ).

Pros and cons of cannabidiol use in chronic pain.

Chronic Pain In The United States

Chronic pain affects between 50 and 116 million American adults, a staggering number that surpasses those affected by heart disease, cancer, and diabetes combined (Committee on Advancing Pain Research Care and Education, 2011; Nahin, 2015; NIH, 2020). In addition, these reports conclude that chronic pain costs between $560 and $635 billion annually in both medical expenses and lost productivity. Although there have been some recent therapeutic advances, many patients with chronic pain develop tolerance to conventional medical treatments or suffer adverse effects from widely used prescription medications, such as non-steroidal anti-inflammatory agents or opiates, that have high addictive potential (Labianca et al., 2012). As early as 2003, formulations containing CBD have been used in the clinic to study its efficacy in reducing pain when traditional treatment options have failed.

Reliability and Safety of Cannabidiol Labeled Products

Human use of Cannabis sativa L. for rituals and medicine dates back millennia, and it has made recent advances in treatment of varied conditions (Kalant, 2001; Whiting et al., 2015; Aviram and Samuelly-Leichtag, 2017; Ren et al., 2019). CBD is the major non-psychoactive constituent of cannabis and is also found in hemp, a subspecies of Cannabis sativa that does not produce psychoactive compounds in significant amounts (Pertwee, 2006; Hilderbrand, 2018). With the exception of Epidiolex, a Schedule V preparation, which is a pharmaceutical CBD extract from the plant, cannabis-derived CBD still remains a Schedule I substance according to the United States (US) Drug Enforcement Administration (Drug Enforcement Administration, 2018). However, the US Hemp Farming Act of 2018 legalized the cultivation and refinement of hemp and its constituents, thus beginning a trend of mass marketing for CBD products both legal and illegal (Hemp Production and the 2018 Farm Bill, 2019; Mead, 2019). In states where cannabis has been approved for recreational and/or medical use, there are efforts to equip dispensary staff with scientific knowledge to make evidence-based recommendations, but these efforts are limited and often overshadowed by anecdotal understanding of CBD and other cannabinoids (Haug et al., 2016; Piermarini and Viswanath, 2019). Of major concern, CBD-labeled products have flooded the markets, including, but not limited to, inhalants, bath salts, cookies, ointments, and liquids, for human use. Many forms tout medicinal value for claims that have not been scientifically evaluated. Reports indicate that the cannabinoid content in products purchased online were only accurate in 26 of the 84 products tested (Bonn-Miller et al., 2017). In a more recent report, safety of using unregulated CBD products has been questioned because, of 20 popular CBD products tested by CannaSafe, a cannabis-testing company in California, only 3 contained the contents claimed on the labels (Rubin, 2019). Of these, 2 products had no CBD, and about half of the CBD products had less than 20% of the CBD content claimed. Additionally, toxic gases and solvents were reported in some of these CBD products. Thus, these unregulated products labeled CBD may be a serious health hazard. An urgent need is to regulate CBD products after reliable testing to prevent the inadvertent harmful effects of unidentified constituents of products labeled CBD.

Clinical Outcomes for Cannabidiol in Intractable Chronic Pain

Since the early 2000s, clinical trials involving CBD for the treatment of chronic pain have shown effects ranging from placebo-equivalent to highly effective; many of these studies have been well-designed randomized, double-blinded, and placebo-controlled. In a mixed cohort of patients suffering from intractable pain due to multiple sclerosis, spinal cord injury, brachial plexus injury, and limb amputation, CBD treatment significantly reduced pain on a visual analog scale (Wade et al., 2003). However, these studies were often limited by small cohorts, and the varied disease states indicated that the beneficial effects of CBD are context dependent, which was illustrated in a study where treatment did not improve outcomes in patients suffering from Crohn’s disease (Naftali et al., 2014). CBD was also seemingly effective in treatment of chronic pain associated with kidney transplantation and when given topically to patients suffering from peripheral neuropathy of their lower extremities (Cuñetti et al., 2018; Xu et al., 2019). As well, in patients with fibromyalgia, CBD treatment decreased pain by more than 30% in significantly more patients than placebo (Van De Donk et al., 2019). In studies of generalized chronic pain, CBD treatment did not significantly reduce measures of pain, however there was consistent improvement in patient-reported quality of life and quality of sleep (Notcutt et al., 2004; Capano et al., 2020). A New Zealand study on the safety of CBD treatment in 400 non-cancer chronic pain patients indicated its safety for prolonged use, which was accompanied by self-reported improvements in pain and quality of life (Gulbransen et al., 2020).

