Table 3.

Studies and outcomes.

Study Title	Study	Study Design	Diagnostic Criteria	Inclusion Criteria	FM Group	Control Group	# of all Study Patients	Median Age	Gender Distribution	Co-Morbidities	Exclusion Criteria	Intervention	Route of Administration	Follow-Up Length	Concurrent Therapies	Primary Outcome	Secondary Outcomes	Outcomes	Conclusions
Nabilone for the Treatment of Pain in Fibromyalgia	Skrabek et al. (2008) [19]	RCT, parallel	1990 ACR	18–70 years old with FM, pain despite oral medications; no prior use of oral cannabinoids for pain management	Nabilone	Placebo with four-week washout period	40 randomized (20 per group), 33 completed (15 intervention, 18 control)	Mean of study group: 47.6 (9.13); mean of control group: 50.11 (5.96)	NR	NR	Heart disease; schizophrenia or other psychotic disorder; severe liver dysfunction; untreated nonpsychotic emotional disorders; cognitive impairment; major illness in another organ system	0.5 mg nabilone PO at bedtime × 1 week, increased to 0.5 mg BID after 1 week, and uptitration to max dose of 1 mg BID.	Oral	2-week visit, 4-week visit, and 8-week visit after a 4-week washout period	None specified, but patients were allowed to continue using adjunctive therapies for pain treatment during the study	VAS at 2 and 4 weeks: significant decrease at 4 weeks (2.04, p < 0.02)	Number of tender points, average tender point pain threshold, Fibromyalgia Impact Questionnaire at 2 and 4 weeks	There were significant decreases in the VAS (2.04, p < 0.02), FIQ (12.07, p < 0.02) and anxiety (1.67, p < 0.02) in the nabilone group at 4 weeks. No significant improvements in the placebo group. More side effects in nabilone group at 2 and 4 weeks (1.58, p < 0.02 and 1.54, p < 0.05)	Nabilone is a beneficial, tolerable treatment option for fibromyalgia patients, with benefit sin pain relief and functional improvement
The Effects of Nabilone on Sleep in Fibromyalgia: Results of a Randomized Controlled Trial	Ware et al. (2010) [16]	RCT, cross-over	1990 ACR	18+ years old, adult men and non-pregnant women with FM1 and self-reported chronic insomnia. Twenty subjects remained on stable analgesic therapy with negative urine screening for cannabinoids at the baseline visit. Subjects who were using a cannabinoid or amitriptyline at screening underwent a 2-week washout period before entering the study	Nabilone	Amitriptyline 10–20 mg × 2 week with 2-week washout period	32 randomized, 29 completed	49.5 (11.2)	26 F, 5 M, 1 missing data	NR	Cancer pain, unstable cardiac disease, psychotic disorder, schizophrenia, recent manic episode (within the past year), seizure disorder, glaucoma, urinary retention, hypersensitivity to cannabinoids, amitriptyline, or related tricyclic antidepressants, or were taking monoamine oxidase inhibitors	Crossover study comparing nabilone 0.5–1.0 mg for 2 weeks with 2-week washout period with amitriptyline 10–20 mg as an active control. Patients received one of either drug for two weeks, followed by a two-week washout period, and then started the second drug	Oral	10-week study (initial washout period for previous cannabinoid/tricyclic use, two weeks of one drug, intervening washout period, two weeks of second drug, final washout). Data collected every two-week period	20 subjects were on stable analgesic therapy but had to be negative for cannabinoid use at baseline	Quality of sleep (Insomnia Severity Index and Leeds Sleep Evaluation Questionnaire)	Pain, mood, QOL, global satisfaction with treatment, AEs	Nabilone was superior to amitriptyline (Insomnia Severity Index difference 3.2; 95% confidence interval 1.2–5.3). Nabilone was marginally better for restfulness (Leeds Sleep Evaluation Questionnaire difference 0.5 [0.0–1.0]) but not for wakefulness (difference 0.3 [0.2 to 0.8]). No effects on pain, mood, or QOL were observed. AEs were mostly mild–moderate and were more frequent with nabilone. The most common AEs for nabilone were dizziness, nausea, and dry mouth	Nabilone is well tolerated and effective in improving sleep in patients with FM. Low-dose nabilone given once daily at bedtime may be considered as an alternative to amitriptyline. Longer trials are needed to determine the duration of effect and to characterize long-term safety
