Cannabis for the Treatment of Fibromyalgia: A Systematic Review

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“Fibromyalgia is a common disease syndrome characterized by chronic pain and fatigue in conjunction with cognitive dysfunction such as memory difficulties. Patients currently face a difficult prognosis with limited treatment options and a diminished quality of life. Given its widespread use and potential efficacy in treating other types of pain, cannabis may prove to be an effective treatment for fibromyalgia. This review aims to examine and discuss current clinical evidence regarding the use of cannabis for the treatment of fibromyalgia. An electronic search was conducted on MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus using Medical Subject Heading (MeSH) terms on all literature published up to October 2022. A follow-up manual search included a complete verification of relevant studies. The results of four randomized controlled trials (RCTs) and five observational studies (a total of 564 patients) that investigated the effects of cannabis on fibromyalgia symptoms were included in this review. Of the RCTs, only one demonstrated that cannabinoids did not have a different effect than placebo on pain responses. Overall, this analysis shows low-quality evidence supporting short-term pain reduction in people with fibromyalgia treated with cannabinoid therapeutics. Although current evidence is limited, medical cannabis appears to be a safe alternative for treating fibromyalgia.”

The modulatory role of cannabis use in subconcussive neural injury

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“Cannabis use has become popular among athletes, many of whom are exposed to repetitive subconcussive head impacts. We aimed to test whether chronic cannabis use would be neuroprotective or exacerbating against acute subconcussive head impacts. This trial included 43 adult soccer players (Cannabis group using cannabis at least once a week for the past 6 months, n = 24; non-cannabis control group, n = 19). Twenty soccer headings, induced by our controlled heading model, significantly impaired ocular-motor function, but the degrees of impairments were less in the cannabis group compared to controls. The control group significantly increased its serum S100B level after heading, whereas no change was observed in the cannabis group. There was no group difference in serum neurofilament light levels at any time point. Our data suggest that chronic cannabis use may be associated with an enhancement of oculomotor functional resiliency and suppression of the neuroinflammatory response following 20 soccer headings.”

“Our data show that chronic cannabis use may be associated with an enhancement of oculomotor functional resiliency and suppression of the neuroinflammatory response following soccer heading.”

Cannabis sativa-based oils against aluminum-induced neurotoxicity

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“The use of terpenoid compounds in different neural-related conditions is becoming useful for several illnesses. Another possible activity of these compounds is the reduction of nervous impairment. Cannabis sativa plants are known for their concentration of two important terpenoids, the delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). CBD and THC have central peripheral activities already described and their usage in different brain diseases, such as Alzheimer’s and multiple sclerosis. Aluminum (Al) is known as an important neurotoxic compound, the physiological action of Al is not known already, and in high concentrations can lead to intoxication and cause neurotoxicity. Here we evaluated the potential effect of two different doses of CBD- and THC-rich based oils against Al-induced toxicity, in the zebrafish model. We evaluated behavioral biomarkers of the novel tank test (NTT) and social preference test (SPT), and biochemical markers: the activity of the enzyme acetylcholinesterase (AChE) and the antioxidant enzymes-catalase, superoxide dismutase, and glutathione-S-transferase. CBD- and THC-based oils were able to increase the AChE activity helping the cholinergic nervous system actuate against Al toxicity which was reflected by the behavioral biomarkers changes. We concluded that the oils have a protective effect and might be used with proposals for neurological and antioxidant impairment avoidance caused by Al intoxications.”

“In our study, we observed that Al is responsible for neurotoxicity, especially causing AChE decrease. The main effect of Al is related to reduced social ability and anxiety-like patterns. The testes oil THC- and CBD-rich have an important role in AChE reestablishment and social ability reacquisition. In addition, both oils exert an outstanding effect on antioxidant enzyme modulations with the re-establishment of the SOD and CTL after Al exposition. The activity of GST was also well modulated indicating that the oils played a crucial role in cellular damage avoidance. However, the oils do not change the impaired anxiety-like behavior that looks to be linked to other central signaling pathways and needs to be well investigated in the next studies. Finally, the oils have a protective effect and might be used with proposals for neurological and antioxidant impairment avoidance.”