The majority of clinical studies for the treatment of intractable chronic pain with CBD typically utilized a combination of 1:1 CBD : THC, which was often in the form of the well-tolerated oromucosal spray Sativex (Nabiximols in the US) (Johnson et al., 2013; Sellers et al., 2013). Combination of the two often improved upon the deleterious and psychoactive effects of THC-only administration (Ueberall et al., 2019). The CBD : THC formulations were effective at reducing mean pain scores in chronic pain patients with multiple sclerosis, improved neurophysical measurements in response to noxious stimuli, reduced intractable chronic pain in advanced cancer, and improved refractory/neuropathic pain following failed spinal cord surgery (Rog et al., 2005; Conte et al., 2009; Johnson et al., 2010; Portenoy et al., 2012; Mondello et al., 2018). There is contradictory evidence that CBD : THC treatment does not always relieve chronic pain in patients with brachial plexus avulsion or advanced-cancer, as evidenced by studies in two-independent cohorts, thus indicating the heterogeneity in disease contexts for which cannabinoids may be effective; of note, although pain was not significantly improved, patients in these studies indicated an improved quality of life (Berman et al., 2004; Fallon et al., 2017; Lichtman et al., 2018). There is a demonstrated need to further understand the mode of action of CBD, and these results are promising, but efficacy of treatment must also be evaluated in other disease states that produce chronic pain such as diabetic neuropathy, rheumatic diseases, and sickle cell disease (Fitzcharles et al., 2016).

Mechanistic Insights For Cannabidiol Treatment Of Chronic Pain

Few preclinical studies have been performed to evaluate the mechanism of analgesia for CBD treatment of chronic pain. Currently available studies rely on rodent and in vitro models but suggest molecular pathways that may be used to enhance CBD use in the clinic, or offer alternative approaches for higher efficacy. Evidence strongly supports that prolonged treatment (i.e. > 7 days) with CBD alleviates chronic pain caused by chronic constriction injury of the sciatic nerve in rats and mice in a cannabinoid receptor-independent manner, and treatment is coincident with decreased hepatic cytochrome p450 and intestinal P-glycoprotein that may increase bioavailable circulating CBD (Costa et al., 2007; Comelli et al., 2008; Casey et al., 2017; Abraham et al., 2019). In vitro studies using human embryonic kidney cells reveal that at high doses CBD interacts with and selectively activates α1– and α1ß-glycine receptors, but these results have yet to be confirmed in vivo (Ahrens et al., 2009; Foadi et al., 2010). Alternatively, there is preliminary evidence that CBD may interact with α3-glycine receptors to reduce inflammation and hyperalgesia following simulated neuropathic pain by ligation of the L5 spinal nerve in adult Sprague-Dawley rats (Xiong et al., 2012). CBD also attenuates hyperalgesia in a mouse model of diabetic neuropathy with data suggesting that treatment reduced inflammatory milieu (Toth et al., 2010). Mouse models of pain associated with chemotherapy were simulated by Paclitaxel treatment, in which CBD produced an analgesic and anti-inflammatory effect via interactions with spinal cord 5-HT(1A) receptors (Ward et al., 2014; King et al., 2017). CBD also exerts analgesia in a 5-HT(1A)-dependent manner in streptozotocin-induced diabetic neuropathy in rats (Jesus et al., 2019). Similar to human studies, CBD did not produce complete analgesia in all models of chronic pain; in a cisplatin-induced mouse model of neuropathy, CBD attenuated but did not prevent hyperalgesia (Harris et al., 2016). Mechanical hyperalgesia was improved by CBD treatment following traumatic brain injury in mice, myofascial pain in rats, and 6-hydroxydopamine-induced mouse model of Parkinson’s disease, however these studies require follow-up to inspect potential mechanisms of action (Belardo et al., 2019; Wong and Cairns, 2019; Crivelaro Do Nascimento et al., 2020). The preclinical work being done to disentangle the mechanisms of CBD in providing analgesic support in chronic pain is flourishing, but much remains in the wake of chronic disease and enhancing our understanding of the mechanisms at play.

