Therapeutic use of cannabinoids for the treatment of neurodegenerative disorders: a potential breakthrough

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“Marijuana, also known as cannabis, is a plant-based illicit drug notorious for its recreational purposes. However, in recent years its extracts are being extensively studied for their overall therapeutic effects. Active substances found in marijuana that interact with the endocannabinoid system are known as cannabinoids, the primary examples being 9-tetrahydrocannabinol (9-THC) and Cannabidiol (CBD). These cannabinoids ligand to receptors such as CB1 (found in CNS) and CB2 (found in immune system cells) to prevent the release of neurotransmitters and modulate immune cell migration as well as cytokine release, respectively (1). In recent years, there has been a surge of interest in the neuroprotective potential of marijuana; however, investigators could not make firm conclusions about the effectiveness of these treatments. A comprehensive review by Bahji A et al. (2022) found an evident link between cannabidiol-based products and relief from the motor as well as behavioural and psychological symptoms spanning Alzheimer’s disease (AD), Huntington’s disease (HD), and Parkinson’s disease (PD) (2). Here we discuss the effects of marijuana and its derivatives on the treating significant neurodegenerative disorders.

Dronabinol (2.5 mg) seemed to lessen the disordered behaviours as assessed by the Cohen-Mansfield Agitation Inventory in 12 patients of AD (p=0.05) (3). Sherman et al. (2018) reported the association of cannabis administration with weight and pain management in AD patients. The adverse effects are typically well tolerated at the levels supplied, even though cannabis is linked to an increased risk of euphoria, sleepiness and psychosis (1). On the other hand, for HD, nabilone (1 or 2 mg) had a substantial therapeutic benefit in a different 10-week placebo-controlled crossover experiment as determined by the overall motor and chorea score on the Unified Huntington’s Disease Rating Scale (UHDRS) (4). Available reviews revealed variable evidence suggesting the clinical benefits of cannabis in treating motor symptoms in patients with PD. A randomized trial found that compared to a placebo, giving a single dosage of 300 mg of CBD successfully decreased tremor amplitude (5).

Neurological diseases, including  the  neurodegenerative diseases,  comprise  8.7% of the disease burden  in lower- middle- income countries (such as Pakistan) (6). Currently, there is no real cure for neurodegenerative disorders, only symptomatic management, such as dopamine treatment for PD or cholinesterase inhibitors for dementia. Cannabinoids might be the lifeline all neurodegenerative disorder patients have been waiting for.”

https://pubmed.ncbi.nlm.nih.gov/37218269/

https://ojs.jpma.org.pk/index.php/public_html/article/view/7805

Cannabidiol Use Patterns and Efficacy for Children Who Have Cerebral Palsy

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“Cannabidiol (CBD)-containing supplements are used by children with cerebral palsy (CP), but the prevalence and efficacy of their use have not been studied. We sought to describe CBD use patterns and perceived efficacy in the pediatric population with CP, evaluating any association between CBD use and health-related quality of life. Patients with CP were prospectively enrolled, and caregivers were offered the Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD) Questionnaire and a survey assessing CBD use. Of 119 participants, 20 (16.8%) endorsed CBD use (CBD+) and 99 (83.2%) denied it (CBD-). Participants in the CBD+ group had worse functional status (85% Gross Motor Function Classification System level IV-V for CBD+ vs 37.4% for CBD-, P<.001) and lower health-related quality of life (mean CPCHILD score of 49.3 for CBD+ vs 62.2 for CBD-, P=.001). Spasticity was the rationale most cited for CBD use (29%), followed by pain and anxiety (both 22.6%). CBD was perceived to be most effective for improving emotional health, spasticity, and pain. Fifty percent of the patients in the CBD+ group underwent surgery in the previous 2 years and most endorsed a general benefit in the postoperative setting. The most common side effects noted were fatigue and increased appetite (both 12%). Most participants endorsed no side effects (60%). CBD may serve as a useful adjunct for some children with CP, especially those with worse disease severity. Caregivers perceive CBD as offering some benefits, particularly in the domains of emotional health, spasticity, and pain. We found no evidence of severe adverse events in our small cohort.”