Delta 9-tetrahydrocannabinol conserves cardiovascular functions in a rat model of endotoxemia: Involvement of endothelial molecular mechanisms and oxidative-nitrative stress

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“In endotoxemic models, the inflammatory parameters are altered to a favorable direction as a response to activation of cannabinoid receptors 1 and 2. The phytocannabinoid Δ9-tetrahydrocannabinol (THC) is an agonist/partial antagonist of both cannabinoid receptors. This report targets the effects of THC on the cardiovascular system of endotoxemic rats. In our 24-hour endotoxemic rat model (E. coli derived lipopolysaccharide, LPS i.v. 5mg/kg) with THC treatment (LPS+THC 10 mg/kg i.p.), we investigated cardiac function by echocariography and endothelium-dependent relaxation of the thoracic aorta by isometric force measurement compared to vehicle controls. To evaluate the molecular mechanism, we measured endothelial NOS and COX-2 density by immunohistochemistry; and determined the levels of cGMP, the oxidative stress marker 4-hydroxynonenal, the nitrative stress marker 3-nitrotyrosine, and poly(ADP-ribose) polymers. A decrease in end-systolic and end-diastolic ventricular volumes in the LPS group was observed, which was absent in LPS+THC animals. Endothelium-dependent relaxation was worsened by LPS but not in the LPS+THC group. LPS administration decreased the abundance of cannabinoid receptors. Oxidative-nitrative stress markers showed an increment, and cGMP, eNOS staining showed a decrement in response to LPS. THC only decreased the oxidative-nitrative stress but had no effect on cGMP and eNOS density. COX-2 staining was reduced by THC. We hypothesize that the reduced diastolic filling in the LPS group is a consequence of vascular dysfunction, preventable by THC. The mechanism of action of THC is not based on its local effect on aortic NO homeostasis. The reduced oxidative-nitrative stress and the COX-2 suggest the activation of an anti-inflammatory pathway.”

“The presented results support the notion that a non-selective CB1/2R agonist–partial antagonist may have therapeutic potential in the treatment of sepsis. In our model, the decrement of cardiac filling and the consequential decline of the cardiac output was prevented by THC treatment, due to the maintained endothelial function. One possible mechanism of the more pronounced endothelium-mediated vasodilation is the decreased thromboxane A2 release due to the lessened inducible cyclooxygenase expression, the other salvaging mechanism is the dampened oxidative-nitrative stress. The activation of endocannabinoid system in inflammation and endotoxemia was earlier described; however, the diminished abundance of both cannabinoid receptors in endotoxemia was not detected. The decreased oxidative-nitrative stress and DNA damage are potentially beneficial in a systemic inflammation, and the reduced inflammatory response may help in the prevention to a quick and robust pro-inflammatory cytokine release (cytokine storm).”

Trial of a Novel Oral Cannabinoid Formulation in Patients with Hypertension: A Double-Blind, Placebo-Controlled Pharmacogenetic Study

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“Cannabidiol (CBD) is a non-psychoactive cannabinoid, and available evidence suggests potential efficacy in the treatment of many disorders. DehydraTECH™2.0 CBD is a patented capsule formulation that improves the bioabsorption of CBD. We sought to compare the effects of CBD and DehydraTECH™2.0 CBD based on polymorphisms in CYP P450 genes and investigate the effects of a single CBD dose on blood pressure. In a randomized and double-blinded order, 12 females and 12 males with reported hypertension were given either placebo capsules or DehydraTECH™2.0 CBD (300 mg of CBD, each). Blood pressure and heart rate were measured during 3 h, and blood and urine samples were collected. In the first 20 min following the dose, there was a greater reduction in diastolic blood pressure (p = 0.025) and mean arterial pressure MAP (p = 0.056) with DehydraTECH™2.0 CBD, which was probably due to its greater CBD bioavailability. In the CYP2C9*2*3 enzyme, subjects with the poor metabolizer (PM) phenotype had higher plasma CBD concentrations. Both CYP2C19*2 (p = 0.037) and CYP2C19*17 (p = 0.022) were negatively associated with urinary CBD levels (beta = -0.489 for CYP2C19*2 and beta = -0.494 for CYP2C19*17). Further research is required to establish the impact of CYP P450 enzymes and the identification of metabolizer phenotype for the optimization of CBD formulations.”