Public Health Hazards And Teratogenicity Of Cannabis Products

Rising legalization and use of medical and recreational cannabis and CBD products raises significant health concerns with regards to both unregulated sources of these products discussed above as well as the health effects of prolonged usage. A recent multistate outbreak of coagulopathy from synthetic cannabinoids has been traced to the presence of long-acting anticoagulant rodenticides in “fake weed” (Arepally and Ortel, 2019). Furthermore, the US Centers for Disease Control and Prevention has increased awareness of the risks of severe pulmonary disease associated with use of electronic cigarette devices to “vape” tobacco and cannabis (Centers for Disease Control and Prevention, August 23, 2019). The effects of long-term cannabinoid use are especially unclear in pregnant women, in whom potential teratogenic effects could have implications on future generations. Cannabis and CBD use are rising amongst pregnant women. An estimated 4% of pregnant women use cannabis, and in California, which recently legalized cannabis, about 20% in a cohort of 18- to 24-year-old pregnant women reported using cannabis products in retrospective studies (Young-Wolff et al., 2017). These numbers are likely to rise as legalization continues throughout the US, and pharmaceutical strength preparations become available for several conditions, and because of the availability of CBD through stores and online sources (Millar et al., 2019). While several studies have focused on THC during pregnancy, investigation focused on the effects of CBD usage by pregnant women before, during, and/or after pregnancy are rare. Thus, there is an unmet need to examine the potential effects of CBD on embryonic and fetal development and the postnatal health of children exposed to CBD before birth. We will summarize here conclusions from both animal and human studies on some possible effects of CBD prenatally, perinatally, and postnatally.

CBD use during early gestation could pose a risk to critical pre-pregnancy and early pregnancy events. Successful pregnancy depends on reciprocal interactions between a competent embryo and a receptive endometrium in the mother. In early gestation CBD, THC, and cannabinol are thought to inhibit embryo implantation and placenta development by altering endometrial receptivity (Neradugomma et al., 2019). However, this effect has yet to be seen outside transformed human endometrial cell models. Exposure to CBD in chick embryos decreases the viability of the embryo by 50% to 80% dependent on CBD concentration and can delay embryonic development (Gustafsson and Jacobsson, 2019). Similar delays in embryonic development have been reported in zebrafish embryos exposed to CBD albeit without the decrease in viability (Valim Brigante et al., 2018). Teratogenicity of CBD has been reported in mice where prenatal exposure leads to an increase in craniofacial malformations and eye defects (Fish et al., 2019). Interestingly, these teratogenic effects are similar though milder than those observed for alcohol, THC, and the synthetic cannabinoids HU-210 and CP55,940 countering the popular perception that CBD is an unequivocally safe alternative to THC and other cannabis constituents (Fish et al., 2019). In humans, retrospective meta-analysis has determined that in utero exposure to cannabis is associated with a decrease in birth weight and increased need for neonatal intensive care in infants (Gunn et al., 2016). This effect is likely due in part to the effects of CBD as low birth weights in mice offspring have been reported in response to prenatal CBD exposure exclusively (Fish et al., 2019). The observed teratogenic effects of CBD exposure may be due to the compound itself and/or due to CBD working synergistically with other teratogenic compounds perhaps by enhancing permeability of xenobiotics through the human placental barrier thereby increasing fetal exposure (Feinshtein et al., 2013).

