fibromyalgia thc or cbd

December 15, 2021 By admin Off

Pathophysiological symptoms of fibromyalgia include a sensitized or hyperactive central nervous system that is associated with an increased gain in pain and sensory processing (Clauw 2015; Queiroz 2013). Fibromyalgia can occur alone but is often comorbid with conditions such as irritable bowel syndrome (IBS) and tension headaches (Clauw 2015). It is also highly comorbid with a variety of autoimmune disorders characterized by inflammation, such as rheumatoid arthritis. When comorbidities are present, centralized pain can stem from various problems, making it hard to identify the precise source. Research has shown that fibromyalgia patients with comorbid disorders where the common pathway is pain are less likely to respond to typical pain treatments such as surgery or opioids (Clauw 2015).

In addition, the selected studies generally failed to clearly record participant symptoms at the start of each study protocol. Symptoms such as constipation, dizziness, dry mouth, and dry eyes consistent with symptoms of fibromyalgia may also be attributable to cannabis use (Van de Donk et al. 2019). Future studies should establish a baseline for symptoms that are commonly associated with fibromyalgia so as to distinguish them from the adverse effects of cannabis. Future studies should also control for cannabis use patterns when assessing adverse side effects, establishing a control group for each category of cannabis user (past uses, current user, naïve user, and non-user).

Studies have indicated that past and concurrent cannabis use influences the efficacy, safety, and tolerance of any form of concurrent analgesic use in chronic pain patients across diverse diagnoses (Salottolo et al. 2018). For example, research has shown that cannabis users with both neuropathic and musculoskeletal pain due to injury experience more inadequate pain control with standard analgesics and cannabis as compared to non-cannabis users with the same type of injuries, which may lead to higher opioid use when cannabis patients engage in concurrent usage patterns (Salottolo et al. 2018). Furthermore, studies have shown that recreational cannabis users have overall lower mean pain ratings than non-users (Yanes 2019). Additionally, research results suggest that the severity of adverse effects among current cannabis users is significantly lower than that of past cannabis users (6 months or more) or those who never had before used cannabis in any form (naïve users) (Ware et al. 2015). Moreover, studies have indicated that chronic cannabis use affects the pain response to injury and often results in increased opioid use (Yanes 2019). Given these results, confirming past and concurrent cannabis use is a critical aspect of study design for this area of research.

Conclusion.

Moreover, results have shown that, in some cases, fibromyalgia patients with multiple comorbid conditions that lead to pain respond well to centrally acting pharmacological therapies, such as cannabis (Fitzcharles et al. 2018; Phillips and Clauw 2013; Russo 2016; Walitt et al. 2016). However, there is conflicting evidence in the extant literature regarding the use of cannabis with fibromyalgia patients. Recent systematic reviews of randomized clinical trials (RCTs) examining the use of medical cannabis in the treatment of chronic pain presented limited and ambiguous evidence that cannabis exhibits analgesic properties for chronic pain resulting from fibromyalgia (Fitzcharles et al. 2018; Walitt et al. 2016). These results, in combination with rapidly changing national policies regarding cannabis use, highlight the need for an investigation of more recently published literature on this topic.

Fibromyalgia is associated with widespread musculoskeletal pain that is commonly accompanied by additional symptoms such as fatigue, cognitive problems, mood disturbances, and problems with sleep (Clauw 2015; Palagini et al. 2016). In the absence of a definitive cure for fibromyalgia, treatment primarily focuses on symptom management and improving patient quality of life. Fibromyalgia is significantly more common in women and has a prevalence rate of 4% across Europe and North America with an approximated worldwide prevalence of 5–7% (Lan et al. 2016; Queiroz 2013). Additionally, some fibromyalgia patients experience psychological, social, and behavioral symptoms that further affect overall functioning and quality of life. While once considered a mysterious or unspecified condition of psychological or emotional origin, there is now empirical evidence, such as brain imaging studies, which have highlighted several biological underpinnings of many common fibromyalgia symptoms (Pomares et al. 2017; Schmidt-Wilcke and Diers 2017).

Although the critically reviewed studies superficially suggest that medical cannabis is a safe and effective treatment for fibromyalgia pain, serious methodological limitations prevent a definitive conclusion regarding the use of cannabinoids for pain management in fibromyalgia patients at this time.

We followed Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines in searching the PubMed and Medline databases using the search terms “cannabis + fibromyalgia” and then “cannabinoids + fibromyalgia.” Inclusion criteria were a) English language, b) published in peer review journals, c) published from 2015 to 2019, d) all study designs except for systematic reviews and meta-analyses, and e) all cannabis preparations.

