A Critical Review of the Role of the Cannabinoid Compounds Δ9-Tetrahydrocannabinol (Δ9-THC) and Cannabidiol (CBD) and their Combination in Multiple Sclerosis Treatment

Abstract

Many people with MS (pwMS) use unregulated cannabis or cannabis products to treat the symptoms associated with the disease. In line with this, Sativex, a synthetic combination of cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC) has been approved to treat symptoms of spasticity. In animals, CBD is effective in reducing the amounts of T-cell infiltrates in the spinal cord, suggesting CBD has anti-inflammatory properties. By doing this, CBD has shown to delay symptom onset in animal models of multiple sclerosis and slow disease progression. Importantly, combinations of CBD and Δ9-THC appear more effective in treating animal models of multiple sclerosis. While CBD reduces the amounts of cell infiltrates in the spinal cord, Δ9-THC reduces scores of spasticity. In human studies, the results are less encouraging and conflict with the findings in animals. Drugs which deliver a combination of Δ9-THC and CBD in a 1:1 ratio appear to be only moderately effective in reducing spasticity scores, but appear to be almost as effective as current front-line treatments and cause less severe side effects than other treatments, such as baclofen (a GABA-B receptor agonist) and tizanidine (an α2 adrenergic receptor agonist). The findings of the studies reviewed suggest that cannabinoids may help treat neuropathic pain in pwMS as an add-on therapy to already established pain treatments. It is important to note that treatment with cannabinoid compounds may cause significant cognitive dysfunction. Long term double-blind placebo studies are greatly needed to further our understanding of the role of cannabinoids in multiple sclerosis treatment.

Efficacy of Phytocannabinoids in Epilepsy Treatment: Novel Approaches and Recent Advances

“…CBD is the most commonly analysed phytocannabinoid after its psychotropic counterpart Δ 9 -THC [ 69 ]. The CBD-based therapeutic Epidoliex ® (Greenwich Biosciences, Carlsbad, CA, USA) has demonstrated significant merit in addressing TRE.…”

Cannabidiol in Neurological and Neoplastic Diseases: Latest Developments on the Molecular Mechanism of Action

“…Therefore, CBD in Sativex may intensify the beneficial effects of ∆ 9 -THC by reducing its psychoactive effect simultaneously. As described by Jones and Vlachou [76], the ability of CBD to inhibit the functional consequences of CB1 activation in the brain may be caused by the indirect enhancement of adenosine A1 receptors' activity through ENT inhibition. This process can clarify the lower risk of developing psychotic symptoms in patients who use preparations based on high ∆ 9 -THC and CBD ratios in comparison If conventional antispastic therapy is not efficient enough, then nabiximols, commercially known as Sativex (containing CBD and THC) were mainly recommended for the treatment of pain and spasticity in MS [72], but can also be applied in inflammatory disease therapy with demyelination and neuronal injury in the brain and spinal cord.…”

“…Currently, it has not been proven that any known receptor site can be connected with CBD. Moreover, the molecular pharmacology of CBD has not been well defined yet [ 76 ]. Due to the high risk of side effects, the efficacy of treatments for MS is very limited.…”

“…To date, cannabis-based medicines have a great interest among MS patients to treat spasticity and pain [ 47 ]. A potential CBD-receptor-mediated signaling pathway is still unknown, but it has been confirmed that many of the CBD actions are related to both central and peripheral actions [ 76 ]. Although numerous CBD effects are related to both central and peripheral actions, the current research is focused on the careful identification of its mechanism.…”

Role of Cannabidiol in the Therapeutic Intervention for Substance Use Disorders

“…It was first synthesized by Roger Adams ( Adams, 1942 ) and isolated by Mechoulam and Shvo in 1963 ( Mechoulam et al, 1963 ), from which a growing interest in its pharmacological actions began to emerge. The results from basic and clinical studies suggested that CBD may present beneficial effects for the management of neurological disorders such as epilepsy ( Carlini and Cunha, 1981 ; Devinsky et al, 2014 ; Devinsky et al, 2016 ), multiple sclerosis ( Kozela et al, 2011 ; Giacoppo et al, 2015 ; Jones and Vlachou, 2020 ), Parkinson’s ( Zuardi et al, 2009 ; Chagas et al, 2014 ) or Alzheimer’s diseases ( Martín-Moreno et al, 2011 ; Cheng et al, 2014 ). Moreover, there is a growing body of evidence suggesting that CBD improves cognition ( Osborne et al, 2016 ) and neurogenesis ( Liput et al, 2013 ; Schiavon et al, 2016 ), and presents antipsychotic ( Zuardi et al, 1991 ; Moreira and Guimarães, 2005 ; Long et al, 2006 ; Leweke et al, 2012 ; Leweke et al, 2016 ; Peres et al, 2016 ), anxiolytic ( Guimarães et al, 1990 ; Moreira et al, 2006 ; Resstel et al, 2006 ; Blessing et al, 2015 ) and antidepressant-like effects ( Zanelati et al, 2010 ; Linge et al, 2016 ; Sartim et al, 2016 ).…”