In the present study, we demonstrated that medical cannabis is an effective and safe option for the treatment of fibromyalgia patients’ symptoms. We found a significant improvement in pain intensity and significant improvement in patients’ overall quality of life and fibromyalgia-related symptoms after six months of medical cannabis therapy. In addition, there were relatively minor adverse effects with a small number of patients who discontinued the use at six months. To the best of our knowledge, this is the first trial to use herbal cannabis in fibromyalgia patients.

A search of the current literature has identified three randomized controlled trials evaluating the effect of medical cannabis on fibromyalgia-related symptoms. Skrabek et al. enrolled 32 patients to receive nabilone, an orally administered cannabinoid, vs. placebo therapy [10]. At four weeks follow-up there was a significant decrease of 2 points of NRS in addition to improvement in anxiety and overall quality of life. Ware et al. enrolled 29 patients in a trial of nabilone vs. amitriptyline to investigate the effect on sleep disorders among fibromyalgia patients over 2 weeks of therapy. The authors found a moderate effect on insomnia, but not on other aspects of sleep, in addition to no improvement in pain and quality of life [11]. Lastly, Fiz et al. enrolled 56 patients to receive either medical cannabis (the type is not mentioned) or standard therapy [15]. The authors reported a significant effect on pain two hours from consumption, with no effect on quality of life or sleep disorders. Data regarding pain intensity longer than 2 h were not available. Compared to the studies mentioned above, our study has several advantages. First, our study represents a real-world experience of herbal cannabis use in the cohort of patient with fibromyalgia. Second, we have assessed a substantially larger cohort of 367 fibromyalgia patients with six months follow-up of 211 patients (vs. 30–56 patients in previous studies). Our data also provided a relatively long follow-up of six months periods (compared to only several weeks follow up), which allowed us to analyze the effect and safety of medical cannabis on fibromyalgia patients over an extended period of time. Lastly, we studied the effect of medical cannabis on every aspect of fibromyalgia: improvement in chronic pain, quality of life, disease perception and specific symptoms, and the incidence of adverse effects.

There are several pharmacological regimes that are recommended to treat fibromyalgia [5]. However, their efficacy is relatively limited. The use of low-dose amitriptyline, a tricyclic antidepressant, was associated with 30% reduction in pain level with minor effect on sleep quality. A similar pain reduction rate was shown in meta-analyses of both anticonvulsants and serotonin–noradrenalin reuptake inhibitors [16,17]. However, withdrawal rates due to side effects in these studies were higher compared with placebo. Our results pointed out that cannabis may be at least equal to these regimes, yet with minor adverse effects that resulted in low dropout rates in our study.

Medical cannabis use was reported to be associated with a change in the utilization of other prescription regimens [18,19,20]. In our cohort, after six months of medical cannabis therapy, a substantial fraction of patients stopped or decreased the dosage of other medical therapies. Of note, 22.2% of opioids users at the baseline reduced or ceased the use of these medications at six months follow-up. Considering that opioid use is coupled with a complex titration process, higher risk for dependency, and a higher rate of serious adverse effects, medical cannabis may pose a reasonable therapeutic alternative [21,22,23].

Previous studies have shown that medical cannabis use was more prevalent among young adults and males [24,25]. However, our cohort was composed of a majority of 40–60 years old women, representing the population most affected by fibromyalgia [26,27]. These findings correlate with more recent reports that indicate a substantial increase in the age of medical cannabis users [28,29]. Although patients baseline NRS was considerably high (9/10), it represents patients who failed to respond to the standard therapy during a follow up of at least a year. Thus, our study cohort represents severe and poorly controlled fibromyalgia patients, which explains the higher symptomatic burden. Previous studies reported similar characteristics. For instance, Fiz et al. reported 37 mm VAS decrease two hours after cannabis administration (baseline VAS was 80mm) [15]. Goldenberg et al. reported a mean VAS of 81.5 mm among placebo users compared to fluoxentine- and amitriptyline-treated fibromyalgia patients [30].

