Open Access Review
Article

DOI: 10.7759/cureus.17332

A Systematic Review of Fibromyalgia and Recent
Advancements in Treatment: Is Medicinal
Cannabis a New Hope?
Hajra Khurshid 1 , Israa A. Qureshi 1 , Nasrin Jahan 2 , Terry R. Went 1 , Waleed Sultan 1 , Alisha Sapkota 2 ,Michael Alfonso 1
1. Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA 2. Psychiatry, California
Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
Corresponding author: Hajra Khurshid, drhajra1@gmail.com

Abstract
Fibromyalgia syndrome (FMS) is a pain disorder characterized by chronic widespread pain, fatigue, and sleep
disturbance, in the absence of any well-defined underlying organic disease. The exact pathophysiology andthe mechanism which links different factors related to the disease is still unknown. Due to unknown precise
pathogenesis, the coexistence of other diseases, and overlapping clinical features, FMS diagnosis may belaborious. Various treatment strategies are used, only a few Food and Drug Administration (FDA) approved,
still we are facing challenges regarding effective treatment. Recently, medicinal cannabis has proven to beeffective in chronic pain conditions such as osteoarthritis, neuropathic pain, and other non-cancer chronic
pain. However, further research is needed about how the cannabinoid system works with the pain pathway.
Using the fact that medicinal cannabis is effective in the treatment of chronic pain and certain rheumatic
diseases, in this review, we aim to analyze the role of the cannabinoid system in fibromyalgia syndrome.
We followed Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines insearching PubMed, MEDLINE (through PubMed), PubMed Central, and Google Scholar using keywords"fibromyalgia, chronic pain, cannabis, cannabinoids, pharmacotherapy, alternative therapy" and Medical
Subject Heading (MeSH) words.
After applying inclusion/exclusion criteria and checking for the quality assessment, 22 articles wereretrieved and used for the analysis of the role of cannabis in the treatment of fibromyalgia. The two main
compounds of cannabis with analgesic and anti-inflammatory properties are cannabidiol (CBD) and delta-9tetrahydrocannabinol (THC), and their ratio determines the effect on various symptoms of FMS. We
included studies regarding the use of cannabinoids in the treatment of fibromyalgia, investigating the use ofnabilone, dronabinol (a synthetic analog of THC), Bedrocan (22.4 mg THC, <1 mg CBD), Bediol (13.4 mg THC,
17.8 mg CBD), and Bedrolite (18.4 mg CBD, <1 mg THC).
In the era of the coronavirus disease 2019 (COVID-19) pandemic and opioid crisis, many adverse outcomesare observed in the patients suffering from FMS due to lack of any definitive treatment and promisingoutcomes from the known treatment options, which led to the need for effective and safer treatment
alternatives.

Received 07/15/2021
Review began 07/27/2021
Review ended 08/17/2021
Published 08/20/2021© Copyright 2021
Khurshid et al. This is an open accessarticle distributed under the terms of theCreative Commons Attribution License

Although the studies reviewed in this article suggest that medical cannabis is a safe and effective treatment
for fibromyalgia pain, several limitations regarding dosage, length of treatment, adverse effects, long-term
follow-up, and dependence needs further investigation.

CC-BY 4.0., which permits unrestricted
use, distribution, and reproduction in any
medium, provided the original author andsource are credited.

Categories: Internal Medicine, Pain Management, Rheumatology
Keywords: fibromyalgia, chronic pain, cannabis, cannabinoids, pharmacotherapy, alternative therapy

Introduction And Background
Fibromyalgia syndrome (FMS) is a pain disorder with an estimated prevalence of 5-7% in the world, with amean prevalence among the American and European populations of 4% [1]. It is more common in women,with a female to male ratio of 2:1, and can develop at any age. This disease also co-exists with otherrheumatic pathologies. It is estimated that about 20-30% of patients with rheumatic diseases have FMS [2].
The syndrome is characterized by chronic widespread pain, fatigue, and sleep disturbance. The exact
pathophysiology is still unknown, but the most accepted pathology is the alteration of central pain
pathways, which results in hyperalgesia. There is also evidence that supports the role of mast cells in
musculoskeletal pain and central sensitization. The mast cells can mediate the activation of microglia
through the production of cytokines like interleukin 1 beta (IL-1B), interleukin 6 (IL-6), and tumor necrosis
factor (TNF) alpha. Despite all the known facts, the mechanism that links different pathological features
including stress, central sensitization, and dysregulation of innate and adaptive immune response is still

