Self-Reported Effects of Medical Cannabis on Illness Severity, Depression and Anxiety in Fibromyalgia Patients: A Large Retrospective Case Series

Introduction

Fibromyalgia is a complex rheumatic condition characterized by widespread chronic pain, tenderness, fatigue, sleep disturbance, mood disorder, cognitive disturbance, and somatic symptoms.¹ Although the etiology of fibromyalgia is not entirely understood, it is thought to be a centralized pain state.²

This theory is supported by recent brain imaging studies that have shown dysregulated processing and transmission of pain signals, changes in brain morphology, and altered levels of neurotransmitters (i.e., lower level of serotonin, norepinephrine and higher levels of glutamate and substance P) in patients with fibromyalgia as cited in Meyer, 2002.³ About 2% to 3% of Canadians are affected by fibromyalgia, with women affected up to 9 times more than men.¹

Currently, treatment of fibromyalgia focuses on improving functioning and quality of life (QoL) while reducing symptoms.¹ Treatment with graded exercise and cognitive-behavioral intervention has the best evidence of benefit, whereas pharmacologic treatment such as NSAIDs, opioids, antidepressants and anticonvulsants has been shown only to have modest benefits.¹

Fibromyalgia is a highly comorbid condition with common coexisting disorders, such as rheumatoid arthritis, lupus, depression, anxiety, post-traumatic stress disorder, and irritable bowel syndrome.^4,5 The lifetime prevalence of major depressive disorder and anxiety in patients with fibromyalgia is estimated at 63% and 30%, respectively.⁵ These comorbidities are not barriers to treatment in this patient population, and a holistic treatment strategy involving comorbid conditions is essential for meeting therapy goals.²

Because fibromyalgia is chronic and disabling, pharmacologic treatment has been shown only to have modest benefit¹ and is heavily stigmatized. Patients often report low QoL and frequently seek alternative treatment strategies.⁶ In an observational study by Grape et al., patients described living with fibromyalgia as “a struggle to maintain everyday life” and reported that recovery brought content and meaning back to their lives.⁷

Observational studies have shown that the use of cannabis products is common among patients with fibromyalgia, with many reporting benefits in pain, sleep, and QoL.^8-11 A review conducted by Russo suggested that the pathophysiology for some objective pain syndromes such as fibromyalgia might point towards an underlying clinical endocannabinoid deficiency. For this reason, exogenous supplementation of cannabis alleviated symptoms for such patients.¹² However, most of these individuals use cannabis without medical supervision, which results in erratic dosing and lack of regular assessment and follow-up.^13,14

Despite reported benefits, there is a paucity of high-quality clinical evidence surrounding the use of cannabis in treating fibromyalgia. Existing research has found cannabis to effectively reduce fibromyalgia severity and pain and the symptoms of anxiety and depression.^15-18 The generalizability of the current literature suffers from using small sample sizes, and no studies have investigated the effect of medical cannabis on patients over time. For these reasons, we believe there is an unmet medical need, and a review of medical cannabis use in patients with fibromyalgia is warranted.  This study aimed to observe the effect of cannabis on fibromyalgia illness severity and related symptoms of depression and anxiety.

Methods

A retrospective chart review was conducted to identify all patients who self-reported being affected by fibromyalgia at Harvest Medicine (HMED) clinics from January 2017 to July 2021. HMED is a Canadian network of specialty medical cannabis clinics owned by VIVO Cannabis with 4 locations across Canada. Clinic locations offer in-person and telemedicine appointments. The clinic limits itself to prescribing medical cannabis only and does not interfere with treatment modalities provided by primary care providers. HMED’s electronic health records and structured assessment tools, were used to capture all patient data. The Children’s Hospital of Ontario (CHEO) Research Ethics Board approved the study protocol.

Data from patients who indicated fibromyalgia as a primary reason for seeking medical cannabis at intake questionnaire and had a minimum of 1 follow-up assessment were included. Any follow-up assessment recorded within 1 week of the previous appointment was excluded. Diagnostic criteria for fibromyalgia were not used. Demographic data extracted at intake included sex, annual household income, employment status, highest level of education, and cannabis use history.  Data regarding cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) dosing or their relative ratios were not used as it was not available on the charts.