The Influence of Oral Cannabidiol on 24-h Ambulatory Blood Pressure and Arterial Stiffness in Untreated Hypertension: A Double-Blind, Placebo-Controlled, Cross-Over Pilot Study

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“Introduction: Studies reveal that cannabidiol may acutely reduce blood pressure and arterial stiffness in normotensive humans; however, it remains unknown if this holds true in patients with untreated hypertension. We aimed to extend these findings to examine the influence of the administration of cannabidiol on 24-h ambulatory blood pressure and arterial stiffness in hypertensive individuals.

Methods: Sixteen volunteers (eight females) with untreated hypertension (elevated blood pressure, stage 1, stage 2) were given oral cannabidiol (150 mg every 8 h) or placebo for 24 h in a randomised, placebo-controlled, double-blind, cross-over study. Measures of 24-h ambulatory blood pressure and electrocardiogram (ECG) monitoring and estimates of arterial stiffness and heart rate variability were obtained. Physical activity and sleep were also recorded.

Results: Although physical activity, sleep patterns and heart rate variability were comparable between groups, arterial stiffness (~ 0.7 m/s), systolic blood pressure (~ 5 mmHg), and mean arterial pressure (~ 3 mmHg) were all significantly (P < 0.05) lower over 24 h on cannabidiol when compared to the placebo. These reductions were generally larger during sleep. Oral cannabidiol was safe and well tolerated with no development of new sustained arrhythmias.

Conclusions: Our findings indicate that acute dosing of cannabidiol over 24 h can lower blood pressure and arterial stiffness in individuals with untreated hypertension. The clinical implications and safety of longer-term cannabidiol usage in treated and untreated hypertension remains to be established.”

Disease-modifying effects of cannabidiol, β-caryophyllene and their combination in Syn1-Cre/Scn1aWT/A1783V mice, a preclinical model of Dravet syndrome

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“Cannabidiol (CBD) has been recently approved as an antiseizure agent in Dravet Syndrome (DS), a pediatric epileptic encephalopathy, but CBD could also be active against associated comorbidities. Such associated comorbidities were also attenuated by the sesquiterpene β-caryophyllene (BCP). Here, we have compared the efficacy of both compounds and further initiated the analysis of a possible additive effect between both compounds in relation with these comorbidities using two experimental approaches. The first experiment was aimed at comparing the benefits of CBD and BCP, including their combination in conditional knock-in Scn1a-A1783V mice, an experimental model of DS, treated since the postnatal day 10th to 24th. As expected, DS mice showed impairment in limb clasping, delay in the appearance of hindlimb grasp reflex and additional behavioural disturbances (e.g., hyperactivity, cognitive deterioration, social interaction deficits). This behavioural impairment was associated with marked astroglial and microglial reactivities in the prefrontal cortex and the hippocampal dentate gyrus. BCP and CBD administered alone were both able to partially attenuate the behavioural disturbances and the glial reactivities, with apparently greater efficacy against glial reactivities obtained with BCP, whereas superior effects in a few specific parameters were obtained when both compounds were combined. In the second experiment, we investigated this additive effect in cultured BV2 cells treated with BCP and/or CBD and stimulated with LPS. As expected, addition of LPS induced a marked increase in several inflammation-related markers (e.g., TLR4, COX-2, iNOS, catalase, TNF-α, IL-1β), as well as elevated Iba-1 immunostaining. Treatment with BCP or CBD attenuated these elevations, but, again and in general, superior results were obtained when both cannabinoids were combined. In conclusion, our results support the interest to continue investigating the combination of BCP and CBD to improve the therapeutic management of DS in relation with their disease-modifying properties.”