How to cite this article
Khurshid H, Qureshi I A, Jahan N, et al. (August 20, 2021) A Systematic Review of Fibromyalgia and Recent Advancements in Treatment: Is
Medicinal Cannabis a New Hope?. Cureus 13(8): e17332. DOI 10.7759/cureus.17332

unknown, making the treatment approach more challenging [3].
A recent study also showed a link between autoantibodies and FMS, as one-third of FMS patients withxerostomia tested positive for Sjogren's syndrome biomarkers and the majority of them were positive for one
or more tissue-specific autoantibodies. The diagnosis of FMS is also challenging due to the coexistence ofother conditions. FMS is rarely a stand-alone diagnosis, as most patients meet the criteria of otheroverlapping chronic pain conditions or mental disorders. Once diagnosed, the treatment is also challenging.
Various treatment options are available including memantine, naltrexone, tapentadol, duloxetine,
palmitoylethanolamide tablets, and cannabinoids. But none of them have 100% promising results [4].
Formulations using cannabis have been used in clinical settings to study its efficacy in reducing pain when
traditional options have failed [5]. Cannabinoids may be useful in the management of rheumatic disorders
for many reasons, their anti-inflammatory and immunomodulatory activity, and their effect on painassociated symptoms [4]. The analgesic effect of cannabinoids is primarily mediated by cannabinoid
receptors via inhibition of presynaptic gamma-aminobutyric acid (GABA) and glutamatergic transmission[6]. There are two cannabinoid receptors (CB), CB1 and CB2, that are found in the human body. CB1
receptors are predominantly expressed in CNS and CB2 receptors are found mostly outside the CNS.
Moreover, activation of these receptors is believed to have anti-nociceptive effects in controlling the humanperception of pain. Studies have also shown, these receptors play an important anti-inflammatory role inchronic pain conditions [7].
Finally, despite considerable uncertainty regarding the mechanism of action and its exact role in the
management of pain and non-pain symptoms of fibromyalgia, medical cannabis has become a very
important focus for research and controversies in the last few years but it also represents hope for many
patients [2]. In this systematic review, our main goal is to explore the beneficial therapeutic effects ofmedicinal cannabis, in addition to its characteristics and its role in the treatment of fibromyalgia.

Review
Methods
The Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) was used for this study[8]. We identified the articles related to our research question from the databases PubMed, PubMed Central(PMC), MEDLINE (through PubMed), and Google scholar for our research. A search was conducted on April
23, 2021, and an advanced search strategy was used while searching the articles in the main databases. Two
reviewers, HK and IQ, went through the screening process and quality assessment independently. Initially,
16,323 articles were found, and when the search was narrowed to the last five years, 3,162 articles wereretrieved. Specific inclusion/exclusion criteria were applied and only studies in the English language, withhuman subjects, randomized clinical trials, observational studies, review, systematic review, and metaanalysis were included and 454 articles were retrieved. After the initial search, 998 articles were retrieved
from Google Scholar. We checked for duplicates and 20 duplicates were found and removed. After applying
the inclusion/exclusion criteria, the articles that were irrelevant to the research question were excluded.

Results
A total of 363 articles were retrieved after title screening. A total of 250 less relevant articles were excluded,
and 163 articles were retained. A total of 114 more articles were excluded after checking the eligibility
criteria and 49 articles were retrieved and checked for the quality assessment using AMSTAR (assessing themethodological quality of systematic reviews) for systematic review and meta-analysis, Cochrane risk bias
assessment tool for clinical trials, Newcastle-Ottawa Scale for observational studies, and SANRA (scale forthe quality assessment of narrative review articles) for review articles, and 49 final full-text articles wereretrieved for study. A total of 25 more articles were excluded after reading the full text, assessing the quality
appraisal and relevance related to the research question. Finally, 22 articles were retrieved for study. Figure
1 shows the flow diagram for the search strategy outlining our search process [8].

2021 Khurshid et al. Cureus 13(8): e17332. DOI 10.7759/cureus.17332

2 of 11FIGURE 1: PRISMA flow diagram (2020) showing the search results andselection process.
PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analysis.