Scores from the Patient Health Questionnaire-9 (PHQ-9), the Generalized Anxiety Disorder-7 (GAD-7), and questions assessing illness severity were included if available for the intake visit and at least first follow-up. Fibromyalgia illness severity is typically evaluated in clinical research using the Revised Fibromyalgia Impact Questionnaire (FIQR). Although the administration of the FIQR has recently been implemented in HMED clinics, sufficient available data were not available to include it in the current study. Thus, PHQ-9, GAD-7, and self-reported illness severity scores were used instead.

The PHQ-9 is a 9-item questionnaire used clinically to screen for, diagnose, and monitor depression.¹⁹ Each item is scored from 0 to 3 based on the frequency of depressive symptoms over the previous 2 weeks; the total score ranges from 0 to 27. A total score of 0 to 4 represents minimal depression, a score of 5 to 9 represents mild depression, a score of 10 to 14 represents moderate depression, a score of 15 to 19 represents moderately severe depression, and a score of 20 to 27 represents severe depression.

The GAD-7 is a 7-item scale used clinically to screen for, diagnose, and monitor anxiety.²⁰ Each item is scored from 0 to 3 based on the frequency of anxiety symptoms over the previous 2 weeks, and the total score ranges from 0 to 21. A total score of 5 to 9 represents mild anxiety, a score of 10 to 14 represents moderate anxiety, and a score of 15 to 21 represents severe anxiety.

A non-validated, self-report severity illness scale was created at the clinic and used at intake and first follow-up. At intake, patients were asked, “How do you rate the severity of your primary symptom for seeking medical cannabis?” At first follow-up, patients were asked, “How do you rate the severity of your condition after starting cannabis treatment?” Both questions assessing severity were rated on a 5-point Likert scale, with 1 being asymptomatic, 2 mild, 3 moderate, 4 severe, and 5 very severe. Data was only analyzed for patients who reported answers at both intake and first follow-up.

Mean PHQ-9, GAD-7, and self-reported illness severity scores were calculated for intake and the first follow-up assessments. The mean time between intake and the first follow-up was also calculated. Mean scores were compared between intake and first follow-up for each outcome using independent paired t tests.

A score reduction of 5 or more on the PHQ-9 scale represents a clinically significant improvement.²¹ A score reduction of 6 or more on the GAD-7 scale represents a clinically significant improvement.²²

The data was extracted from an electronic medical record called Input health (TELUS Health Application) and imported into Microsoft Access, whereas statistics were performed using IBM SPSS Statistics (version 26). Subgroups for analysis were created based on demographic and first follow-up data. Mean outcome scores were compared between each subgroup at intake and first follow-up using independent t tests, where appropriate (statistical differences reported at P<0.05)

Subgroups examined included sex, income level, employment status, highest level of education, and cannabis use history (Table 1). For cannabis use history, patients were considered cannabis-naive if they had never used cannabis, whereas cannabis non-naive was defined as any history of cannabis use. Finally, inhaled herbs included THC dry flower and CBD dry flower and ingested oil included CBD oil, THC oil, and balanced oil (Table 2).

Results

The chart review identified 1923 patients with the primary concern of fibromyalgia. Of these 1923 patients, 817 had at least 1 follow-up assessment (Table 1). Of the 817 patients, PHQ-9 scores at intake and at least 1 follow-up were available for 446, GAD-7 scores at intake and at least 1 follow-up were available for 593, and intake and illness severity scores at intake and least 1 follow-up were available for 805 patients. Most patients (76.1%) reported using CBD oil at the first follow-up. There was an almost 43% dropout rate between intake and first follow-up.

PHQ-9 (Depression)                                                                 

The mean PHQ-9 score was 10.0 ± 6.6, indicating moderate to moderately severe depression, at intake (n = 446) and 8.0 ± 6.0, indicating mild to moderate depression (n = 446), at first follow-up (t = 333 ± 199 days; P<0.001). At first follow-up, 119 of 446 patients (27%) had a clinically significant reduction in PHQ-9 score, 288 of 446 (65%) had no clinically significant change, and 39 of 446 (9%) had clinically significant worsening. 