Cannabis Use in Patients with Fibromyalgia: Effect on Symptoms Relief and Health-Related Quality of Life	Fiz et al. (2011) [11]	OBS, cross-sectional	1990 ACR	18+ years old with moderate–severe FM symptomatology and resistance to pharmacological treatment	Cannabis		56 (28 THC users, 28 non-users)	50 (11.9)	53 females (26 users, 27 non-users) 3 males (2 users, 1 non-user)	NR	Severe illness and history of abuse or dependence for cannabis or other psychoactive substances	Observational study comparing survey responses of cannabis users and nonusers on perceived benefits of cannabis use, adverse effects, and quality of life	Oral (54%), smoked (46%), and combined (43%)		Concurrent therapies used but no significant differences between THC users and non-users	Quality of life (Fibromyalgia Impact Questionnaire and short-form health survey)	Sleep (Pittsburgh sleep quality index) and perceived benefits of cannabis (VAS)	After 2 h of cannabis use, VAS scores showed a statistically significant (p = 0.001) reduction in pain and stiffness, enhancement of relaxation, and an increase in somnolence and feeling of wellbeing. Mental health component summary score of the SF-36 was significantly higher (p = 0.05) in cannabis users than in non-users. No significant differences were found in the other SF-36 domains, in the FIQ, or in the PSQI	The use of cannabis was associated with beneficial effects on some FM symptoms
An experimental randomized study on the analgesic effects of pharmaceutical-grade cannabis in chronic pain patients with fibromyalgia	Van de Donk et al. (2019) [17]	RCT, cross-over	2010 ACR	18+-year-old females with FM, pain score ≥ 5 for most of the day (pain scale from 0 = no pain to 10 = max)	Each of the subjects tried all 4 substances, including placebo		20	39 (13)	NR	NR	Age < 18 years old, any medical, neurological, or psychiatric illness, use of strong opioids or other painkillers except paracetamol and/or ibuprofen, benzodiazepine use, any known allergies to study medication, illicit drug or alcohol use, recent use of cannabis, pregnancy, breastfeeding, and the presence of pain syndromes other than FM	Patients visited the research unit on 5 occasions. On first visit, the patients were screened and familiarized with the experimental setup. On each of their next visits, the patients received 1 of 4 possible cannabis treatments (in a random order), with at least 2 weeks between visits. These were Bedrocan (22.4 mg THC, <1 mg CBD; Bedrocan International BV, Veendam, the Netherlands), Bediol (13.4 mg THC, 17.8 mg CBD; Bedrocan International BV, Veendam, the Netherlands), Bedrolite (18.4 mg CBD, <1 mg THC; Bedrocan International BV, Veendam, the Netherlands), and a placebo variety without any THC or CBD	Inhaled vapor from balloon	Visits every 2 weeks	Not reported	Relief of experimental pressure pain, electrical pain, and spontaneous pain (VAS)	Plasma concentrations and drug high (Bowdle questionnaire)	No treatment had an effect greater than that of the placebo on spontaneous or electrical pain responses. More subjects receiving Bediol had a 30% decrease in pain scores compared to the placebo (90% vs. 55% of patients, p = 0.01), with spontaneous pain scores correlating with the magnitude of drug high (ρ = −0.5, p < 0.001). Cannabis treatments containing THC caused a significant increase in pressure pain threshold relative to the placebo (p < 0.01). Cannabidiol inhalation increased THC plasma concentrations but diminished THC-induced analgesic effects	None of the treatments were effective in reducing spontaneous pain scores more than the placebo. Further studies are needed to assess efficacy and safety in clinical trials with prolonged treatment periods
Effect of adding medical cannabis to analgesic treatment in patients with low back pain related to fibromyalgia: an observational cross-over single centre study. Clin Exp Rheumatol. 2019 Jan-Feb;37 Suppl 116(1):13–20.	Yassin et al. (2019) [12]	OBS, crossover	Not reported	Symptomatic FM for at least 12 months, symptomatic LBP of more than 12 months between T12 and the gluteal fold, failure of opiate therapy for at least 12 months	N/A	N/A	31	33.4 (12.3)	Not reported	NR	Malignancy, improvement in pain to VAS < 4 after opiate therapy, refusal to undergo medication with duloxetine and opiates, inability to sign an informed consent form, severe cardiovascular disease preventing cannabis administration according to a cardiologist, severe psychiatric disease preventing cannabis administration according to a psychiatrist	3 months of standardized analgesic therapy: 5 mg of oxycodone hydrochloride and 2.5 mg of naloxone hydrochloride twice a day, and duloxetine 30 mg once a day. Following 3 months of this therapy, the patients could opt for medical cannabis (20 g per month) and were treated for a minimum of 6 months	Inhaled (smoking or vaporization)	3- and 6-month follow-up after start of medical cannabis therapy	Oxycodone 5 mg and duloxetine 30 mg	FIQR, VAS, ODI, SF-12, and lumbar range of motion using the modified Schober test	Analgesic drug use was assessed according to the patients’ medical records, including the list of pharmacy-dispensed medications	Medical cannabis therapy allowed a significantly higher improvement in all patient-reported outcomes at 3 months after initiation of medical cannabis, and the improvement was maintained at 6 months. ROM improved after 3 months of medical cannabis therapy and continued to improve at 6 months	Supplementation of analgesic therapy with medical cannabis therapy can alleviate pain in FM patients suffering from LBP