https://pubmed.ncbi.nlm.nih.gov/37216564/

https://journals.healio.com/doi/10.3928/01477447-20230517-06

Cannabidiol Protects Dopaminergic-like Neurons against Paraquat- and Maneb-Induced Cell Death through Safeguarding DJ-1CYS106 and Caspase 3 Independently of Cannabinoid Receptors: Relevance in Parkinson’s Disease

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“Parkinson’s disease (PD), a progressive neurodegenerative movement disorder, has reached pandemic status worldwide. This neurologic disorder is caused primarily by the specific deterioration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNc). Unfortunately, there are no therapeutic agents that slow or delay the disease progression. Herein, menstrual stromal cell-derived dopamine-like neurons (DALNs) intoxicated with paraquat (PQ2+)/maneb (MB) were used as a model system to elucidate the mechanism by which CBD protects the neural cell from apoptosis in vitro. According to immunofluorescence microscopy, flow cytometry, cell-free assay, and molecular docking analysis, we demonstrate that CBD offers protection to DALNs against PQ2+ (1 mM)/MB (50 μM)-induced oxidative stress (OS) by simultaneously (i) decreasing reactive oxygen species (ROS: O2•-, H2O2), (ii) maintaining the mitochondrial membrane potential (ΔΨm), (iii) directly binding to stress sensor protein DJ-1, thereby blunting its oxidation from DJ-1CYS106-SH into DJ-1CYS106-SO3, and (iv) directly binding to pro-apoptotic protease protein caspase 3 (CASP3), thereby disengaging neuronal dismantling. Furthermore, the protective effect of CBD on DJ-1 and CASP3 was independent of CB1 and CB2 receptor signaling. CBD also re-established the Ca2+ influx in DALNs as a response to dopamine (DA) stimuli under PQ2+/MB exposure. Because of its powerful antioxidant and antiapoptotic effects, CBD offers potential therapeutic utility in the treatment of PD.”

https://pubmed.ncbi.nlm.nih.gov/37220279/

https://pubs.acs.org/doi/10.1021/acschemneuro.3c00176

Long-term safety of medical cannabis in Parkinson’s disease: A retrospective case-control study

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“Background: Whole-plant medical cannabis (MC) products are widely used for controlling symptoms associated with Parkinson’s disease (PD). Despite its widespread use, few studies have investigated the long-term impact of MC on the progression of PD or its safety profile. This study examined the effects of MC on PD in a real-life setting.

Methods: A retrospective case-control study of 152 idiopathic PD patients (mean age 69.1 ± 9.0 years), followed at the Sheba Medical Center Movement Disorders Institute (SMDI) from 2008 to 2022 was conducted. Seventy-six patients who used licensed whole-plant medical cannabis (MC) for at least a year were compared to a matched group who did not receive MC in terms of their Levodopa Equivalent Daily Dose (LEDD), Hoehn and Yahr (H&Y) stage, and cognitive, depressive, and psychotic symptoms.

Results: The median monthly dose of MC was 20 g (IQR: 20-30), with a median Tetrahydrocannabinol (THC) percentage of 10 (IQR: 9.5-14.15) and a median Cannabidiol (CBD) percentage of 4 (IQR: 2-10). There were no significant differences between the MC and the control groups for LEDD or H&Y stage progression (p = 0.90, 0.77, respectively). A Kaplan-Meier analysis showed no evidence of relative worsening of psychotic, depressive, or cognitive symptoms reported by patients to their treating physicians over time in the MC group (p = 0.16-0.50).