Of the many cannabinoids identified in cannabis, tetrahydrocannabinol (THC) and cannabidiol (CBD) represent two principal components (Madras 2019). THC, the major psychoactive component of cannabis, has been shown to influence pain, appetite, orientation, and mood. In contrast, CBD, a non-psychoactive component of cannabis products, has anti-inflammatory, anti-anxiety, and analgesic effects (Stith et al. 2019). Although THC and CBD both elicit pharmacological effects through interactions with cannabinoid CB1 and CB2 receptors, THC is a receptor partial agonist, while CBD is a negative allosteric modulator of the CB1 receptor (Hryhorowicz et al. 2019). Due to their varying properties and molecular interactions, the relative proportion of THC to CBD in cannabis products determines the type of effect, pharmacokinetics, and adverse effects associated with each unique strain (Madras 2019).

Widely understood to be a safer alternative, recent studies suggest that vaporization of the cannabis flower may provide distinct therapeutic advantages as compared to other ROAs (Aston et al. 2019; Lanz et al. 2016; Russo 2016). Vaporization of the botanical cannabis flower should not be confused with the use of the e-cigarette (vaping), which heats a concentrated form of cannabis oil to a high temperature and has recently been implicated in vaping-related acute lung injury (VpRALI) and adverse effects on the cardiovascular system (Fonseca Fuentes et al. 2019; Qasim et al. 2017). Only one of the studies selected for this review utilized vaporization in 100% of study participants (Van de Donk et al. 2019).

Diagnostic continuity.

The use of such a wide variety of assessments for determining treatment outcome, particularly concerning measuring chronic pain levels, decreases the generalizability of results across studies and the overall broader fibromyalgia patient population. Further, chronic pain as a construct was not operationalized in any of the five selected studies. Continuity regarding pain as a construct will help researchers to determine appropriate assessment measures. Operationalizing the specific type of pain that is being targeted in fibromyalgia patients in relation to cannabis as an analgesic and selecting appropriate outcome measures will be an important aspect of future studies.

Evidence highlighting the efficacy of cannabis in the treatment of chronic pain for fibromyalgia patients will not have acceptable validity if the type, strain, and dosage is not carefully tracked. Further, correlations between assessed outcomes and specific types of cannabis cannot be accurately determined if dosage and strain are not carefully tracked alongside outcomes. In the selected studies, Sagy et al. (2019) utilized 14 unspecified strains of cannabis that had been approved by the Israeli Ministry of Health with unverified self-reported dosages. Yassin et al. (2019) assessed the effects of unspecified strains of medical cannabis (1:4 THC: CBD) with a set dosage of 20 g from producers that had also been approved by the Israeli Ministry of Health.

Literature search process.

Studies have indicated that ROA appears to have a distinct influence on health outcomes from cannabis use, with some ROAs having a higher instance of adverse health effects than others (Aston et al. 2019; Russo 2016). The most common ROAs include smoking, inhalation via vaporization, oral administration, and transdermal (Bridgeman and Abazia 2017). As revealed in multiple systematic reviews, respiratory problems such as coughing and wheezing, increased phlegm production, reduced pulmonary function, bronchodilation, and chronic bronchitis have been associated with smoking cannabis (Gates et al. 2014; Ghasemiesfe et al. 2018; Martinasek et al. 2016; Tashkin 2014). Additionally, researchers have noted that daily cannabis use via inhalation may cause adverse pulmonary effects over an extended period (Nugent et al. 2017). Habib and Artul (2018) noted that patients whose primary ROA was smoking were more likely to report transient adverse side effects of dry mouth and redness of the eye. Russo (2016) noted that smoking is undesirable for therapeutic application of cannabis, particularly with patients who have chronic conditions.

Gender.

The Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) was used for this review (Moher et al. 2009). We identified Medline and PubMed as databases for our research. A search was conducted in October 2019 using the keywords “cannabis + fibromyalgia” and then “cannabinoids + fibromyalgia.” Specific inclusion criteria were as follows: a) English language, b) published in peer review journals, c) published from 2015 to 2019, d) RCTs, comparative studies, observational studies, or retrospective reviews, and e) all cannabis preparations. Systematic reviews, meta-analyses, and literature older than 2015 were not included in this review.