Safety and Efficacy of Medical Cannabis in Fibromyalgia. J Clin Med. 2019 Jun 5;8(6)	Sagy et al. (2019) [14]	OBS	2010 ACR	FM who initiated treatment with medical cannabis from January 2015 to December 2017	N/A	N/A	367	52.9 (8.3)	301 (82%)	Cigarette smokers (37.3%), cancer (9.5%), PTSD (6%)	NR	Low dose of cannabis (e.g., a drop of 15% THC-rich cannabis TID) with gradual increase (e.g., a single drop per day) until they achieved a therapeutic effect (e.g., subjective relief of their pain, significant improvement in their QOL). 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 a therapeutic effect was achieved.	Oil, inflorescence (i.e., smoke), or both	6-Month follow-up	Not reported	Treatment response defined as at least moderate or significant improvement in a patient’s condition at 6-month follow-up	Pain intensity—(NRS) Quality of life—global assessment by the patient using the Likert scale, with five options: very good, good, neither good nor bad, bad, or very bad. Perception of the general effect of cannabis—global assessment by using a Likert scale with seven options: significant improvement, moderate improvement, slight improvement, no change, slight deterioration, moderate deterioration, or significant deterioration	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 a 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 outcomes. The most common adverse effects were dizziness (7.9%), dry mouth (6.7%), and gastrointestinal symptoms (5.4%)	Medical cannabis appears to be a safe and effective alternative for the treatment of fibromyalgia symptoms
Ingestion of a THC-Rich Cannabis Oil in People with Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Pain Med. 2020	Chaves et al. (2020) [18]	RCT, parallel	2010 ACR	>18 years old with moderate-to-severe FM symptoms (presenting functional limitation in everyday activities) despite therapies in use, at least one medical or nursing consultation at the health center in the last year	THC-rich cannabis oil	Olive oil	18	51.9 (9.8)	All F	NR	Decompensated organic comorbidities and/or risk of psychiatric conditions (schizophrenia, psychosis, severe personality disorder, current suicidal ideation), another well-defined cause of chronic pain, current pregnancy/lactation, moderate or severe cognitive impairment, and history of cannabinoid sensitivity	The cannabis group received a 30 mL green glass dropper bottle containing cannabis oil (olive oil extraction) of the White Widow variety, at a 24.44 mg/mL concentration of THC and 0.51 mg/mL of CBD—at a proportion of ∼48/1 THC/CBD, along with small quantities of other cannabinoids such as cannabigerol, tetrahydrocannabivarin, cannabinol, and cannabicromen. The initial dose in both groups was one drop (∼1.2  mg of THC and 0.02 mg of CBD) per day sublingually. Participants in both groups were seen at baseline and every 10 days for eight weeks. Dose increases respected the maximum of one drop for each evaluation moment. At each visit, patients filled out the Fibromyalgia Impact Questionnaire (FIQ)	Oral (Oil)	Participants in both groups were seen at baseline and every 10 days for 8 weeks.	Participants in the cannabis group had previously used antidepressants (62.5%), opioids (25%), and benzodiazepines (12.5%). In the placebo group, the rates of the same classes of medications use were 67%, 33%, and 11%, respectively. Patients self-medicated with mild analgesics and anti-inflammatory pills whenever necessary in both groups	Physical function, work status, wellbeing, and associated physical and mental symptoms in FM patients (FIQ)	Clinical and adverse effects	There were no significant differences in baseline FIQ scores between groups. The cannabis group presented a significant decrease in FIQ score in comparison with the placebo group (p  =  0.005) and in comparison with the cannabis group’s baseline score when compared to post-intervention. (p  <  0.001). The cannabis group presented significant improvements in the “feel good”, “pain”, “do work”, and “fatigue” scores. The placebo group presented significant improvements in “depression” score after the intervention. There were no severe adverse effects	Phytocannabinoids can be an economically feasible and well-tolerated therapy to reduce symptoms and increase the quality of life of patients with fibromyalgia

RCT, randomized controlled trial; OBS, observational study; NR, not reported; F, female; M, male; FM, fibromyalgia; VAS, visual analog scale; NRS, Numeric Rating Scale; ODI, Oswestry Disability Index; FIQR, Fibromyalgia Impact Questionnaire; THC, Tetrahydrocannabinol; SF-12, Short Form Health Survey; AEs, adverse events; BID, twice a day; PO, per os; QOL, quality of life.