Analgesic properties of next generation modulators of endocannabinoid signaling: leveraging modern tools for the development of novel therapeutics

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“Targeting the endocannabinoid (eCB) signaling system for pain relief is an important treatment option that is only now beginning to be mechanistically explored.

In this review, we focus on two recently appreciated cannabinoid-based targeting strategies, treatments with cannabidiol (CBD) and a/b-hydrolase domain containing 6 (ABHD6) inhibitors, which have the exciting potential to produce pain relief through distinct mechanisms of action (MOA) and without intoxication.

We review evidence on plant-derived cannabinoids for pain, with an emphasis on CBD and its multiple molecular targets expressed in pain pathways. We also discuss the function of eCB signaling in regulating pain responses and the therapeutic promises of inhibitors targeting ABHD6, a 2-arachidonoylglycerol (2-AG) hydrolyzing enzyme. Finally, we discuss how the novel cannabinoid biosensor, GRABeCB2.0, may be leveraged to enable the discovery of targets modulated by cannabinoids at a circuit-specific level. 

Significance Statement Cannabis has been used by humans as an effective medicine for millennia, including for pain management. Recent evidence emphasizes the therapeutic potential of compounds that modulate endocannabinoid signaling. Specifically, cannabidiol and inhibitors of the enzyme ABHD6 represent promising strategies to achieve pain relief by modulating endocannabinoid signaling in pain pathways via distinct, non-intoxicating, mechanisms of action.”

https://pubmed.ncbi.nlm.nih.gov/39060165/

https://jpet.aspetjournals.org/content/early/2024/07/26/jpet.124.002119

Examining the moderating role of cannabis use on the relationship between alcohol consumption and inflammation in individuals with alcohol use disorder

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“Inflammation appears to be a critical mechanism in the development of alcohol use disorder (AUD) and a consequence of chronic alcohol use.

The potential anti-inflammatory properties of cannabis may modulate the proinflammatory effects of alcohol.

This study sought to extend previous work investigating the relationship between alcohol consumption, cannabis use and circulating interleukin (IL)-6 levels in a sample with AUD. One hundred and thirty-three individuals with an AUD provided blood samples to assess IL-6 and answered questions regarding alcohol and cannabis use. An ordinary least squares multiple regression analysis was conducted to assess the effect of alcohol and cannabis use on IL-6. A moderation analysis examined cannabis use as a potential moderator of the relationship between alcohol use and circulating IL-6 levels.

Alcohol use was predictive of higher log IL-6 levels (standardized β = 0.16, p = 0.03), while cannabis use was not predictive of log IL-6 levels (p = 0.36). Days of cannabis use moderated the relationship between alcohol use and IL-6 levels, such that the relationship between alcohol use and IL-6 levels was only significant in individuals with AUD without recent cannabis use. This study extends previous work to a clinical sample with an AUD and underscores the importance of considering cannabis use in studies on alcohol use and inflammation. This study also indicates the need for in-depth analyses on cannabinoids and inflammation and the interaction between cannabinoids and alcohol use on inflammation.”

https://pubmed.ncbi.nlm.nih.gov/39091190/

https://onlinelibrary.wiley.com/doi/10.1111/adb.13431

Long-term efficacy and safety of cannabidiol in patients with tuberous sclerosis complex: 3-year results from the cannabidiol expanded access program

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“Objective: The cannabidiol (CBD) Expanded Access Program provided compassionate access to CBD for patients with treatment-resistant epilepsy, including tuberous sclerosis complex (TSC), at 35 US epilepsy centers. Here, we present the long-term efficacy and safety outcomes for add-on CBD treatment in patients with TSC.

Methods: Patients received plant-derived, highly purified CBD (Epidiolex® 100 mg/mL, oral solution), increasing from 2 to 10 mg/kg/d to tolerance or maximum of 25-50 mg/kg/d. Efficacy endpoints were percentage change from baseline in median monthly convulsive, focal, and total seizure frequency and ≥ 50%, ≥75%, and 100% responder rates across 12-week visit windows through 144 weeks. Adverse events (AEs) are reported through 233 weeks.

Results: Thirty-four patients with confirmed TSC were included. Mean age was 12.4 years (range, 1.8-31.2), and patients were receiving a median of 3 (range, 1-7) antiseizure medications (ASMs) at baseline. Median CBD dose was 25-28 mg/kg/d for 36 weeks and then 20-50 mg/kg/d through 228 weeks. Dose reduction from baseline occurred for most ASMs, except topiramate. Median reduction in the frequency of convulsive, focal, and total seizures was 44%-81%, 51%-87%, and 44%-87%, respectively, through 144 weeks. Responder rates (≥50%, ≥75%, and 100% reduction) were 43%-71%, 14%-58%, and 0%-25% for convulsive seizures; 52%-75%, 35%-60%, and 7%-32% for focal seizures; and 46%-79%, 26%-65%, and 0%-13% for total seizures. A total of 94% of patients experienced ≥1 AE; 47% had serious AEs, considered treatment unrelated by the investigator. Treatment-related AEs (TRAEs) occurred in 71% of patients. The most frequently reported TRAEs were somnolence, diarrhea, and ataxia. Two patients experienced AEs leading to discontinuation. There were no deaths.