Discussion
Fibromyalgia (FM) is a syndrome characterized by chronic pain with multiple tender points, increased pain
sensitivity, and other systemic symptoms like cognitive dysfunction, sleep disturbance, anxiety, chronic
fatigue, and depression, in the absence of any well-defined underlying organic disease [9]. In most cases, thepain is not explained by inflammation or injury. In other words, there is sensory hyperresponsiveness andhypersensitization to pain [3].
With the recent coronavirus disease 2019 (COVID-19) pandemic situation, the patients with FM syndrome
reported adverse mental and physical outcomes, and this exacerbation of symptoms can be related to theincreasing level of anxiety, economic hardships, and social isolation [10], which led to the importance of
exploring the definitive effective treatment options for FMS.
Pathophysiology and Diagnosis
The etiology of this disease is still unknown, and the research in this field has expanded considerably,
exploring the genetics, immune system, autonomic system, inflammatory response, neurotransmitters, andpsychological factors [2]. Initially, it was recognized as pain syndrome in individuals with a high level of2021 Khurshid et al. Cureus 13(8): e17332. DOI 10.7759/cureus.17332

3 of 11stress, but now it is known that there is not a single trigger defining this disease. The most important
pathological mechanism is the alteration of central pathways or central sensitization with amplification ofpain perception. The hypothalamic-pituitary-adrenal (HPA) axis is considered to play an important role in
the establishment of central sensitization [3,4]. Additionally, stress causes the release of corticotropinreleasing hormone (CRH) from the hypothalamus, which acts on the anterior pituitary resulting in therelease of adrenocorticotropic hormone (ACTH) from the anterior pituitary, which modulates the immune
response through the secretion of glucocorticoids by stimulating the adrenal glands. This includes mast cells
degranulation, which can lead to sensitization of peripheral and central nociceptors and the increase of proinflammatory cytokines [3]. Figure 2 shows the proposed mechanisms of FMS pathogenesis.

FIGURE 2: FMS pathogenesis.
FMS, fibromyalgia syndrome; CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone.

In addition to the stress regulation and inflammatory response, the HPA axis and the sympathetic adrenalmedullary axis are also involved. Some studies in animals also suggest the involvement of T-cells
autoimmune response in hyperalgesia; nevertheless, the results of the studies indicating the changes
specific to T-cell are inconclusive [3]. One interesting hypothesis favors the role of the thalamic mast cellthat may contribute to the release of histamine, interleukin-1 beta, IL-6, tumor necrosis factor (TNF), andcalcitonin gene-related peptide, which stimulates nociceptive neurons directly or indirectly by stimulationof microglia [4]. The evidence that supports the role of mast cells in fibromyalgia states that CCL1 (eotaxin1) and CCL2 (eotaxin-2), which function as potent chemoattractants for inflammatory cells, were found to beelevated in patients with FMS [3].
It is also hypothesized that lack of endocannabinoids activity is the possible pathophysiology offibromyalgia [1,9,11], and cannabinoids can reduce sensitization of nociceptive sensory pathways in chronic
pain states, but there is no evidence enough to support this hypothesis yet [6]. Recent research said FMS
pain is non-nociceptive and non-neuropathic, and the new term introduced is “Nociplastic Pain,” referringto the pain without any obvious tissue damage. For example, pain arising from altered nociception despite
any clear evidence of inflammation [4]. The term nociplastic pain also has its limitations; it can be applied tosome of the pathologies related to FBS but it does not apply to FM syndrome if we consider the bio-psychosocial model to understand the natural history of fibromyalgia [2].
The exact diagnosis requires certain guidelines that reflect not only the classification criteria but also explain
the pathogenesis. Due to still unknown pathophysiology, the diagnosis is even more challenging and about
75% of patients remain undiagnosed [4,9]. As it is not possible to rely on a single symptom,
various composite indices have been described, encompassing the main features of this poly-symptomatic
disease such as pain, fatigue, sleep alteration, neurocognitive disorders, anxiety, and depression. The mostwidely used diagnostic tools include the Fibromyalgia Impact Questionnaire (FIQ) and its revised version(FIQR), the Fibromyalgia Assessment Status (FAS), the Fibromyalgia Survey Criteria (FSC), and the Patient
Health Questionnaire 15 (PHQ15) [2].
Treatment Strategies
Various pharmacological and non-pharmacological therapies can be used for the treatment of FM.
Pharmacological therapy is primarily aimed at lowering the level of pro-nociceptive neurotransmitters.
There are only a few drugs approved by the Food and Drug Administration (FDA) for FM: pregabalin,2021 Khurshid et al. Cureus 13(8): e17332. DOI 10.7759/cureus.17332