Conclusion: Over the 1-3 years of follow-ups, the MC treatment regimens appeared to be safe. MC did not exacerbate neuropsychiatric symptoms and had no detrimental effects on disease progression.”

https://pubmed.ncbi.nlm.nih.gov/37211456/

https://www.prd-journal.com/article/S1353-8020(23)00129-3/fulltext

Cannabidiol as an adjuvant treatment in adults with drug-resistant focal epilepsy

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“Cannabidiol oil (CBD) has been approved as an anti-seizure medication for the treatment of uncommon types of epilepsy, occurring in children: Dravet syndrome, Lennox-Gastaut syndrome, and Tuberous Sclerosis Complex. There are few publications in relation to use the CBD in adult patients with focal drug-resistant epilepsy. The objective of this study was to evaluate the efficacy, tolerability, safety, and quality of life, of adjuvant treatment with CBD, in adult patients with drug-resistant focal epilepsy for at least 6 months. An open, observational, prospective cohort study was conducted using a before-after design (time series) in adult patients undergoing outpatient follow-up in a public hospital in Buenos Aires, Argentina. From a total of 44 patients, 5% of patients were seizure-free, 32% of patients reduced more than 80% of their seizures and 87% of patients reduced 50% of their monthly seizures. Eleven percent presented a decrease of less than 50% in seizure frequency. The average final dose was 335 mg/d orally administered. Thirty-four percent of patients reported mild adverse events and no patient reported severe adverse effects. At the end of the study, we found in most patients a significant improvement in the quality of life, in all the items evaluated. Adjuvant treatment with CBD in adult patients with drug-resistant focal epilepsy was effective, safe, well tolerated, and associated with a significant improvement in their quality of life.”

https://pubmed.ncbi.nlm.nih.gov/37196452/

“Most patients have a significant improvement in their quality of life.”

https://www.epilepsybehavior.com/article/S1525-5050(23)00129-4/fulltext

Effervescent cannabidiol solid dispersion-doped dissolving microneedles for boosted melanoma therapy via the “TRPV1-NFATc1-ATF3” pathway and tumor microenvironment engineering

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“Background: Conventional dissolving microneedles (DMNs) face significant challenges in anti-melanoma therapy due to the lack of active thrust to achieve efficient transdermal drug delivery and intra-tumoral penetration.

Methods: In this study, the effervescent cannabidiol solid dispersion-doped dissolving microneedles (Ef/CBD-SD@DMNs) composed of the combined effervescent components (CaCO3 & NaHCO3) and CBD-based solid dispersion (CBD-SD) were facilely fabricated by the “one-step micro-molding” method for boosted transdermal and tumoral delivery of cannabidiol (CBD).

Results: Upon pressing into the skin, Ef/CBD-SD@DMNs rapidly produce CO2 bubbles through proton elimination, significantly enhancing the skin permeation and tumoral penetration of CBD. Once reaching the tumors, Ef/CBD-SD@DMNs can activate transient receptor potential vanilloid 1 (TRPV1) to increase Ca2+ influx and inhibit the downstream NFATc1-ATF3 signal to induce cell apoptosis. Additionally, Ef/CBD-SD@DMNs raise intra-tumoral pH environment to trigger the engineering of the tumor microenvironment (TME), including the M1 polarization of tumor-associated macrophages (TAMs) and increase of T cells infiltration. The introduction of Ca2+ can not only amplify the effervescent effect but also provide sufficient Ca2+ with CBD to potentiate the anti-melanoma efficacy. Such a “one stone, two birds” strategy combines the advantages of effervescent effects on transdermal delivery and TME regulation, creating favorable therapeutic conditions for CBD to obtain stronger inhibition of melanoma growth in vitro and in vivo.

Conclusions: This study holds promising potential in the transdermal delivery of CBD for melanoma therapy and offers a facile tool for transdermal therapies of skin tumors.”

https://pubmed.ncbi.nlm.nih.gov/37198657/

“In summary, the novel Ef/CBD-SD@DMNs system developed in this study offers a promising approach to improve the efficacy of CBD-based therapy for melanoma. Ef/CBD-SD@DMNs combines the advantages of effervescence and CBD-based solid dispersion to achieve better transdermal and tumoral delivery of CBD. The in vitro and in vivo results demonstrate that Ef/CBD-SD@DMNs can not only effectively induce melanoma apoptosis via the “Ca2+ influx-NFATc1-ATF3” pathway but also activate the tumor microenvironment probably through increasing intra-tumoral pH environment. This study provides a facile and efficient design for a transdermal delivery system that may have a significant impact on the development of new melanoma therapies.”