Hair Regrowth with Novel Hemp Extract: A Case Series

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“Introduction: The endocannabinoid system (ECS), discovered in the 1990s, is a system involved with maintaining cellular homeostasis by down-regulating the damaging inflammatory responses and upregulating regenerative processes. Cannabidiol (CBD), tetrahydrocannabivarin (THCV), and cannabidivarin (CBDV) are all phytocannabinoids found in varying quantities in hemp extract. These three cannabinoids have novel therapeutic effects on hair regrowth through the ECS. The method of action is different from and synergistic with current hair regrowth therapies. The three cannabinoids are fat-soluble and poorly absorbed past the epidermis, but topical application easily reaches hair follicles where they act as partial or full CB1 antagonist and agonist of transient receptor potential vanilloid-1 (TRPV1) and vanilloid receptor-4 (TRPV4). All these ECS receptors relate to hair follicle function. Blocking the CB1 receptor on the hair follicle has been shown to result in hair shaft elongation; in addition, the hair follicle cycle (anagen, catagen, and telogen phases) is controlled by TRPV1. The effects of CBD on hair growth are dose dependent and higher doses may result in premature entry into the catagen phase through a different receptor known as TRPV4. CBD has also been shown to increase Wnt signaling, which causes dermal progenitor cells to differentiate into new hair follicles and maintains anagen phase of the hair cycle.

Objective: This study was conducted on subjects with androgenetic alopecia (AGA), as follow-up to a prior published study using hemp extract high in CBD without CBDV or THCV. That study showed an average 93.5% increase in hair numbers after 6 months of use. This subsequent study is being done to determine if daily topical application of a hemp-oil high in CBD, THCV, and CBDV concentrations would result in improved hair regrowth in the area of the scalp most affected by AGA.

Materials and methods: A case series study was done of 31 (15 men and 16 women, 27 Caucasian, 2 Asian, and 1 mixed race) subjects with AGA. They used a once-daily topical hemp extract formulation, averaging about 33 mg/day for 6 months. A hair count of the greatest area of alopecia was carried out before treatment was started and again after 6 months of treatment. To facilitate consistent hair count analysis, a permanent tattoo was placed at the point for maximum hair loss on the scalp. The subjects were also asked to qualitatively rate their psychosocial perception of “scalp coverage” improvement after the study was completed. The qualitative scale included “very unhappy,” “unhappy,” “neutral,” “happy,” and “very happy.” The subjects were photographed in a standard manner before and after the study. The photographs were compared for improvements in “scalp coverage” by an independent physician. The qualitative scale included “none,” “mild,” “moderate,” and “extensive” improvement of scalp coverage.

Results: The results revealed that all subjects had some regrowth. This ranged from 31.25% (from 16 to 21 hairs) to 2000% (from 1 to 21 hairs). The average increase was statistically significant 246% (15.07 hairs/cm2 increase) in men and 127% (16.06 hairs/cm2) in women. There were no reported adverse effects. All subjects rated their psychosocial perception of the effects of the hair loss, as “happy” or “very happy.” Independent review of the photographs revealed evidence of “mild” to “extensive” scalp coverage improvements for all of the subjects.