4 of 11duloxetine, and milnacipran [11]. As there is no conclusive evidence providing the benefit of any specifictherapy for the treatment of FMS, thus none of the drugs has been approved by the European Medicine
Agency [9], and European League against Rheumatism [EULAR] guidelines suggest non-pharmacologicalinterventions as the first line of treatment [12].
Due to the complex nature of the disease, a multidimensional approach is proposed, including nonpharmacological methods in addition to pharmacological treatment, which include acupuncture, cognitive
behavioral therapy, hyperbaric oxygen therapy, mindfulness, massage, and transcranial magnetic
stimulation. Although outcomes are encouraging, further studies are required to assess the effectiveness ofthese methods alone or in combination [13].
New treatment options are under investigation: mirtazapine, an alpha-2 antagonist with serotonergic andnoradrenergic effects, milnacipran, a serotonin-norepinephrine reuptake inhibitor, and opioids. The
mentioned treatments have been assessed for effectiveness, but the results are so far controversial. The
cannabis plant seems to be a promising tool to fight fibromyalgia chronic pain [2]. Therefore, there is anintense need to explore other pharmacological effects, efficacy, and safety of cannabis for the treatment offibromyalgia.
Cannabinoids for Fibromyalgia
Given the fact that we are in the era COVID-19 pandemic and an ongoing opioid crisis, there is an absoluteneed for effective and safer treatment alternatives for chronic pain syndrome including FM. With a highmargin of safety and proposed regulatory effects of tetrahydrocannabinol (THC) and cannabidiol (CBD) on
major endogenous pain circuitry systems, cannabis is emerging as a promising alternative treatment option
for the management of chronic pain [14].
Regarding the complex function of the endocannabinoid system in pain modulation, it is hypothesized thatlack of endocannabinoids activity is among the underlying pathophysiology of FM but there is no clear
evidence to support this assumption [1,9,11,15]. It is also hypothesized that cannabinoids reduce thesensitization of nociceptive sensory pathways in chronic pain states [15]. Moreover, the endocannabinoid
system is involved in the modulation of other physiological functions, such as inflammation, endocrine
function, cognition, memory, nausea, anti-nociception, and vomiting [9]. A study suggests thatcannabinoids might function to reduce stress and modulate cognitive and emotional functions [15]. The
endocannabinoids act as ligands at cannabinoid receptors CB1 and CB2; CB1 receptors are predominantly
expressed in the central nervous system (CNS), whereas CB2 receptors are found mostly outside the CNS.
Abundant preclinical data support that when these receptors are activated, pain stimulus is suppressed,
influencing nociception [7,15].
The analgesic effects of cannabinoids and their ligands are primarily mediated by the CB1 receptor via
inhibition of presynaptic gamma-aminobutyric acid (GABA) and glutamatergic transmission, which
suppresses neuronal excitability [6]. Although many cannabinoids are identified, out of them only
tetrahydrocannabinol (THC) and cannabidiol (CBD) are the clinically relevant components. Both act on CB1
and CB2 receptors. THC influences pain, appetite, orientation, and mood; while CBD has anti-inflammatory,
anti-anxiety, and analgesic effects. Although THC and CBD both act on cannabinoid CB1 and CB2 receptors;
THC is a receptor partial agonist, while CBD is a negative allosteric modulator of the CB1 receptor. Due totheir varying properties, the proportion of THC to CBD in cannabis products determines the therapeutic andadverse effects [1]. According to the “entourage theory,” the combination of THC and CBD creates asynergistic effect suggesting that there could be a benefit in using cannabis as an analgesic or therapeutic
agent [12]. As cannabis and cannabinoids were recommended for the treatment of neuropathic pain and dueto the similarities between neuropathic pain and fibromyalgia; it is hypothesized that cannabis orcannabinoids might be effective for fibromyalgia-associated pain as well [12]. Several review articles wereassessed for data extraction. The summary of these articles along with the results and conclusions is given
in Table 1.

Authors
and yearPurpose of studyofpublication
Walitt etal. (2016)[15]

Lawson etal. (2017)

To determine the efficacy,
safety, and tolerability ofcannabinoids forfibromyalgia.