Significance: Long-term add-on CBD use was associated with reduced seizure frequency through 144 weeks. The safety profile was consistent with previous reports.

Plain language summary: In this study, we evaluated efficacy and safety of cannabidiol (CBD) treatment in patients with tuberous sclerosis complex receiving CBD in addition to other antiseizure treatments in an Expanded Access Program. After starting CBD, 46%-79% of patients had at least 50% reduction and 26%-65% had at least 75% reduction in the number of seizures per month; up to 13% had no seizures through 144 weeks. Safety results were similar to prior studies; sleepiness and diarrhea were common treatment-related side effects. These results show that long-term CBD treatment was associated with fewer seizures and mild/moderate side effects.”

https://pubmed.ncbi.nlm.nih.gov/39088193/

“The results of this pooled analysis of data from a cohort of patients with TSC in the CBD EAP show that add-on CBD treatment was associated with a reduction in the frequency of seizures through 144 weeks of treatment, and its safety profile was similar to that observed in previously reported EAP analyses and clinical trials, supporting the long-term use of CBD for patients with TSC.”

https://onlinelibrary.wiley.com/doi/10.1002/epi4.13013

β-Caryophyllene Confers Cardioprotection by Scavenging Radicals and Blocking Ferroptosis

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“Ferroptosis is a form of regulated cell death triggered by iron-dependent lipid peroxidation and has been associated with heart diseases. However, there are currently no approved drugs that specifically inhibit ferroptosis in clinical practice, which largely limits the translational potential of this novel target.

Here, we demonstrated that β-caryophyllene (BCP; 150 μM), a natural dietary cannabinoid, protects cardiomyocytes against ferroptotic cell death induced by cysteine deprivation or glutathione peroxidase 4 (GPX4) inactivation. Moreover, BCP preserved the mitochondrial morphology and function during ferroptosis induction. Unexpectedly, BCP supported ferroptosis resistance independent of canonical antiferroptotic pathways.

Our results further suggested that BCP may terminate radical chain reactions through interactions with molecular oxygen, which also explains why its oxidation derivative failed to suppress ferroptosis. Finally, oral BCP administration (50 mg/kg, daily) significantly alleviated doxorubicin (15 mg/kg, single i.p. injection)-induced cardiac ferroptosis and cardiomyopathy in mice.

In conclusion, our data revealed the role of BCP as a natural antiferroptotic compound and suggest pharmacological modification based on BCP as a promising therapeutic strategy for treating ferroptosis-associated heart disorders.”

https://pubmed.ncbi.nlm.nih.gov/39088660/

https://pubs.acs.org/doi/10.1021/acs.jafc.4c03239

“Beta-caryophyllene is a dietary cannabinoid.” https://www.ncbi.nlm.nih.gov/pubmed/18574142

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”   http://www.ncbi.nlm.nih.gov/pubmed/23138934


Unmasking the cannabis paradox: in-hospital outcomes of cannabis users admitted with acute myocardial infarction over a 20-year period in the United States

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“Introduction: Cannabis is increasingly becoming a socially acceptable substance, with multiple countries having legalised its consumption. Epidemiological studies have demonstrated an association between cannabis use and an increased risk of developing coronary artery disease. However, there is a lack of studies about the influence of cannabis consumption on the outcomes following acute myocardial infarction (AMI).

Material and methods: We retrospectively analysed hospitalised patients with a primary diagnosis of AMI from the 2001 to 2020 National Inpatient Sample (NIS). Pearson’s χ2 tests were applied to categorical variables, and t-tests for continuous variables. We conducted a 1:1 propensity score matching (PSM). Multivariate regression models were deployed on the PSM sample to estimate the differences in several events and all-cause mortality.

Results: A total of 9,930,007 AMI patients were studied, of whom 117,641 (1.2%) reported cannabis use. Cannabis users had lower odds of atrial fibrillation (aOR = 0.902, p < 0.01), ventricular fibrillation (aOR = 0.919, p < 0.01), cardiogenic shock (aOR = 0.730, p < 0.01), acute ischaemic stroke (aOR = 0.825, p < 0.01), cardiac arrest (aOR = 0.936, p = 0.010), undergoing PCI (aOR = 0.826, p < 0.01), using IABP (aOR = 0.835, p < 0.01), and all-cause mortality (aOR = 0.640, p < 0.01), but with higher odds of supraventricular tachycardia (aOR = 1.104, p < 0.01), ventricular tachycardia (aOR = 1.054, p < 0.01), CABG use (aOR = 1.040, p = 0.010), and acute kidney injury (aOR = 1.103, p < 0.01).