Habib and Avisar (2018) did not document specific type or strain and study participants self-reported using as many as three or more unspecified and unverified strains of cannabis throughout the study. Additionally, Habib and Artul (2018) noted that only licensed cannabis (by the Israeli government) was used, but also did not document type, strain, or provide a description. Further, Van de Donk et al. (2019) assessed the characteristics and effects of cultivated cannabis substances administered in controlled dosages: Bedrocan (22.4 mg THC, < 1 mg CBD), Bedrolite (18.4 mg CBD, < 1 mg THC), and Bediol (13.4 mg THC, 17.8 mg CBD). Van de Donk et al. (2019) were the only researchers across the selected studies that precisely tracked agent type and dosage with outcome across each participant. Both Yassin et al. (2019) and Van de Donk et al. (2019) noted the ratio of THC to CBD in each dosage, which is an additional methodological practice that should be followed in all such studies. Official monitoring of cannabis type, strain, composition, and dosage, as well as verified dosage adherence, are critical aspects of study validity.

Therefore, a key aspect in determining the efficacy and safety of cannabis agents needs to involve not only tracking the precise agent used with patient outcomes but also noting the ratio of THC to CBD in each dosage. However, identification and isolation of cannabinoids across products is challenging due to the lack of available information in this area. Moreover, as previously noted, research has shown that the mechanism of entry into the human body of different agents plays a role in efficacy and safety. Future research is needed to ascertain the most appropriate ROA for each agent, which is currently difficult due to rapidly changing cannabis-related technology.

For example, the prevalence of depression in the fibromyalgia population is 25–60%, and research has shown that fibromyalgia patients with comorbid long-term or preexisting depression are less responsive to certain pain medications than fibromyalgia patients with short-term depression (Silverman et al. 2017). While two of the selected studies asked participants about comorbidities as part of the demographic questionnaire, none of the studies controlled for comorbidities or considered them during analyses. Establishing a baseline across fibromyalgia patients with diverse comorbidities is another critical aspect of methodological design, which is essential for assessing the efficacy, safety, and tolerance of cannabis for pain management. Additionally, comorbidities should be taken into consideration when establishing baselines, control groups, and reference groups.

As previously noted, the majority of participants across the selected studies were female; 85% (Habib and Avisar 2018; Habib and Artul 2018), 82% (Sagy et al. 2019), 90% (Yassin et al. 2019), and 100% (Van de Donk et al. 2019). The high rate of female participants across studies might be expected due to an overall higher prevalence of fibromyalgia diagnosis in females. However, the three studies that included both males and females failed to take into consideration the differences in cannabis use patterns, propensity for addiction, and the biological mechanisms of cannabis interaction between sexes. Further, four of the five studies did not consider controlling for gender when analyzing and reporting results. Additionally, there is little research highlighting the differences in efficacy and safety of agent, strain, and ROA across genders. More research is needed in order to assess the generalizability of cannabis efficacy results across genders. Of the selected studies, the results of Van de Donk et al. (2019) (100% female) are the most generalizable across diverse female populations.

Quality of life prior and six months after the initiation of cannabis treatment ( p < 0.001).

Perception of the general effect of cannabis on the patient’s condition after six months of treatment.

At treatment initiation, 328 (89.4%) patients received 20 g or less of cannabis per month, which was administrated to 247 (67.3%) patients using inflorescence ( Table 1 ). During the study follow-up, a total mean of 3.3 regimens was prescribed per patient, with a total of 952 (56.4%) THC-rich regimens used compared to 129 (21.7%) CBD-rich regimes (Table S2).

The intake questionnaire included demographic details, daily habits, substance abuse, medical background, concurrent use of other medications, symptoms checklist, and quality of life (QOL) assessment, stratified by components in 5 points Likert scale (e.g., sleep; appetite; sexual activity; and how a patient would assess their quality of life on a 5 points scale, with 1 being very poor and 5 being very good). Fibromyalgia symptoms after six months were assessed using 8-points Likert scale (1—severe symptomatic deterioration, to 8—maximal symptomatic improvement). A certified nurse educated the patients on the use of medical cannabis; gave instructions on route of administration according to the medical cannabis license (oil vs. inflorescence), delivery methods (drops, flowers, capsules, or cigarettes), and possible adverse effects; and provided an explanation on regulatory issues. The nurse also advised on selecting the cannabis strain (out of 14 strains available) and treatment dose according to titration protocol.

Continuous variables with normal distribution were presented as means with standard deviation. Ordinal variables or continuous variables with non-normal distribution were presented as medians with an interquartile range (IQR). Categorical variables were presented as counts and percent of the total. We used t-test for the analysis of the continuous variables with normal distribution. The non-parametric Wilcoxon test was used whenever parametric assumptions could not be satisfied. We utilized logistic regression for the multivariate analysis of factors associated with treatment success to control possible confounders. The final model was selected according to the statistical significance of coefficients, their clinical relevance, and the model discriminatory characteristic, which were evaluated by calculating the c-statistic, in addition to choosing the minimal −2 log likelihood of each model. We considered a p -value of 0.05 or less (two-sided) as statistically significant. IBM SPSS software, version 25.0, was used for statistical analysis.