To explore the latest
pharmacological strategies

Results

No evidence of at least 30-50% reduction inpain, no significant difference from the effect ofConclusion

The tolerability of nabilone is low andno convincing evidence was foundplacebo.

suggesting that nabilone can be used
for the treatment of FM.

The cannabinoids nabilone (0.5-1.0 mg/d) andDue to certain limitations including thedronabinol (a synthetic form of delta-9
tetrahydrocannabinol (THC); 7.5 mg/d)

incidence of adverse effects and dropout rates up to 25% during the clinical2021 Khurshid et al. Cureus 13(8): e17332. DOI 10.7759/cureus.17332

5 of 11[13]for the treatment ofsignificantly reduced pain, depression, andtrials; no concluding evidence can be

fibromyalgia.

anxiety levels in patients with FM also leading
to an improved quality of life.

drawn of cannabinoids for thetreatment of FM.

Medical cannabis for the

There are some suggestions of benefit with

The results are inconclusive, cannabis-

Banerjee et treatment of chronic pain,al. (2019)neuropathic pain,

cannabis for neuropathic pain; however,findings are inconsistent for the effect ofbased medicines may or may not be
offered; depending on the type of[16]

cannabis-based medicines in patients withrheumatic disease and fibromyalgia.

cannabis-based medicine and patient
condition

rheumatologic pain,
fibromyalgia.
To study the literature

Cameronet al.

(2015–2019) on the safety
and efficacy of medical(2020) [1]cannabis for the treatmentof fibromyalgia.

Tal Gonen

Use of cannabinoids andet al.
(2020) [12]cannabis as a treatment forrheumatic diseases.

Tzadok et

To study current and

There are certain limitations in the
Medical cannabis is found to be a safe andeffective treatment for fibromyalgia pain.

Nabilone and dronabinol showed Improvement

Maffei et

To study the diagnostical. (2020)[9]criteria for FM as well as toexplore pharmacotherapy.

To study the etiology,
pathogenesis, andtreatment of FM.

To review the literature
Birks et al.
(2021) [17]regarding the effects ofcannabinoids and/or
cannabis on chronic pain.

Chang etal. (2021)[18]

Medical cannabis forpatients with chronic
noncancerous pain
including neuropathic pain,
low back pain, rheumatoid
arthritis, and fibromyalgia.

cannabis-based medicines regarding
the treatment of FM and need more
research.

in pain and anxiety in several randomized
emerging pharmacotherapy
controlled trials and meta-analyses. THC and
for fibromyalgia.
CBD, therefore, determines the overall effect.

al. (2020)[4].

pain management in fibromyalgia
patients cannot be made.
The results are inconclusive ofCannabis and cannabinoids could relieve someof the symptoms associated with fibromyalgia.

al. (2020)[11]

Bazzichi etstudies due to which conclusions
regarding the use of cannabinoids for

Research suggests the use of
cannabinoids for FM patients withsleep abnormalities. Further studies
are needed to determine the exact
pathogenesis of FM, andendocannabinoid system alteration.

The synthetic cannabinoid and nabilone areSome adverse effects weresuperior to placebo and showed significant
reductions in the visual analog scale (VAS) for

experienced, which suggests further
studies to modify the dose-effectpain.

relationship.

There is a promising analgesic role of cannabis

There are promising analgesic effectsof cannabinoids observed in FM

patients. The complex behavior of
products when used alone or in combination forinhaled cannabinoids in patientsthe treatment of fibromyalgia patients.
suffering from chronic pain needs
further study.
There was no evidence of cannabinoids and/or
cannabis effectiveness in individuals sufferingfrom chronic pain.

Cannabinoids can be used for neuropathic pain
but first-line therapy should not be replaced.
This study was on neuropathic pain includingFM, not exclusively on FM; and then results canbe inconclusive.

There was no evidence for the use of
cannabinoids and/or cannabis in thetreatment of chronic pain. Futurestudies should be done.
Well-designed and large RCTs withreasonable long-term follow-up are
required with detailed discussions on
benefits in reducing pain and potential
adverse effects are required before its
prescription.

TABLE 1: Showing the summary of systematic review and literature review articles along withresults and conclusions.
THC, tetrahydrocannabinol; CBD, cannabidiol; FM, fibromyalgia; RCT, randomized control trials.