For the subgroup of patients with PHQ-9 scores ³10 (n = 214), the mean PHQ-9 score at baseline was 15.6 ± 4.6. The mean PHQ-9 score at first follow-up for this subgroup was 11.1 ± 6.3. The mean reduction was 4.5 ± 5.7 (P<0.001). A clinically significant reduction in PHQ-9 score (reduction of ³5) was seen in 103 patients (48%), and 11 (5%) reported a clinically significant increase in PHQ-9 scores.  

No significant differences were found in score reduction between intake and first follow-up PHQ-9 scores by sex, education level, income level, employment status, or cannabis use history.

GAD-7 (Anxiety) 

In the subgroup for whom GAD-7 scores were available (n = 593), the mean GAD-7 score was 8.0 ± 6.1, indicating mild to severe anxiety at baseline and 5.9 ± 5.4, indicating mild to moderate anxiety at first follow-up (t= 327 ± 190 days; P<0.001). At first follow-up, 132 of 593 patients (22%) had a clinically significant improvement in GAD-7 score, 431 (73%) had no significant change, and 30 (5%) had clinically significant worsening. 

For the subgroup of patients with baseline GAD-7 scores ³10 (n = 216), the mean GAD-7 score was 15.0 ± 3.5 at intake and 9.6 ± 5.9 at first follow-up. The mean reduction was 5.4 ± 5.7 (P<0.001). Clinically significant reduction (reduction ³6) in GAD-7 score was seen in 104 patients in this subgroup (48%), and 4 (2%) showed a clinically significant increase in GAD-7 score.  

No significant differences in score reduction was observed between intake and first follow-up GAD-7 scores by sex, education level, income level, employment status, or cannabis use history (P > 0.05).

Illness Severity

In the subgroup of patients with available illness severity scores (n = 805), the mean score was 4.12 ± 0.7, indicating severe to very severe illness, at intake and 2.9 ± 1.0 and moderate to severe illness, at first follow-up (t = 181 ± 142 days; P<0.001). In this subgroup, 604 patients (75%) experienced an overall decrease in illness severity score, 298 (37%) had a score reduction >2, 185 (23%) reported no change, and 24 (3%) saw an increase.

No significant differences in score reduction was seen between intake and first follow-up severity scores by sex, education level, income level, or employment status and cannabis use history (P > 0.05).

Discussion

To our knowledge, this was one of the first studies to examine medical cannabis use in a large sample of patients with fibromyalgia  The study’s demographics align with previous research on  patients with fibromyalgia, with most patients being women, middle-aged, and unemployed or disabled.¹³Most of the sample (76.1%) also reported using CBD oil at first follow-up, which aligns with the current practice guidelines for  authorizing medical cannabis  as an adjuvant therapy for managing chronic pain.^23,24  Results also showed that 2.8% of patients did not order or use cannabis at first follow-up, however, this is unlikely to have an effect on the results.

The primary findings from the present study are a significant reduction in all 3 scores measuring depression, anxiety, and illness severity between baseline and first follow-up. About 75% of patients saw a decrease in their self-reported illness severity, and >20% had a clinically significant reduction in depression and anxiety severity ranking from intake. These results agree with those of Giorgi et al., who found that adding medical cannabis to standard analgesic therapy such as opioids (tramadol), anticonvulsants (pregabalin), SNRIs (duloxetine or muscle relaxants (cyclobenzaprine) resulted in 33% of patients seeing significant improvement in FIQR scores and 50% of patients seeing improvement in self-rated depression and anxiety scales.¹⁶

Additionally, patients with clinical depression or anxiety at intake based on a higher PHQ-9 or GAD-7 score reported better clinical improvement than the overall group. Scores on these measures are not expected to change in patients not experiencing depression or anxiety. Interestingly, there was no difference in outcome between naive and previous cannabis users.

In further research, we may be able to assess how a strong support system such as following a structured medical cannabis program under the skilled guidance of a healthcare practitioner (HCP) might benefit and improve patient outcomes.