Table 2.

Cannabis products are composed of two major active components: tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is the psychoactive component, which affects pain, appetite, orientation, and emotions, through CB1 and CB2 receptors. CBD has analgesic, anti-inflammatory, and anti-anxiety effects via a complex mechanism acting as a negative allosteric modulator of CB1 receptor [14]. The relative proportion of THC:CBD determines each strain’s type of effect, pharmacokinetics, and adverse events. In addition, more than 60 other cannabinoids have been identified, with a variety of clinical effects (e.g., anti-inflammatory and analgesic effects) and pharmacokinetics.

Medical cannabis represents a promising therapeutic option for fibromyalgia patients due to its effectiveness and relatively low rate of serious adverse effects [7,8]. Although the identification of cannabinoid receptors and their endogenous ligands has triggered a large body of studies, there is a paucity of large-scale and prospective clinical trials regarding their role in fibromyalgia [9]. Only a handful of studies have examined the effect of medical cannabis on fibromyalgia. These studies had rather small sample sizes (31–40 subjects) and a short duration of follow up, which makes the generalizability of the results questionable [10,11,12]. In the current analysis of the prospective registry, we aim to investigate the safety and effectiveness of fibromyalgia patients receiving medical cannabis.

Background: Chronic pain may be treated by medical cannabis. Yet, there is scarce evidence to support the role of medical cannabis in the treatment of fibromyalgia. The aim of the study was to investigate the characteristics, safety, and effectiveness of medical cannabis therapy for fibromyalgia. Methods: A prospective observational study with six months follow-up period based on fibromyalgia patients who were willing to answer questionnaire in a specialized medical cannabis clinic between 2015 and 2017. Results: Among the 367 fibromyalgia patients, the mean age was 52.9 ± 15.1, of whom 301 (82.0%) were women. Twenty eight patients (7.6%) stopped the treatment prior to the six months follow-up. The six months response rate was 70.8%. Pain intensity (scale 0–10) reduced from a median of 9.0 at baseline to 5.0 ( p < 0.001), and 194 patients (81.1%) achieved treatment response. In a multivariate analysis, age above 60 years (odds ratio [OR] 0.34, 95% C.I 0.16–0.72), concerns about cannabis treatment (OR 0.36, 95% C.I 0.16–0.80), spasticity (OR 2.26, 95% C.I 1.08–4.72), and previous use of cannabis (OR 2.46 95% C.I 1.06–5.74) were associated with treatment outcome. The most common adverse effects were mild and included dizziness (7.9%), dry mouth (6.7%), and gastrointestinal symptoms (5.4%). Conclusion: Medical cannabis appears to be a safe and effective alternative for the treatment of fibromyalgia symptoms. Standardization of treatment compounds and regimens are required.

For effectiveness analysis, the primary outcome was treatment response, defined as at least moderate or significant improvement in a patient’s condition at six months follow-up without the cessation of treatment or serious side effects. Patients lost to follow-up were considered as failures for the purposes of the effectiveness analysis. In addition, we assessed the following secondary outcomes:

For safety analysis, we assessed the frequency of medical cannabis-related side effects, including those of patients who ceased cannabis use before six months had passed. We also assessed patients’ perceptions regarding the change in fibromyalgia symptoms in the 6 month follow-up. The following symptoms were included: headaches, dizziness, nausea, vomiting, constipation, drop in sugar, drowsiness, weakness, dry mouth, cough, increased/lack of appetite, hyperactivity, restlessness, cognitive impairment, depression, anxiety, confusion, and disorientation. For disease-related symptoms, patients were asked to report whether each symptom disappeared, improved, deteriorated, or remained unchanged at six months follow up.