Conclusions: Among patients aged 18-80 years admitted to hospital with AMI between 2001 and 2020 in the United States, cannabis use was associated with lower risks of cardiogenic shock, acute ischaemic stroke, cardiac arrest, PCI use, and in-hospital mortality.”

https://pubmed.ncbi.nlm.nih.gov/39086618/

https://amsad.termedia.pl/Unmasking-the-cannabis-paradox-in-hospital-outcomes-of-cannabis-users-admitted-with,189731,0,2.html

Occasional cannabis use is associated with higher premorbid functioning and IQ in youth at clinical high-risk (CHR) for psychosis: Parallel findings to psychosis cohorts

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“Background: Neurocognitive deficits have been widely reported in clinical high-risk for psychosis (CHR) populations. Additionally, rates of cannabis use are high among CHR youth and are associated with greater symptom severity. Cannabis use has been sometimes shown to be associated with better neurocognition in more progressed psychosis cohorts, therefore in this study we aimed to determine whether a similar pattern was present in CHR.

Methods: CHR participants ages 12-30 from the North American Prodromal Longitudinal Study (NAPLS-3) (N = 698) were grouped according to: “minimal to no cannabis use” (n = 406), “occasional use” (n = 127), or “frequent use” (n = 165). At baseline, cannabis use groups were compared on neurocognitive tests, clinical, and functional measures. Follow-up analyses were used to model relationships between cannabis use frequency, neurocognition, premorbid, and social functioning.

Results: Occasional cannabis users performed significantly better than other use-groups on measures of IQ, with similar trend-level patterns observed across neurocognitive domains. Occasional cannabis users demonstrated better social, global, and premorbid functioning compared to the other use-groups and less severe symptoms compared to the frequent use group. Follow-up structural equation modeling/path analyses found significant positive associations between premorbid functioning, social functioning, and IQ, which in turn was associated with occasional cannabis use frequency.

Discussion: Better premorbid functioning positively predicts both better social functioning and higher IQ which in turn is associated with a moderate cannabis use pattern in CHR, similar to reports in first-episode and chronic psychosis samples. Better premorbid functioning likely represents a protective factor in the CHR population and predicts a better functional outcome.”

https://pubmed.ncbi.nlm.nih.gov/39084107/

“This study contributed to emerging studies in CHR and provided parallel findings to existing evidence from both FEP and chronic psychosis populations of better neurocognitive performance among those who use cannabis”

https://www.sciencedirect.com/science/article/pii/S0920996424003384?via%3Dihub

Combinatorial approach of cannabidiol and active-targeted-mediated photodynamic therapy in malignant melanoma treatment

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“Malignant melanoma (MM) continues to claim millions of lives around the world due to its limited therapeutic alternatives. Photodynamic therapy (PDT) has gained popularity in cancer treatment due it increased potency and low off-target toxicity. Studies have pointed out that the heterogeneity of MM tumours reduces the efficacy of current therapeutic approaches, including PDT, leading to high chances of recurrences post-treatment.

Accumulating evidence suggests that cannabidiol (CBD), a non-psychoactive derivative of cannabis, can synergise with various anticancer agents to increase their efficacy. However, CBD demonstrates low bioavailability, which is attributed to factors relating to poor water compatibility, poor absorption and rapid metabolism. Nanotechnology offers tools that address these issues and enhance the biological efficiency and targeted specificity of anticancer agents. Herein, we highlighted the standard therapeutic modalities of MM and their pitfalls, as well as pointed out the need for further investigation into PDT combination therapy with CBD.”

https://pubmed.ncbi.nlm.nih.gov/39074910/

“Accruing evidence suggests that CBD holds potential for inhibiting angiogenesis, metastasis, as well as prevents cellular proliferation by inducing cell death in cancer cells, thus counteracting metastasis.’

https://onlinelibrary.wiley.com/doi/10.1002/jbio.202400191

Immunomodulatory effects of cannabinoids against viral infections: a review of its potential use in SARS-CoV2 infection

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“The COVID-19 pandemic is a global health crisis affecting millions of people worldwide. Along with vaccine development, there is also a priority to discover new drugs and treatments. One approach involves modulating the immune system to manage inflammation and cytokine storms. Patients with a high severity of complications exhibit a high level of inflammatory cytokines, particularly IL-6, in the airways and other infected tissues.

Several studies have reported the function of the endocannabinoid system in regulating inflammation and different immune responses. Cannabinoids are a class of natural chemicals found in the Cannabis plant. Recently, the anti-inflammatory properties of cannabinoids and their mediatory immunosuppression mechanisms through the endocannabinoid system have engrossed scientists in the health field for infectious conditions.