A key limitation of these results is the lack of validated, disease-specific outcome data. In addition to FIQR scores, validated scales for pain and sleep disturbance were missing from the study due to a lack of available data. The PHQ-9, GAD-7, and self-reported illness severity are not validated measures of fibromyalgia severity; however, the lifetime prevalence of depression in patients with fibromyalgia has been estimated at 63%, and the lifetime prevalence of anxiety at 30%.²⁵ These common comorbid mood disorders can contribute to more severe illness and act as a barrier to treatment. Thus, they are necessary outcome measures.

The high attrition rate acted as another limitation of the current study. The significant loss to follow-up could have been due to patients discontinuing medical cannabis due to lack of efficacy or presence of adverse effects or by patients who saw benefit from medical cannabis entering the recreational cannabis market based on cost and convenience. According to a recent Canadian Cannabis Survey in 2022, 13% of Canadians over 16 years old reported having used cannabis for medical purposes, and 73% did not have an authorization from an HCP. ²⁶

Our study may be biased as the patients that continued with the service were only patients that reported benefit from medical cannabis. Patients who may have not experienced benefit and decided to discontinue their therapy are not included in the analysis. Cost is known to be the most significant barrier to accessing medical cannabis, hence patients may not be able to purchase or use medical cannabis regularly as per the recommendations made by their HCPs.^27,28

Despite patient compassionate care programs and medical cannabis income tax benefits, many patients may be lured by discounted value products in the recreational market and unregulated, low-quality, affordable products in the illicit market.^29,30 The largest cross-sectional study on cannabis use in Canadian patients with rheumatic conditions  showed that only 20% accessed cannabis through the medicolegal route.¹³

The current study accommodated potential attrition bias by including patients with a minimum of 1 follow-up assessment and focusing on differences between intake and first follow-up. These results demonstrate the need for more regularly scheduled follow-up visits in medical cannabis patients to assess better the safety, efficacy, and convenience of cannabinoid-based therapy.

Overall, there was a modest reduction in symptoms of depression and anxiety in patients with fibromyalgia evidenced by these data.  The most significant improvements were seen in self-reported illness severity, with 75% of patients seeing improvement. The improvement in self-reported illness severity also seemed to be independent of patient demographics. The large, nonspecific improvement rate could be attributed to very high illness severity, leaving little room for worsening on the scale. Medical cannabis is also often a late-line therapy for treating fibromyalgia; because of this, patient cases can be more complicated and, therefore, more severe.³¹

Although a non-validated clinical measurement tool was used, a mean improvement in illness severity of 1.2 points may suggest a modest improvement. A change from ‘very severe’ to ‘severe’ or from ‘severe’ to ‘moderate illness’ may be interpreted as a positive improvement in a patient’s QoL given the disabling features attributed to fibromyalgia.⁷

Another limitation of the present study was the potential impact of medications such as antidepressants, opioids, and analgesics for pain relief between intake and first follow-up as prescribed by primary care providers. The improvement in health could also be a placebo effect. Additionally, the diagnosis of fibromyalgia was based on self-reported answers on the clinic intake form and was not confirmed by clinical criteria. Another limitation could be the selective reporting of outcomes by patients and their HCPs and the lack of rigorous chart audits.

Additionally, variability between the product types used might have led to different treatment responses. Specific CBD or THC dosing information was not available. Medical cannabis use by our patient population was also not restricted to one product. Even though an authorizing physician is encouraged to offer guidance on the form, strength and dosing, the dispensed form is often determined by the licensed producer.³² Therefore, patients are able to purchase and use a variety of products. Future studies performed at HMED should include a more in-depth analysis of these factors.

Conclusion

These data shows that medical cannabis may play an effective role in the management of fibromyalgia and associated symptoms of depression and anxiety. Clinical improvements in all 3 measures of disease severity, depressive symptoms, and anxiety symptoms were seen in a large portion of the sample following the initiation of medical cannabis.

Despite this, the conclusions were limited by high attrition rates and a lack of validated outcomes measuring fibromyalgia severity. Future research would benefit from the use of comprehensive outcomes to assess fibromyalgia symptoms, including illness severity, pain, mood disorder, and sleep disturbance.