https://biomaterialsres.biomedcentral.com/articles/10.1186/s40824-023-00390-x

Cannabinoids as multifaceted compounds

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Phytochemistry

“Since ancient times, Cannabis and its preparations have found various applications such as for medical, recreational and industrial purposes. Subsequently the 1930s, legislation in many countries has restricted its use due to its psychotropic properties. More recently, the discovery of endocannabinoid system, including new receptors, ligands, and mediators, its role in maintaining the homeostasis of the human body and the possible implication in various physiological and pathophysiological processes has also been understood. Based on this evidence, researchers were able to develop new therapeutic targets for the treatment of various pathological disorders. For this purpose, Cannabis and cannabinoids were subjected for the evaluation of their pharmacological activities. The renewed interest in the medical use of cannabis for its potential therapeutic application has prompted legislators to take action to regulate the safe use of cannabis and products containing cannabinoids. However, each country has an enormous heterogeneity in the regulation of laws. Here, we are pleased to show a general and prevailing overview of the findings regarding cannabinoids and the multiple research fields such as chemistry, phytochemistry, pharmacology and analytics in which they are involved.”

https://pubmed.ncbi.nlm.nih.gov/37196772/

https://www.sciencedirect.com/science/article/abs/pii/S0031942223001346?via%3Dihub

Development, Characterization and Evidence of Anti-Endometriotic Activity of Phytocannabinoid-Rich Nanoemulsions

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International Journal of Pharmaceutics

“During the last decades, the cannabinoid research for therapeutic purposes has been rapidly advancing, with an ever-growing body of evidence of beneficial effects for a wide sort of conditions, including those related to mucosal and epithelial homeostasis, inflammatory processes, immune responses, nociception, and modulating cell differentiation. β-caryophyllene (BCP) is a lipophilic volatile sesquiterpene, known as non-cannabis-derived phytocannabinoid, with documented anti-inflammatory, anti-proliferative and analgesic effects in both in vitro and in vivo models. Copaiba oil (COPA) is an oil-resin, mainly composed of BCP and other lipophilic and volatile components. COPA is reported to show several therapeutic effects, including anti-endometriotic properties and its use is widespread throughout the Amazonian folk medicine. COPA was nanoencapsulated into nanoemulsions (NE), then evaluated regarding the potential for transvaginal drug delivery and providing endometrial stromal cell proliferation in vitro. Transmission electron microscopy (TEM) showed that spherical NE were obtained with COPA concentration that varied from 5 to 7 wt%, while surfactant was maintained at 7.75 wt%. Dynamic light scattering (DLS) measurements showed droplet sizes of 30.03 ± 1.18, 35.47 ± 2.02, 43.98 ± 4.23 and PdI of 0.189, 0.175 and 0.182, respectively, with stability against coalescence and Ostwald ripening during 90 days. Physicochemical characterization results suggest that NE were able to both improve solubility and loading capacity, and increase thermal stability of COPA volatile components. Moreover, they showed slow and sustained release for up to eight hours, following the Higuchi kinetic model. Endometrial stromal cells from non-endometriotic lesions and ectopic endometrium were treated with different concentrations of COPA-loaded NE for 48h to evaluate its effect on cell viability and morphology. The results suggested significant decrease in cell viability and morphological modifications in concentrations higher than 150 μg/ml of COPA-loaded NE, but not when cells were treated with the vehicle (without COPA). Given the relevance of Copaifera spp. species in folk medicine and their bio economical importance in the Amazon, the development of novel formulations to overcome the technological limitations related to BCP and COPA, is promising. Our results showed that COPA-loaded NE can lead to a novel, uterus-targeting, more effective and promising natural alternative treatment of endometriosis.”

https://pubmed.ncbi.nlm.nih.gov/37196880/

https://www.sciencedirect.com/science/article/abs/pii/S0378517323004696?via%3Dihub

Cannabidiol alleviates neuroinflammation and attenuates neuropathic pain via targeting FKBP5

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Brain, Behavior, and Immunity