Patients in our and other studies are often reporting that medical cannabis is more tolerable and with fewer adverse events compared to other therapies [31]. Similar to previous studies, we found that medical cannabis use is safe among fibromyalgia patients [7,32]. At six months follow-up, there was a relatively low rate of minor adverse events, and only 28 patients (7.6%) stopped using medical cannabis. In concordance with the literature, we found that dizziness, dry mouth, hyperactivity, drowsiness, and gastrointestinal symptoms are all possible adverse effects of cannabis use [14,33].

In our cohort, we had a relatively low rate of adverse events. For instance, the most commonly reported adverse events after six months were dizziness (7.9%), dry mouth (6.7%), and vomiting/nausea (5.4%). Yet, comparing our findings to other studies using the same titration approach yields similar rates of the adverse events. For instance, among 2736 elderly patients (65 and older) who used medical cannabis, dizziness was reported by 9.7% after six months of use [8]. First, as mentioned above, this may be associated with the gradual titration process, which may lead to the mitigation of most of cannabis’ adverse effects. Second, the evaluation of adverse events occurred only after six months of therapy. Since most of the patients developed tolerance to adverse effects in days, this may have led to lower rate of reported adverse events at six months follow-up. These findings further support the previously suggested cannabis titration approach of “start low, go slow, and stay low” to minimize both adverse events and the risk of addiction [14]. Lastly, the majority of our cohort used relatively low dosage (20 g or less per month) of cannabis at baseline and after six months (89.4% and 78.1%, respectively). The mean THC and CBD did not change between the first and last month of follow-up. These findings can also explain the low rate of adverse events, which were mostly dose-dependent. Clinicians should be aware of unjustified dose escalations (e.g., above 3 g/day in non-cancer patients) to prevent misuse or addiction to cannabis [34].

We found that patients’ concerns and worries regarding cannabis prior to treatment initiation were associated with lower odds of treatment success, whereas previous experience with cannabis was associated with treatment success. We acknowledge that these findings and the observational nature of our study could constitute evidence for the strong placebo effect associated with cannabis use, and emphasize the importance of double-blinded clinical trials, especially when testing subjective outcomes such as pain and quality of life. Yet, even blinded clinical trials may be biased towards overestimating the effectiveness of medical cannabis due to the lack of the psychoactive effect of placebo substances [35].

Our study has several important limitations. First, this study was of an observational nature and could not establish causality between medical cannabis use and improvement in fibromyalgia outcomes. The improvement at six months may be alternatively explained by regression to the mean phenomenon. Since this was not a randomized controlled trial, we can recommend neither a specific dosage nor specific cannabis product. Second, the close to 30% non-respondent rate in the six months follow-up may have resulted in a non-response bias. Yet, there were no significant differences between respondents to the non-respondents at the baseline characteristics, and more than 85% of the non-respondents were still using medical cannabis at six months. In addition, we cannot evaluate the actual compliance on a monthly basis. In concordance with the vast majority of studies, data on the actual utilization of cannabis were not available. Third, the fibromyalgia diagnosis was established by the referring rheumatologist; therefore, we could not verify that the American College of Rheumatology preliminary diagnostic criteria for fibromyalgia were fulfilled in every case [13]. Fourth, we had no control group to compare the clinical outcomes of medical cannabis use. Hence, some of the improvement may be attributed to spontaneous improvement in the course of the disease rather than medical cannabis utilization. Moreover, the patients in this study used 14 different strains, which prevented us from conducting a comparison between THC and CBD strains and products in terms of effectiveness and safety. Fifth, the change in the utilization of other drugs (than cannabis) for the treatment of fibromyalgia was based on self-reports and was prone to recall biases. Yet, we showed that most patients ceased, reduced, or at least did not change the dosage of their chronic drugs for fibromyalgia while receiving medical cannabis. Additionally, although we found that cannabis use is relatively safe among fibromyalgia patients, the conclusion should not be made about safety while driving under the influence of cannabis, as it was not a measured outcome of this study. The data of this study was provided by a registry that included cannabis users with several clinical indications. Hence, the questionnaire that was used did not include specific symptoms of fibromyalgia (e.g., fibro fog). Lastly, at this stage of medical cannabis research, we are not in a position to identify and thus synthesize single or multiple agents that are responsible for the therapeutic effects.