The results of several old studies showed certain limitations as most of them involved the use ofnabilone and dronabinol (a synthetic delta-9-THC), and concluded with the certain incidence of noticeable
adverse effects and low tolerability depending upon the patient’s conditions and loss of follow-up with mostof the patients [13,15,16]. However, some recent studies showed that cannabinoids could be safe, effective,
and potentially alleviate some of the symptoms associated with fibromyalgia; also, they found that nabilone
is superior to placebo and showed significant reductions in visual analog scale (VAS) for pain [1,4,9,12]. One
study consisting of cannabinoids for non-cancer pain, which also included FM patients, concluded thatcannabinoids can be used for neuropathic pain but should not replace the first-line therapy. As this study
was on neuropathic pain including FM, not exclusively on FM, results are inconclusive and we cannot

2021 Khurshid et al. Cureus 13(8): e17332. DOI 10.7759/cureus.17332

6 of 11generalize the results based on these findings only [18].
In one other recent study, nabilone and dronabinol showed improvement in pain and anxiety in several
randomized controlled trials and meta-analyses. Tetrahydrocannabinol to cannabidiol ratio (THC:CBD)
therefore determines the overall effect. It also concluded that manipulating the endocannabinoid system isgradually emerging as another fascinating strategy for treating pain and suggested future research into theclinical utility of endocannabinoid metabolism manipulation in FMS [11].
Therapeutic Use of Cannabis for Fibromyalgia
Findings regarding the use of cannabinoids in the treatment of fibromyalgia consisted of several studies,
investigating the use of nabilone, dronabinol, a synthetic analog of THC, Bedrocan (22.4 mg THC, <1 mg
CBD), Bediol (13.4 mg THC, 17.8 mg CBD), and Bedrolite (18.4 mg CBD, <1 mg THC) [19]. The clinical studies
assessed and their findings are summarized in Table 2.

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7 of 11

Authorand yearofpublication

Yassin etal. (2019)[20]

Van deDonk et al.
(2019) [19]Purpose of study

Effect of adding
cannabis toanalgesic
treatment in FM
patients with low
back pain.

No. of

Type ofpatients study

31

Observationalcross-oversingle-center
study.

The analgesic
effects ofRandomized

pharmaceuticalgrade cannabis inchronic pain
patients withplacebocontrolled
crossovertrial.

20

fibromyalgia.

Safety andSagy et al.
(2019) [21]efficacy of
medical cannabis
in fibromyalgia.

367

study.

Adding medicalcannabis toGiorgi et al. standard(2020) [22] analgesic
treatment for
fibromyalgia.

A prospective
observational102

A prospective
observational
study.

A
Chaves etal. (2020)[23]

Safakish etal. (2020)[14]

Ingestion of THCrich cannabis oilin people withfibromyalgia.

Medical cannabis
for painmanagement andquality of life
improvement.

17

751

randomized,
double-blind,placebocontrolled
clinical trial.
Alongitudinal,prospective,
observational
study.

Results

Medical cannabis showed asignificant improvement in threemonths after initiation of therapy andthe improvement was maintained at
six months.

This experimental trial showed thecomplex behavior of different
inhaled cannabinoids compounds inchronic pain patients with just small
analgesic responses after a single
inhalation.
Pain intensity (scale 0–10) reduced
from a median of 9.0 at baseline to
5.0 (p < 0.001), and 81.1% of
patients achieved treatment
response. Mild adverse effects weredizziness, dry mouth, andgastrointestinal symptoms.

Conclusion

This observational crossoverstudy showed improvement ofback pain in FM patients treatedwith medical cannabis. Further
randomized clinical trial studies
are suggested for assessment.

Further studies are needed todetermine long-term treatment
effects on spontaneous painscores, THC–CBD interactions,and their role in pain relief.

Medical cannabis appears to bea safe and effective alternative
for the treatment of fibromyalgia
symptoms. Standardization oftreatment regimens is required.

After six months, 50% showed a
There is a possible clinicalmoderate improvement in the anxiety advantage of medical cannabis
and depression scales. One-third
experienced mild adverse events but
did not cause any significant
treatment modifications.
Cannabis showed a decrease in
Fibromyalgia Impact Questionnaire(FIQ) score in comparison with theplacebo group (p = 0.005). There
were no intolerable adverse effects.
Medical cannabis was associatedwith improvements in pain severity
and interference (p < 0.001)
observed at one month andmaintained over 12 months.

in FM patients, especially inthose with sleep dysfunctions;further studies are needed toconfirm these data.
Cannabinoids can be used toreduce symptoms and increase
the quality of life of patients withfibromyalgia. Future studies arestill needed to assess long-term
benefits.
The results were promising but
the percentage of patients withfibromyalgia included in thisstudy is 17.6%, which is very
low to make any conclusion.
Cannabinoids may be used as

Mazza etal. (2021)[24]

Medical cannabis
for the treatmentof fibromyalgia
syndrome.