Research suggests that the immune system can regulate cytokine activation through cannabinoid receptors, particularly with Cannabidiol (CBD), the second most prevalent compound in cannabis. While CBD has been deemed safe by the World Health Organization and shows no signs of abuse potential, excessive CBD use may lead to respiratory depression. CBD shows promise in reducing immune cell recruitment and cytokine storms in organs affected by SARS-CoV2. However, before clinical use, it’s crucial to evaluate cannabinoid-based medications’ active ingredient concentrations and potential interactions with other drugs, along with associated side effects.

Indication-based dosing, consistent formulations, and ensuring purity and potency are essential. This review highlights cannabinoids’ effects on COVID-19 management and prognosis, drawing from preclinical and clinical studies.”

https://pubmed.ncbi.nlm.nih.gov/39071880/

https://link.springer.com/article/10.1007/s13337-024-00871-0

Neuroprotective Efficacy and Complementary Treatment with Medicinal Herbs: A Comprehensive Review of Recent Therapeutic Approaches in Epilepsy Management

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“Central Nervous System (CNS) disorders affect millions of people worldwide, with a significant proportion experiencing drug-resistant forms where conventional medications fail to provide adequate seizure control. This abstract delves into recent advancements and innovative therapies aimed at addressing the complex challenge of CNS-related drug-resistant epilepsy (DRE) management. The idea of precision medicine has opened up new avenues for epilepsy treatment.

Herbs such as curcumin, ginkgo biloba, panax ginseng, bacopa monnieri, ashwagandha, and rhodiola rosea influence the BDNF pathway through various mechanisms. These include the activation of CREB, inhibition of NF-κB, modulation of neurotransmitters, reduction of oxidative stress, and anti- inflammatory effects. By promoting BDNF expression and activity, these herbs support neuroplasticity, cognitive function, and overall neuronal health. Novel antiepileptic drugs (AEDs) with distinct mechanisms of action demonstrate efficacy in refractory cases where traditional medications falter. Additionally, repurposing existing drugs for antiepileptic purposes presents a cost-effective strategy to broaden therapeutic choices.

Cannabidiol (CBD), derived from cannabis herbs, has garnered attention for its anticonvulsant properties, offering a potential adjunctive therapy for refractory seizures.

In conclusion, recent advances and innovative therapies represent a multifaceted approach to managing drug-resistant epilepsy. Leveraging precision medicine, neurostimulation technologies, novel pharmaceuticals, and complementary therapies, clinicians can optimize treatment outcomes and improve the life expectancy of patients living with refractory seizures. Genetic testing and biomarker identification now allow for personalized therapeutic approaches tailored to individual patient profiles. Utilizing next-generation sequencing techniques, researchers have elucidated genetic mutations.”

https://pubmed.ncbi.nlm.nih.gov/39069797/

https://www.eurekaselect.com/article/141950

Investigating Cannabidiol’s Potential as a Supplementary Treatment for Schizophrenia: A Narrative Review

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“Schizophrenia presents a complex mental health challenge, often inadequately addressed by existing antipsychotic treatments, leading to persistent symptoms and adverse effects. Hence, developing alternative therapeutic approaches is crucial.

Cannabidiol (CBD), a nonpsychoactive compound in Cannabis sativa, has been extensively explored for its therapeutic potential in treating psychiatric disorders, including schizophrenia. CBD exhibits antipsychotic, anxiolytic, and neuroprotective effects. However, distinguishing the individual effects of CBD and THC remains challenging. Therefore, this review aims to critically analyze the potential role of CBD as an adjunctive therapy in schizophrenia treatment.

The therapeutic action of CBD may involve activating the 5-hydroxytryptamine 1A receptors and suppressing the G-protein-coupled receptor 55, thereby affecting various neurotransmitter systems. Additionally, the anti-inflammatory and antioxidative effects of CBD may contribute to alleviating neuroinflammation linked to schizophrenia. Compared to typical antipsychotics, CBD demonstrates a lower incidence of side effects and it exhibited favorable tolerability in clinical trials. A 2012 clinical trial demonstrated the efficacy of CBD in reducing both positive and negative symptoms of schizophrenia, presenting a safer profile than that of traditional antipsychotics. However, further research is needed to fully establish the safety and efficacy of CBD as an adjunctive treatment.

Future research directions encompass exploring detailed antipsychotic mechanisms, long-term safety profiles, interactions with current antipsychotics, optimal dosing, and patient-specific factors such as genetic predispositions. Despite these research needs, the potential of CBD to enhance the quality of life and symptom management positions it as a promising candidate for innovative schizophrenia treatment approaches.”

https://pubmed.ncbi.nlm.nih.gov/39068976/

https://www.sciencedirect.com/science/article/abs/pii/S0014299924005107?via%3Dihub