Effects on hormonal and reproductive function following maternal exposure to CBD have been reported in male mice. CBD exposed mice had lower testicular weights and lower overall levels of testosterone (Dalterio et al., 1984). These effects are in line with reports of hormonal and reproductive effects due to postnatal exposure to CBD or cannabis in rats and monkeys. Chronic doses of THC or CBD in rat suppress hepatic testosterone oxidation by selective inhibition of male-specific cytochrome p450 in the adult male rat (Narimatsu et al., 1988). Chronic doses of CBD in rat also cause a significant reduction in testosterone formation and a decrease in testicular enzyme activity (List et al., 1977). In both rhesus monkeys and rats, gonadal function is altered due to exposure to THC or CBD which leads to hormonal imbalance including a decrease in testosterone in male rats and an increase in follicle-stimulating hormone in male monkeys (Rosenkrantz and Esber, 1980). Together, these data suggest that CBD may influence spermatogenesis and libido in males.

Maternal exposure to CBD is also likely to cause neurochemical changes in the brain of the offspring. The α1-adrenergic and D2-dopaminergic receptors in the cerebral cortex and striatum of rats exposed prenatally to either CBD or THC exhibited smaller binding affinities for their respective ligands and hypothalamic dopamine levels in mice have been observed to be greatly depleted in CBD-exposed males as well (Dalterio et al., 1984; Walters and Carr, 1988). Overall, these studies suggest that prenatal exposure to CBD is likely to alter the production of testosterone, the function of the male gonads, and the receptor ligand interactions in the brain of offsprings.

Conclusion

Rising prevalence of the non-psychoactive cannabinoid CBD presents an opportunity for the treatment of intractable chronic pain for which primary treatments are insufficient or not possible. As depicted by the studies reviewed herein, the use of CBD is context-specific, and it should not be used indiscriminately (see Table 1 ). Preliminary mechanistic studies indicate conservation of function via modulation of hepatic cytochrome p450 leading to increased bioavailability of endogenous mediators of pain (i.e. serotonin) and exogenous analgesics (i.e. THC). Therefore, it is important to continue studies into the conditions for which CBD may be effective as a treatment via novel actionable targets. Simultaneously, the growing access to unregulated CBD products, which may be adulterated with potentially toxic compounds, requires regulation and education about CBD for its potential benefits and/or adverse effects in health and disease. This is especially the case in pregnant women, which raises the highest possible risk for the developing fetus and future offsprings. Unfortunately, efforts to discuss the dangers of CBD use have been severely lacking and require immediate attention to prevent the irreparable harm to the masses from the tsunami of CBD products.

Table 1

Consequence of Cannabidiol treatment in preclinical and clinical settings.