A
38

retrospective,
open-labelcase series.

Significant improvements (p < 0.01)
were observed in NRS, ODI, WPI,and SyS for 12 months.

an alternative treatment forpatients with FM who areunresponsive to conventional
therapy. However, it is limited by
the incidence of non-serious
adverse effects.

TABLE 2: Showing the observational studies, clinical trials, and case series conducted on the useof cannabis for the treatment of fibromyalgia.
THC, tetrahydrocannabinol; CBD, cannabidiol; FM, fibromyalgia; FIQ, Fibromyalgia Impact Questionnaire; NRS, Numerical Rating
Scale; ODI, Oswestry Disability Index; WPI, Wide Pain Index; SyS, severity score.

In one experimental study designed to examine the effect of adding medical cannabis to analgesic
treatment, which consisted of 38 patients treated for three months with standard analgesic therapy withminor improvement in the symptoms, treated with medical cannabis therapy for a minimum of six months,

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8 of 11

which resulted in higher improvement in all patient-reported outcomes (PROs), which included
Fibromyalgia Impact Questionnaire (FIQ), visual analog scale (VAS), Oswestry Disability Index (ODI), andlumbar range of motion (ROM), which was recorded using the modified Schober’s test [20].
Another study, consisting of 20 patients carried on the same principle but different cannabis compounds,
showed the complex behavior of different inhaled cannabinoids compound in chronic pain patients with justsmall analgesic responses after a single inhalation. Four different cannabis varieties were tested including
Bedrocan (22.4 mg THC, <1 mg CBD), Bediol (13.4 mg THC, 17.8 mg CBD), Bedrolite (18.4 mg CBD, <1 mg
THC), and a placebo variety without any THC or CBD. The study results showed that none of the treatments
had an effect greater than placebo on spontaneous or electrical pain responses, although more subjects
receiving Bediol displayed a 30% decrease in pain scores compared to placebo. It also showed antagonistic
pharmacodynamic interactions of THC and CBD. So further studies are needed to determine long-term
treatment effects on spontaneous pain scores, THC-CBD interactions, and their effects on pain relief. In thisstudy, two experimental pain tests were performed, the electrical pain test and pressure pain test; pressure
pain threshold increased significantly in patients treated with Bedrocan and Bediol. In addition, Bediol had
notably greater effects than Bedrolite so significantly more patients responded to Bediol. Bedrolite, acannabis variety with a high CBD content, was devoid of analgesic activity in any of the spontaneous or
evoked pain models [19].
About further studies, one study consisting of 367 patients conducted to investigate the safety and efficacy
of medical cannabis in fibromyalgia was conducted on patients who were willing to answer the questionnaire
in a specialized medical cannabis clinic between 2015 and 2017. It concluded that medical cannabis appears
to be a safe and effective alternative for the treatment of fibromyalgia symptoms with certain limitations likestandardization of treatment compounds and regimens, which require more research. This study included
patients with six months follow-up and the response rate was 70.8%. The pain intensity reduced from a
median of 9.0 at baseline to 5.0 on a pain scale 0-10 (p < 0.001), and 194 patients (81.1%) achieved treatment
response. The most common adverse effects were mild and included dizziness, dry mouth, andgastrointestinal symptoms [21].
With previous knowledge on two different compounds (Bedrocan and Bediol), another study carried out tostudy further outcomes, included 102 FM patients to assess any clinical improvement following the additionof medical cannabis treatment (MCT) to the stable (≥ three months) standard analgesic treatment of FM
patients. Patients were prescribed two oil-diluted cannabis extracts: Bedrocan (22% THC, <1% CBD), andBediol (6.3% THC, 8% CBD). FM severity was periodically assessed using the Fibromyalgia Impact
Questionnaire (FIQ), Fibromyalgia Assessment Scale (FAS), Functional Assessment of Chronic Illness
Therapy (FACIT) Fatigue score, Pittsburgh Sleep Quality Index (PSQI), and Zung Depression and Anxiety
Scales. During the study, patients were allowed to reduce or stop their concomitant analgesic therapy.
Finally, 50% showed a moderate improvement in anxiety and depression; besides, analgesic treatment was
reduced or suspended in 47% of the patients. In general, only one-third experienced mild adverse events.
Overall, it showed that adjunctive MCT offers a possible clinical advantage in FM patients [22].
In another study, a double-blind randomized placebo-controlled clinical trial consisting of 17 women thatwere conducted for eight weeks to determine the benefit of THC-rich cannabis oil on symptoms and qualityof life, concluded that cannabinoids can be a low-cost and well-tolerated therapy to reduce symptoms andincrease the quality of life of patients with fibromyalgia. The Fibromyalgia Impact Questionnaire (FIQ) wasapplied at pre- and post-intervention moments and in five visits over eight weeks. After the intervention,
the cannabis group presented a significant decrease in FIQ score in comparison with the placebo group [23].
A study on the effect of cannabinoids on chronic pain patients including 132 FM patients out of a total of
751 patients with chronic pain with other underlying conditions, also showed promising results, but thepercentage of patients with fibromyalgia included in this study is 17.6%, which is very low to make arelevant assumption. Nevertheless, results concluded over patients were promising with improved painscores over 12 months. Moreover, the medical cannabis (MC) treatment course in this study was not
associated with increases in the frequency of undesired adverse events, but rather decreased the frequencyof headaches, fatigue, feelings of anxiety, and nausea [14].
Recently a retrospective, open-label case series consisting of 38 patients was conducted to study the efficacy
and adverse events (AEs) of short- and long-term MC treatment for FM concluded that MC may be used as
an alternative treatment for patients with FMS who are unresponsive to conventional therapy. However, its
application may be limited by the incidence of non-serious adverse effects. The study was conducted for 12months with follow-up at 1, 3, and 12 months. The results were interpreted based on certain scales including
Numerical Rating Scale (NRS), Oswestry Disability Index (ODI), Hospital Anxiety and Depression Scale(HADS), Widespread Pain Index (WPI), and Severity Score (SYS). The most common side effects were mental
confusion, dizziness, nausea/vomiting, and restlessness/irritation [24].
All these studies showed the significant advantage of MC in treating pain in patients with FMS with a few
non-serious adverse effects. Medical cannabis appears to be a safe and effective alternative for the treatmentof fibromyalgia symptoms.

