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Regulation of cannabinoid and opioid receptor levels by endogenous and pharmacological chaperones

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“Cannabinoid and opioid receptor activities can be modulated by a variety of posttranslational mechanisms including the formation of interacting complexes.

This study examines the involvement of endogenous and exogenous chaperones in modulating the abundance and activity of cannabinoid CB1 receptor (CB1R), delta opioid receptor (DOR), and CB1R-DOR interacting complexes.

Focussing on endogenous protein chaperones namely receptor transporter proteins (RTPs), we examined relative mRNA expression in the mouse spinal cord and found RTP4 to be expressed at higher levels compared to other RTPs. Next, we assessed the effect of RTP4 on receptor abundance by manipulating RTP4 expression in cell lines. Overexpression of RTP4 causes an increase and knock-down causes a decrease in the levels of CB1R, DOR, and CB1R-DOR interacting complexes; this is accompanied by parallel changes in signaling. The ability of small molecule lipophilic ligands to function as exogenous chaperones was examined using receptor-selective antagonists. Long term treatment leads to increases in receptor abundance and activity with no changes in mRNA supporting a role as pharmacological chaperones.

Finally, the effect of cannabidiol (CBD), a small molecule ligand and a major active component of Cannabis, on receptor abundance and activity in mice was examined. We find that CBD administration leads to increases in receptor abundance and activity in mouse spinal cord.

Together, these results highlight a role for chaperones (proteins and small molecules) in modulating levels and activity of CB1R, DOR, and their interacting complexes potentially through mechanisms including receptor maturation and trafficking. 

Significance Statement This study highlights a role for chaperones (endogenous and small membrane-permeable molecules) in modulating levels of CB1R, DOR, and their interacting complexes. These chaperones could be developed as therapeutics for pathologies involving these receptors.”

https://pubmed.ncbi.nlm.nih.gov/39103231/

https://jpet.aspetjournals.org/content/early/2024/08/05/jpet.124.002187

Clinical Benefits and Safety of Medical Cannabis Products: A Narrative Review on Natural Extracts

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“Interest in medical cannabis and cannabis-based medicinal products (CBMPs) has increased greatly in recent years. Two cannabinoids are of principal importance; delta-9-tetrahydrocannabinol (∆9-THC), the primary psychoactive component, and also cannabidiol (CBD), considered non-intoxicating. Each has distinct mechanisms of action and different therapeutic potentials. CBMPs differ in their ∆9-THC and CBD components; predominantly ∆9-THC, balanced formulations with equivalent ∆9-THC and CBD elements, and CBD-predominant products.

In this narrative review, we evaluate the published evidence for the clinical benefits of CBMPs and overall benefits in well-being. We also review the overall safety profile and discuss the potential for dependence with CBMPs. Evidence can be drawn from a wide range of randomized and other controlled studies and from observational real-world studies.

Most data from observational registry studies are supportive of ∆9-THC-based products (∆9-THC-predominant or balanced CBMPs) in the management of chronic neuropathic pain. Balanced products are also effective in reducing spasticity in multiple sclerosis. Most CBMPs show benefit in providing symptomatic benefits in reducing anxiety, nausea, and in improving sleep, but the place of specific products is more subtle, and choice guided by specific circumstances. Symptomatic improvements are accompanied by improved quality of life and well-being. Safety data indicate that CBMPs are generally well tolerated in most patients without specific contraindications. The majority of adverse effects are non-serious, and transient; most are principally associated with ∆9-THC and are dose-dependent. In contrast to recreational cannabis use, there is little evidence from clinical studies that CBMPs have any potential for dependence.”

https://pubmed.ncbi.nlm.nih.gov/39096481/

https://link.springer.com/article/10.1007/s40122-024-00643-0

Cannabis sativa essential oils orally administered to CD1 mice: Tissue distribution of main constituents

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“The essential oil (EO) obtained from hemp (Cannabis sativa L.) biomass is rich of bioactive constituents and its oral administration can be valuable.

In this paper two different hemp EOs were orally administered to CD1 mice. One EO, obtained from the fresh plant material resulted rich in monoterpenes (monoterpene rich oil, MRO) and the other, obtained from the dried biomass, contained mainly sesquiterpenes and CBD (sesquiterpene rich oil, SRO). The blood levels of the most abundant constituents were evaluated in the animals 30 and 90 min after oral administration of hemp EOs. Furthermore, compounds were also measured in brain, liver, kidney, spleen, and cecum content to evaluate their tissue distribution at the same times.

Results showed the easy absorption and the ability of the major hemp EOs constituents to reach brain, liver, and kidney. Oral administration of MRO resulted in blood levels of monoterpenes in the range 45-115 ng/g at 30 min and significant tissue distribution with the detection of monoterpenes in brain, liver, and kidney. Oral administration of SRO resulted in blood levels, at 30 min, in the range 70-80 ng/g of sesquiterpenes and 139 ng/g of CBD. The compounds are still detectable in blood and brain 90 min after oral administration and significant concentrations of terpenoids are observed in liver and kidney.

MRO and SRO can be considered as valuable sources of these bioactive compounds and further investigations are needed to evaluate the potential uses of hemp EO as constituent of innovative drug formulations.”

https://pubmed.ncbi.nlm.nih.gov/39094699/

https://www.sciencedirect.com/science/article/abs/pii/S0367326X24003307?via%3Dihub

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

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

Effect of cannabidiol as a neuroprotective agent on neurodevelopmental impairment in rats with neonatal hypoxia

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“Objective: This study aims to investigate the neuroprotective effects of cannabidiol (CBD) on neurodevelopmental impairments in rats subjected to neonatal hypoxia, specifically examining its potential to mitigate motor and sensory deficits without the confounding effects of ischemia.