“Microglia is a heterogeneous population that mediates neuroinflammation in the central nervous system (CNS) and plays a crucial role in developing neuropathic pain. FKBP5 facilitates the assembly of the IκB kinase (IKK) complex for the activation of NF-κB, which arises as a novel target for treating neuropathic pain. In this study, cannabidiol (CBD), a main active component of Cannabis, was identified as an antagonist of FKBP5. In vitro protein intrinsic fluorescence titration showed that CBD directly bound to FKBP5. Cellular thermal shift assay (CETSA) indicated that CBD binding increased the FKBP5 stability, which implies that FKBP5 is the endogenous target of CBD. CBD was found to inhibit the assembly of the IKK complex and the activation of NF-κB, therefore blocking LPS-induced NF-κB downstream pro-inflammatory factors NO, IL-1β, IL-6 and TNF-α. Stern-Volmer analysis and protein thermal shift assay revealed that tyrosine 113 (Y113) of FKBP5 was critical for FKBP5 interacting with CBD, which is consistent with in silico molecular docking simulation. FKBP5 Y113 mutation (Y113A) alleviated the effect of CBD inhibiting LPS-induced pro-inflammatory factors overproduction. Furthermore, systemic administration of CBD inhibited chronic constriction injury (CCI)-induced microglia activation and FKBP5 overexpression in lumbar spinal cord dorsal horn. These data imply that FKBP5 is an endogenous target of CBD.”

https://pubmed.ncbi.nlm.nih.gov/37196785/

“Cannabidiol (CBD) is the main active component of cannabis with good BBB permeability (Calapai et al., 2020) and has been gaining great attention for its safety, non-psychoactive effect and several beneficial pharmacological activities (Devinsky et al., 2016, Lucas et al., 2018, Pisanti et al., 2017). CBD has a good anti-neuroinflammatory effect (Atalay et al., 2019) and is used to treat neurological diseases caused by neuroinflammation, such as major depression (Florensa-Zanuy et al., 2021) and Parkinson’s disease (Giuliano et al., 2021) in animal models as well as autism spectrum disorder (Carbone et al., 2021) and multiple sclerosis (Nielsen et al., 2018) in clinical trials. As CBD has a low affinity for cannabinoid receptors (Rosenthaler et al., 2014), it would be worthy to explore the molecular target, which mediates the anti-inflammatory activity of CBD. Herein, FKBP5 was found as an endogenous target of CBD. CBD inhibited the assembly of the IKK complex and the activation of NF-κB, therefore suppressing LPS-induced pro-inflammatory factors. The FKBP5 tyrosine 113 (Y113) mutation abolished FKBP5 interacting with CBD, therefore ameliorating the effect of CBD inhibiting LPS-induced pro-inflammatory factors. Moreover, oral CBD attenuated peripheral nerve injury-induced overexpression of FKBP5 in activated microglia of lumbar spinal cord dorsal horn in vivo. These data implicate that FKBP5 is a direct binding target of CBD.”

https://www.sciencedirect.com/science/article/abs/pii/S0889159123001265?via%3Dihub

Cannabis Pharmacogenomics: A Path to Personalized Medicine

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“Cannabis and related compounds have created significant research interest as a promising therapy in many disorders. However, the individual therapeutic effects of cannabinoids and the incidence of side effects are still difficult to determine. Pharmacogenomics may provide the answers to many questions and concerns regarding the cannabis/cannabinoid treatment and help us to understand the variability in individual responses and associated risks. Pharmacogenomics research has made meaningful progress in identifying genetic variations that play a critical role in interpatient variability in response to cannabis. This review classifies the current knowledge of pharmacogenomics associated with medical marijuana and related compounds and can assist in improving the outcomes of cannabinoid therapy and to minimize the adverse effects of cannabis use. Specific examples of pharmacogenomics informing pharmacotherapy as a path to personalized medicine are discussed.”

https://pubmed.ncbi.nlm.nih.gov/37185752/

https://www.mdpi.com/1467-3045/45/4/228


“Personalized medicine could transform healthcare”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5492710/