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As FM is a syndrome of symptoms with still not completely known pathogenesis, it might pose additionaldifficulty in treating it. Also, with the recent advancements and studies regarding lack of endocannabinoid
activity as a possible cause of the disease process, cannabis is considered a future hope for treating FM
syndrome as it has shown a significant advantage in treating this condition with very few adverse effects.
Future studies are still needed to assess long-term benefits, THC-CBD interactions, and their effects on pain
relief, to determine and standardize treatment regimens, to assess long-term benefits, dose-response
relationship, and dependence.

Limitations
There are certain limitations in our study, as we only used articles in the English language, conducted only
on humans, and published in the last five years; hence, certain valuable studies could have been excluded.

Conclusions
Our main aim was to assess the safety and efficacy of cannabinoid compounds for the treatment of FMS. At
this point, the data suggest that the use of cannabinoids and cannabis carries limited side effects in thetreatment of FM, and they can also improve some common and debilitating symptoms associated with FM,
thus making them an adequate potential treatment option, when other treatment lines have been
exhausted.
Ultimately, we believe that the use of cannabis and cannabinoids for pain relief in fibromyalgia has shown
great potential and maybe a source of hope for those suffering from chronic pain associated with thiscondition, and for the physicians treating them; however, benefits need to be weighed against the harmful
effects, and more research into this area should be conducted, for longer periods, to assess for long-term
efficacy, adverse effects, and dependence. The ratio of TCH:CBD also seems to be an important factor in theoutcome, which needs further research. So more clinical trials with long-term follow-up and study on thedose-response relationship and dependence need to be done.

Additional Information
Disclosures
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare thefollowing: Payment/services info: All authors have declared that no financial support was received fromany organization for the submitted work. Financial relationships: All authors have declared that they haveno financial relationships at present or within the previous three years with any organizations that might
have an interest in the submitted work. Other relationships: All authors have declared that there are noother relationships or activities that could appear to have influenced the submitted work.

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