Methods: Neonatal Sprague-Dawley rats were allocated to one of four groups: Control, Control-CBD, Hypoxia, and Hypoxia-CBD. Hypoxia was induced on postnatal days 0 and 1. CBD (50 mg/kg) was administered orally for 14 days starting at postnatal day 0. Neurodevelopmental outcomes were assessed using the Neurodevelopmental Reflex Testing in Neonatal Rat Pups scale and the Revised Neurobehavioral Severity Scale for rodents. Statistical analyses were conducted using two-way and one-way ANOVA, with Tukey’s post-hoc tests for group comparisons.

Results: Pup weights were recorded on specified postnatal days, with no significant differences observed across the groups (p = 0.1834). Significant neurological impairments due to hypoxia were noted in the Control group compared to the Hypoxia group, particularly in hindlimb grasping on postnatal day 3 (p = 0.0025), posture on postnatal day 12 (p = 0.0073), and in general balance and sound reflex on postnatal day 20 (p = 0.0016 and p = 0.0068, respectively). Additionally, a statistically significant improvement in posture was observed in the Hypoxia-CBD group compared to the Hypoxia group alone (p = 0.0024).

Conclusion: Our findings indicate that CBD possesses neuroprotective properties that significantly counteract the neurodevelopmental impairments induced by neonatal hypoxia in rats. This study not only supports the therapeutic potential of CBD in managing conditions characterized by neurodevelopmental challenges due to hypoxia but also underscores the necessity for further investigation into the specific molecular mechanisms driving CBD’s neuroprotective effects. Further research is essential to explore CBD’s clinical applications and its potential role in treating human neurodevelopmental disorders.”

https://pubmed.ncbi.nlm.nih.gov/39068045/

https://www.brainanddevelopment.com/article/S0387-7604(24)00097-4/abstract

Effects of Biomaterials Derived from Germinated Hemp Seeds on Stressed Hair Stem Cells and Immune Cells

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“Androgenetic alopecia is a genetic disorder that commonly causes progressive hair loss in men, leading to diminished self-esteem.

Although cannabinoids extracted from Cannabis sativa are used in hair loss treatments, no study has evaluated the effects of germinated hemp seed extract (GHSE) and exosomes derived from the calli of germinated hemp seeds on alopecia. Therefore, this study aimed to demonstrate their preventive effects against alopecia using various methodologies, including quantitative PCR, flow cytometry, ELISA, and immunocytochemistry.

Our research highlights the preventive functions of GHSE (GE2000: 2000 µg/mL) and exosomes from the calli of germinated hemp seeds (E40: 40 μg/mL) in three biochemical categories: genetic modulation in hair follicle dermal papilla stem cells (HFDPSCs), cellular differentiation, and immune system modulation.

Upon exposure to dihydrotestosterone (DT), both biomaterials upregulated genes preventing alopecia (Wnt, β-catenin, and TCF) in HFDPSCs and suppressed genes activating alopecia (STAT1, 5α-reductase type 1, IL-15R). Additionally, they suppressed alopecia-related genes (NKG2DL, IL2-Rβ, JAK1, STAT1) in CD8+ T cells. Notably, E40 exhibited more pronounced effects compared to GE2000. Consequently, both E40 and GE2000 effectively mitigated DT-induced stress, activating mechanisms promoting hair formation.

Given the limited research on alopecia using these materials, their pharmaceutical development promises significant economic and health benefits.”

https://pubmed.ncbi.nlm.nih.gov/39063064/

“Positive evaluations of these experiments in the future will be pivotal in advancing the development of new therapies for androgenic alopecia. Moreover, GE2000 possesses the advantage of being applicable to the development of various products, potentially serving as a bridgehead for the advancement of the hemp industry. This suggests that it could play a crucial role in revitalizing the future natural materials market.”

https://www.mdpi.com/1422-0067/25/14/7823

Cannabielsoin (CBE), a CBD Oxidation Product, Is a Biased CB1 Agonist

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“Cannabielsoin (CBE) is primarily recognized as an oxidation byproduct of cannabidiol (CBD) and a minor mammalian metabolite of CBD. The pharmacological interactions between CBE and cannabinoid receptors remain largely unexplored, particularly with respect to cannabinoid receptor type 1 (CB1).

The present study aimed to elucidate the interaction dynamics of CBE in relation to CB1 by employing cyclic adenosine monophosphate (cAMP) and β-arrestin assays to assess its role as an agonist, antagonist, and positive allosteric modulator (PAM). To our knowledge, this is the first publication to investigate CBE’s receptor activity in vitro.

Our findings reveal that S-CBE acts as an agonist to CB1 with EC50 = 1.23 µg/mL (3.7 µM) in the cAMP assay. No agonist activity was observed in the β-arrestin assay in concentrations up to 12 µM, suggesting a noteworthy affinity towards G-protein activation and the cAMP signaling pathway. Furthermore, in silico molecular docking simulations were conducted to provide a structural basis for the interaction between CBE and CB1, offering insights into the molecular determinants of its receptor affinity and functional selectivity.”

https://pubmed.ncbi.nlm.nih.gov/39062125/

https://www.mdpi.com/2227-9059/12/7/1551