The findings of this case series of fibromyalgia patients from the UKMCR show a potential association between initiation of CBMP treatment and improvement in clinical outcomes across a variety of health outcomes up until 12 months. Statistically significant improvements can be observed in validated fibromyalgia‐specific, pain, sleep, anxiety, and health‐related quality of life metrics. Furthermore, a statistically significant reduction in opioid consumption was seen at the end of follow‐up. Seventy‐two (23.53%) patients reported 979 adverse events, with the majority being either mild or moderate, and none of which were life‐threatening or disabling. However, the incidence of adverse events is higher than that typically reported across all indications for enrolment in the UKMCR.

Fibromyalgia Symptom Severity scores displayed a reduction compared to baseline up until 6 months. While this is the first study to consider this measure in relation to CBMP use, studies using the Revised Fibromyalgia Impact Questionnaire showed similar findings (Giorgi et al., 2020; Habib & Artul, 2018). Specifically, in the 2018 analysis of registry data, all 26 included patients reported a significant improvement in every questionnaire parameter (Habib & Artul, 2018). While this study has a small sample size, the unanimous effect recorded is worth noting. In a 2020 study of a similar size to the present analysis, 81.1% of patients reported moderate to significant improvement in their condition after 6 months of cannabis treatment (Sagy et al., 2019). The overall improvement in condition severity appears to be consistent across multiple observational studies, which, although promising, requires further assessment in randomized controlled trials.

In measuring overall health‐related quality of life, the EQ‐5D‐5L index values showed improvement at every follow‐up compared to baseline. Similar results were found in a study documenting an average improvement of 0.025 in the index value across a 6‐week comparison in chronic pain patients using medical cannabis (Peterson et al., 2021). In a previous analysis of the UKMCR observing chronic pain patients, including fibromyalgia, statistically significant improvement in the index value compared to baseline was seen after 1 and 3 months of CBMP treatment (Kawka et al., 2021). The present study showed similar improvements in fibromyalgia, which was maintained up to 12 months. When considering the subscales of the measure, all five domains of the EQ‐5D‐5L showed statistically significant improvement in 1‐, 3‐, and 6‐month follow‐ups. Improvement in Self‐Care is contrary to prior studies involving chronic pain cohorts that showed either no statistically significant difference or a decline in this domain (Kawka et al., 2021; Peterson et al., 2021). This further supports the proposal of a supplementary benefit specifically to the fibromyalgia cohort within chronic pain, and improvement in the central sensitivity symptoms. Further dedicated analysis according to the impact of these symptoms may help further elucidate the mechanism of action via which fibromyalgia patients derive clinical benefit after initiating CBMP treatment.

There was also a decrease in reported pain, as shown by the EQ‐5D‐5L‐Pain and Discomfort scores and VAS‐Pain scores, where there were statistically significant improvements in the pain severity at 1‐, 3‐, and 6‐month follow‐ups. In a placebo‐controlled trial involving fibromyalgia patients using THC‐rich cannabis oil lasting 8 weeks, the intervention group showed significant improvement in their pain scores (Khasabova et al., 2011), supporting the hypothesis that CBMP treatments can improve fibromyalgia‐related pain in the short term. Nabilone, a synthetic THC analogue, has also previously demonstrated analgesic effects in fibromyalgia patients (Slivicki et al., 2021). A 2006 study showed significant alleviation in both daily perceived pain and experimentally evoked pain after orally administered THC, suggesting a central mechanism of action (Schley et al., 2006). These findings support the mechanism of action proposed by preclinical studies that show CB1 agonists to promote analgesia (Khasabova et al., 2011; Slivicki et al., 2021).

Sleep quality was also improved as shown by the increase in SQS scores up to 6 months. The positive effects of CBMPs on sleep quality in the setting of fibromyalgia have been noted in various studies (Chaves et al., 2020; Fiz et al., 2011; Giorgi et al., 2020), and is a promising finding as sleep disturbance contributing to fatigue affects 76% of patients with the condition (Choy, 2015). The role of the endocannabinoid system in sleep regulation is complex with contrasting effects described in the literature (Babson et al., 2017). When compared in a randomized controlled trial to amitriptyline, a first‐line therapy in fibromyalgia, nabilone, a THC analogue, was found to be superior in improving sleep (Ware et al., 2010). However, a 2017 review of cannabis and sleep quality suggested that high‐dose CBD contributes to a decrease in sleep latency, decreases frequency of arousals during the night, and has an overall sedating effect, where low‐dose CBD is associated with increased wakefulness (Babson et al., 2017). As a result, future analyses should evaluate the effects of the THC:CBD ratio in participants to provide insight into the dose–response relationship of CBMPs and sleep quality.