Source Species Effect References
Beneficial Effects
CBD
( 1 Sigma)
HEK cells Activation of α1 and α1ß -glycine receptors Ahrens et al., 2009 1 ; Foadi et al., 2010 1
CBD
( 1 Enecta Group;
2 Cayman; 3 NIH; 4 NS)
Mice ↓inflammation; ↓hyperalgesia Belardo et al., 2019 1 ; 4 ,Crivelaro Do Nascimento et al., 2020; (Toth et al., 2010) 2 ; (Ward et al., 2014; King et al., 2017); 3 (Harris et al., 2016);
CBD
( 1 NIH; 2 THC Pharm; 3 GW Pharma; 4 Cayman; 5 NS)
Rat ↓inflammation; ↓hyperalgesia;
↓ hepatic cytochrome p450
(Costa et al., 2007; Comelli et al., 2008; Casey et al., 2017; Abraham et al., 2019) 3 ; (Xiong et al., 2012) 1 ; (Jesus et al., 2019) 5 ; Wong and Cairns, 2019 4
CBD
( 1 Stanley Brothers; 2 Bedrocan International; 3 Ananda Professional; 4 Tilray; 5 NS)
Humans Patient-reported: ↓ chronic pain;
↑ quality of life; ↑ quality of sleep
(Wade et al., 2003) 5 ; (Cuñetti et al., 2018; Xu et al., 2019); (Van De Donk et al., 2019) 2 ; (Notcutt et al., 2004; Capano et al., 2020) 5 ; (Gulbransen et al., 2020) 4
1:1
CBD : THC
(GW Pharma.)
Humans improved refractory/neuropathic pain;
Patient-reported ↓ chronic pain; ↑ quality of life;
Improved responses to noxious stimuli
Johnson et al., 2013; Sellers et al., 2013; Ueberall et al., 2019; (Rog et al., 2005; Conte et al., 2009; Johnson et al., 2010; Portenoy et al., 2012; Mondello et al., 2018) (Berman et al., 2004; Fallon et al., 2017; Lichtman et al., 2018); > NCT01424566; > NCT01361607; > NCT01262651; > NCT01606189; > NCT01337089
Adverse Effects
CBD
(NS)
HES model cells Adversely impact embryo implantation; Delay placenta development Neradugomma et al., 2019
CBD
(The Hebrew University)
MCF7/P-gp, BeWo and Jar cells ↑ placental xenobiotic permeability Feinshtein et al., 2013
CBD
(BSPG Pharm.)
Zebrafish embryos Delay in embryo development;
↑ embryo activity
Valim Brigante et al., 2018
CBD
(Tocris)
Chick embryos 50–80% ↓ in embryo viability;
Delay in embryo development
Gustafsson and Jacobsson, 2019
CBD
(Cayman Chemical)
Mice offspring ↑ Eye defects; ↓ birth weight;
Abnormal craniofacies; ↓ testicular weight;
↓ testicular testosterone levels
↓ hypothalamic dopamine levels
Dalterio et al., 1984; Fish et al., 2019
CBD
( 1 NIH; 2 Kyushu University)
Rat offspring ↓ hepatic cytochrome p450
↓ testicular testosterone levels
↓ binding affinities for α1-adrenergic and D2-dopaminergic receptors
List et al., 1977 1 ; Rosenkrantz and Esber, 1980 1 ; Narimatsu et al., 1988 2 ; Walters and Carr, 1988 1
CBD
(NIH)
Rhesus monkeys ↑ follicle-stimulating hormone;
hormonal imbalance
Rosenkrantz and Esber, 1980
Cannabis
(NS)
Humans ↓ birth weight
↑ need for neonatal intensive care
Gunn et al., 2016

CBD, cannabidiol; THC, tetrahydrocannabinol; HEK cells, human embryonic kidney cells; HES cells, human endometrial stroma cells; JAr cells, human choriocarcinoma cells; BeWo cells, human placental cell line from choriocarcinoma; MCF7/P-gp cells, MCF-7 breast carcinoma cells expressing P-glycoprotein; NIH, National Institutes of Health National Institute on Drug Abuse; NS, not specified. The superscripted numbers corresponds with the vendor in the source and the cited article within that row. The symbols “↓” and “↑” indicate worsening and improvement of outcomes, respectively.

Author Contributions

DA wrote the manuscript and prepared it for communication. CV co-wrote the manuscript and prepared the table. SK reviewed the contents and prepared the figure. VS contributed to the structure and edited the manuscript. KG defined the content, searched the literature, supervised the writing, and edited the manuscript.

Funding

We gratefully acknowledge funding from NIH grants U18 EB029354 and HL147562 to KG. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Conflict of Interest

KG reports grants from Grifols, Cyclerion, and 1910 Genetics, and honorarium from Novartis, Tautona Group, and CSL Behring, outside the submitted work.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

We acknowledge creative commons for their licensing of images used in the figure. All images are freely available through pixabay.com under creative commons license.