In this study, we used a gradual titration process rather than a fixed dose. Initially, all patients received a low dose of cannabis below the therapeutic effect (e.g., a drop of 15% THC-rich cannabis TID). Patients then were instructed to increase the dosage gradually in small intervals (e.g., a single drop per day) until they reached a therapeutic effect (e.g., subjective relief of their pain, significant improvement in their quality of life). In case of inflorescence (each cigarette contained 0.75 g of cannabis), patients were instructed to use one breath every 3–4 h, and to increase the amount gradually in this interval until therapeutic effect is reached. Mixing of oil and inflorescence at the same usage was not recommended. In case of adverse events, patients were instructed to use the last dosage that did not cause undesirable symptoms. The titration was similar for both THC- and CBD-rich strains. In addition, the cannabis provider operated a 24/7 call center to address any concerns that might have been raised by the patients. The final dosage depended on the primary indication for cannabis use, age, medical background, parallel use of other analgesic regimes, and previous exposure to cannabis. All patients underwent one and six month follow-up telephonic interviews. The later was extensive and included an assessment of the change in medical cannabis dose and regimen, change in QOL, disease- and medical cannabis-related symptoms, and alteration in the use and dosage of other medications.

The following are available online at https://www.mdpi.com/2077-0383/8/6/807/s1, Figure S1: Quality of life components on a 5-points Likert scale at baseline and at six months of follow-up. Table S1: Baseline characteristics of the patients stratified by response at six months follow-up. Table S2: Cannabis used by the patients. Table S3: Medical cannabis related adverse events after six months. Table S4: Symptom prevalence at intake and after six months. Table S5: Changes in other drug regimens after six months of treatment with cannabis. Table S6: Study outcomes stratified by primary vs. secondary fibromyalgia.

The change in the utilization of other drugs for the treatment of fibromyalgia after six months is shown in Table S5. Most patients ceased, reduced, or at least did not change the dosage of their chronic drugs for fibromyalgia while receiving medical cannabis. At six months, 28 out of 126 patients (22.2%) stopped or reduced their dosage of opioids (<0.001), and 24 out of 118 (20.3%) reduced their dosage of benzodiazepines ( p < 0.001). When stratifying the analysis to patients with primary vs. secondary fibromyalgia (Table S6), both groups show the same improvement at six months in terms of pain intensity and overall quality of life.

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.

Baseline characteristics of the patient population.

3.2. Safety Analysis.

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 a multivariate logistic regression ( Table 2 ), age above 60 (O.R 0.34, 95% C.I 0.16–0.72) and concerns about cannabis treatment (O.R 0.36, 95% C.I 0.16–0.80) were associated with treatment failure, whereas spasticity at treatment initiation (O.R 2.26, 95% C.I 1.08–4.72) and previous use of cannabis (O.R 2.46 95% C.I 1.06–5.74) were associated with treatment success.

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.

The evaluation of QOL (in 5 points Likert scale) prior to and after six months of medical cannabis treatment is shown in Figure 4 . Whereas prior to treatment initiation 10 patients (2.7%) reported good or very good QOL, after six months of treatment 148 patients (61.9%) reported their QOL to be good or very good ( p < 0.001). When analyzing QOL components, sleep quality, appetite, and sexual activity significantly improved at six months ( p < 0.001, 0.02, and 0.03 respectively, Figure S1). Other components (e.g., mobility, dressing, and concentration) did not improve, and the quality of daily activities deteriorated at six months ( p < 0.001).

Flow chart of the study population.

I.S., L.B.-L.S., and V.N. are responsible for study conception and design. L.B.-L.S. extracted the data. I.S. Drafted the manuscript and conducted the statistical analysis. L.B.-L.S., M.A.-S. and V.N. gave critical revisions.

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].

3.1. Cohort Characteristics.

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].

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.

We identified 367 patients with fibromyalgia who had started the treatment with medical cannabis. During the study period, 35 received medical cannabis for less than six months and were not eligible for six months follow-up, 28 stopped medical cannabis treatment before six months follow-up, four switched to another medical cannabis supplier, and two died within the first six months ( Figure 1 ). Out of the remaining 298 patients treated for six months, 211 responded with the follow-up questionnaire (70.8% response rate). In addition, out of the 87 patients who did not respond to the six months questionnaire, 76 patients (87.3%) were using cannabis at six months. To minimize selection bias, we compared baseline characteristics among six months respondents and non-respondents. As shown in Table S1, there were no differences in baseline characteristics among those who responded to the six months follow-up questionnaire compared to those who did not.

Medical cannabis-related adverse events, reported by patients six months after cannabis use, are shown in Table S3. Overall the most common symptoms were dizziness reported by 19 patients (7.9%), dry mouth by 16 patients (6.7%), nausea/vomiting by 13 patients (5.4%), and hyperactivity by 12 patients (5.5%).

Assessment of the pain intensity on the 0–10 scale before and after six months of cannabis therapy ( p < 0.001).

BMI—body mass index, SD—standard deviation I.Q range—interquartile range, and PTSD—post traumatic stress disorder.

Multivariate analysis for treatment response at six months.

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].