There was an improvement in GAD‐7 in all follow‐ups and EQ‐5D‐5L‐Anxiety and Depression at 1 and 3 months. At least 75% of patients had either “mild” or subclinical anxiety at every follow‐up. These findings are supported by fibromyalgia patients in a controlled trial responding with significant improvement in questionnaire items “feel good” and “depression” after cannabis therapy (Chaves et al., 2020). On the other hand, in a meta‐analysis of CBMP treatment for anxiety and depression, mixed results were seen (Kosiba et al., 2019), likely to be related to the inverted U‐shaped dose–response curve observed in both animal and human studies investigating the anxiolytic effects of CBD (Guimarães et al., 1990; Linares et al., 2019; Nazario et al., 2015; Zuardi et al., 2017). These effects are supported by preclinical research that highlights the anxiolytic properties of cannabinoids mediated via effects of CB1, serotoninergic, and TRPV1 receptors of the central nervous system (Zuardi et al., 2017). The potential for CBMPs to address multiple domains of burden in fibromyalgia is a promising area of future evaluation.

The findings of this study propose an association between CBMPs and a reduction in opioid consumption. Statistically significant reduction in median oral morphine equivalent at 3 months and at extraction dates compared to baseline was observed. The high proportion of current cannabis consumers at baseline may indicate that some participants had already reduced or substituted prescribed opiates for cannabis and therefore the effects may not have been fully captured in the present analysis. The reduction is unable to imply clinical significance, as this study has not employed the Medication Quantification Scale to formally measure the negative impact of opioids on the patient cohort (Goudman et al., 2020). In a large prospective study of Canadian patients prescribed medical cannabis, a 78% reduction in mean opioid dosage was observed at the 6‐month follow‐up (Lucas et al., 2021). A systematic review similarly reported a 64%–75% reduction in opioid dose when CBMPs were used as an adjunct, but all studies had a high risk of bias (Okusanya et al., 2020). Furthermore, opioids are commonly prescribed in fibromyalgia patients, and CBMPs lower the incidence of serious adverse events and dependence in comparison (Sagy et al., 2019).

There was an incidence of 3.20 adverse events per individual in this study, where the majority were rated moderate or mild, and none were life‐threatening/disabling. A total of 35.34% of the participants in the cannabis naïve at baseline treatment group reported adverse events. Short‐term use of CBMPs has been associated with higher risks of nonserious adverse events (Wang et al., 2008), and a previous study found high‐dose THC to be associated with dissipated incidence of somnolence as treatment period increased (Gorelick et al., 2013). Furthermore, the adverse effects of THC, including anxiety, have been seen to be reversed by other cannabinoids, notably CBD (Andre et al., 2016; Russo & Guy, 2006). This points to a likelihood that these patients may see these events resolve as they continue treatment, after an initial adjustment period or alterations of their preparations.

The incidence rate of adverse events observed in this cohort was relatively high compared to analyses of other conditions using data from the UKMCR. This may be due to central sensitivity syndromes such as fibromyalgia being associated with a higher incidence of adverse events in response to medication (Liu et al., 2016). Women are also seen to report more adverse events (Watson et al., 2019), and fibromyalgia disproportionately affects women at a 2:1 ratio (Ablin & Sarzi‐Puttini, 2020; Cameron & Hemingway, 2020). Fibromyalgia is highly associated with irritable bowel syndrome, another central sensitivity syndrome, hypothesized to be the result of an altered microbiota, supported by pain reduction following treatment with antibiotics (Erdrich et al., 2020; Marum et al., 2017; Pimentel et al., 2010)—irritable bowel syndrome is also associated with an elevated drug intolerance, adverse effect incidence, and resultant treatment discontinuation (Lembo, 2004; Poitras et al., 2008). The postulation of a predisposition toward adverse events is also shown to be secondary to the nocebo effect, which accounts for 81.7% of event rate in fibromyalgia patients experiencing adverse events in active medications (Häuser et al., 2012). A proposed study to examine the effects of central sensitization in fibromyalgia in respect to treatment response may produce pertinent findings to further this discussion (ClinicalTrials.gov, 2019). Selection bias due to self‐reporting may also escalate the adverse event incidence, but in a 2021 open‐label case series, 48.6% patients reported adverse events, a twofold increase compared to the proportion of patients affected by adverse effects in the present study, suggesting that overreporting has not occurred (Mazza, 2021).

Subgroup analysis suggests that those with prior exposure to cannabis were likely to experience improvements in more domains, as well as fewer adverse events, compared to cannabis‐naïve counterparts. This suggests that despite potential to develop pharmacological tolerance to the effects of compounds contained within CBMPs, there were additional benefits derived from accessing a pharmaceutical‐grade product prescribed under supervision of expert clinicians. These additional benefits may be derived from the improved consistency of product characteristics and safety provided by CBMPs (Hazekamp, 2016). However, this may also represent a selection bias within the cohort as those who had previously consumed cannabis may be self‐selecting as responders to therapeutic properties of cannabinoids. Moreover, while these individuals were counselled against the continued consumption of illicit cannabis, it is not possible to ensure that individuals did not continue to consume illicit cannabis while in receipt of a prescription.