Conclusion: Although the exact mechanism of therapeutic effects is not known, THCV and CBDV are most likely functioning as full CB1 receptor neutral antagonists and CBD is most likely functioning as a partial CB1 receptor antagonist and potentially through Wnt messaging. All three cannabinoids were functioning as TRPV1 agonists. The addition of menthol through the peppermint extract is probably acting through promoting a rapid onset of anagen phase. This topical hemp formulation was superior to oral finasteride, 5% minoxidil once daily foam and CBD topical extract alone. Since this hemp extract works through novel mechanisms entirely different from both finasteride and minoxidil, it can be used in conjunction with these current drugs and would be expected to have synergistic effects. However, safety and efficacy of this combination would be to be evaluated.”;year=2023;volume=15;issue=1;spage=18;epage=24;aulast=Smith

The therapeutic potential of purified cannabidiol

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“The use of cannabidiol (CBD) for therapeutic purposes is receiving considerable attention, with speculation that CBD can be useful in a wide range of conditions. Only one product, a purified form of plant-derived CBD in solution (Epidiolex), is approved for the treatment of seizures in patients with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex. Appraisal of the therapeutic evidence base for CBD is complicated by the fact that CBD products sometimes have additional phytochemicals (like tetrahydrocannabinol (THC)) present, which can make the identification of the active pharmaceutical ingredient (API) in positive studies difficult. The aim of the present review is to critically review clinical studies using purified CBD products only, in order to establish the upcoming indications for which purified CBD might be beneficial.

The areas in which there is the most clinical evidence to support the use of CBD are in the treatment of anxiety (positive data in 7 uncontrolled studies and 17 randomised controlled trials (RCTs)), psychosis and schizophrenia (positive data in 1 uncontrolled study and 8 RCTs), PTSD (positive data in 2 uncontrolled studies and 4 RCTs) and substance abuse (positive data in 2 uncontrolled studies and 3 RCTs). Seven uncontrolled studies support the use of CBD to improve sleep quality, but this has only been verified in one small RCT. Limited evidence supports the use of CBD for the treatment of Parkinson’s (3 positive uncontrolled studies and 2 positive RCTs), autism (3 positive RCTs), smoking cessation (2 positive RCTs), graft-versus-host disease and intestinal permeability (1 positive RCT each). Current RCT evidence does not support the use of purified oral CBD in pain (at least as an acute analgesic) or for the treatment of COVID symptoms, cancer, Huntington’s or type 2 diabetes.

In conclusion, published clinical evidence does support the use of purified CBD in multiple indications beyond epilepsy. However, the evidence base is limited by the number of trials only investigating the acute effects of CBD, testing CBD in healthy volunteers, or in very small patient numbers. Large confirmatory phase 3 trials are required in all indications.”

Preclinical effects of cannabidiol in an experimental model of migraine

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“Migraine is a disabling disorder characterized by recurrent headaches, accompanied by abnormal sensory sensitivity and anxiety. Despite extensive historical use of cannabis in headache disorders, there is limited research on the nonpsychoactive cannabidiol (CBD) for migraine and there is no scientific evidence to prove that CBD is an effective treatment. The effects of CBD are examined here using a calcitonin gene-related peptide (CGRP)-induced migraine model that provides measures of cephalic allodynia, spontaneous pain, altered light sensitivity (photophobia), and anxiety-like behavior in C57BL/6J mice. A single administration of CGRP induced facial hypersensitivity in both female and male mice. Repeated CGRP treatment produced progressively decreased levels in basal thresholds of allodynia in females, but not in males. A single CBD administration protected both females and males from periorbital allodynia induced by a single CGRP injection. Repeated CBD administration prevented increased levels of basal allodynia induced by repeated CGRP treatment in female mice and did not lead to responses consistent with migraine headache as occurs with triptans. Cannabidiol, injected after CGRP, reversed CGRP-evoked allodynia. Cannabidiol also reduced spontaneous pain traits induced by CGRP administration in female mice. Finally, CBD blocked CGRP-induced anxiety in male mice, but failed in providing protection from CGRP-induced photophobia in females. These results demonstrate the efficacy of CBD in preventing episodic and chronic migraine-like states with reduced risk of causing medication overuse headache. Cannabidiol also shows potential as an abortive agent for treating migraine attacks and headache-related conditions such as spontaneous pain and anxiety.”