Author Archives: David

Efficacy of cannabidiol alone or in combination with Δ-9-tetrahydrocannabinol for the management of substance use disorders: An umbrella review of the evidence

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“Background and aims: Substance use disorders (SUD) lead to a high burden of disease, yet treatment options are limited. Cannabidiol (CBD) is being investigated as a potential therapeutic target due to its pharmacological properties and mode of action in the endocannabinoid system. Recent systematic reviews (SR) on CBD and SUDs have shown inconsistent results. The objective of this umbrella review was to determine whether CBD alone or in combination with Δ-9-tetrahydrocannabinol (THC) is effective for managing and treating SUDs.

Methods: Following a registered protocol, we searched PubMed, Web of Science and Epistemonikos databases for SRs, with or without a meta-analysis, of randomized controlled trials focusing on interventions dispensing CBD, alone or in combination with THC, to treat SUDs, published from 1 January 2000 to 15 October 2024. Screening, data extraction and quality assessment with the AMSTAR 2 tool were performed by two researchers in parallel and duplicated.

Results: 22 SRs were included, 5 of which performed a meta-analysis. We found mixed evidence regarding the efficacy of CBD to manage and treat SUDs. Findings were interpreted in light of the quality of the SRs. Nabiximols, which contains CBD and THC, demonstrated positive effects on cannabis withdrawal and craving symptoms. Evidence supporting the efficacy of CBD is limited and inconclusive for abstinence, reduction or cessation of use of cannabis, tobacco, alcohol, opiates and other psychoactive substances.

Conclusion: Cannabidiol (CBD) monotherapy does not appear to be efficacious for treatment of substance use disorders. CBD primarily exhibits effects on cannabis withdrawal and craving when combined with Δ-9-tetrahydrocannabinol (THC). Existing data on the efficacy of CBD alone with regard to other outcomes related to substance use disorders are limited.”

https://pubmed.ncbi.nlm.nih.gov/39947878/

“This umbrella review does not suggest any efficacy of CBD monotherapy as a therapeutic agent in SUDs. CBD primarily exhibits effects on cannabis withdrawal and craving symptoms when combined with THC in nabiximols. The CBD:THC 1:1 effects suggest that the potential benefits observed in cannabis withdrawal and craving may be because of THC, with CBD providing no additional benefit. We found no evidence for CBD alone, in the absence of THC, in managing cannabis and other SUDs. “

https://onlinelibrary.wiley.com/doi/10.1111/add.16745

The Presence of the Endocannabinoid System in an In Vitro Model of Gorham-Stout Disease and Its Possible Role in the Pathogenesis

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“Gorham-Stout syndrome (GSD), also known as disappearing bone disease, is an extremely rare bone disorder, characterized by a huge bone loss, which is followed by a lack of new matrix deposition and an excessive proliferation of both blood vessels and lymphatics. Unfortunately, the biological causes of GSD are still unknown. Recent studies that have tried to understand the etiopathogenesis of GSD have been principally focused on the vascular and osteoclastogenic aspects, not considering the possibility of a lack of osteoblast function. Nowadays, a diagnosis is still difficult, and is often made by exclusion of the presence of other pathologies, as well as on radiological evidence, and finally confirmed by histological examination. Treatment also remains a critical issue for clinicians today, who mostly try to control the progression of the disease.

Over the last two decades, clear evidence has emerged that the endocannabinoid system plays an important role in bone metabolism, leading scientists to hypothesize that it could be involved in physiological and pathological bone processes. In this work, we analyzed the presence of the ES in a primary cell line of human mesenchymal stem cells derived from a GSD patient for the first time, to understand if and how this complex network may play a role in the pathogenesis of the syndrome.

Our preliminary results demonstrated that the ES is also present in the pathological tissue. Moreover, the qRT-PCR analysis showed an altered expression of the different ES components (i.e., CNR1, CNR2, TRPV1, and GPR55). We observed an upregulation of CNR1 and TRPV1 expression, while the opposite trend was noticed for CNR2 and GPR55 expression. Thus, these results could lead us to speculate that possible deregulation of the ES may play an important role in the lack of bone regeneration in GSD patients. However, further studies will be necessary to confirm the role of the ES in the progression of GSD and understand whether the natural components of Cannabis Sativa could play a therapeutic role in the treatment of the disease.”

https://pubmed.ncbi.nlm.nih.gov/39940911/

“In conclusion, this is only a preliminary study, and further future analyses are needed to understand the role of the ES during osteogenic differentiation better and to try to comprehend what the molecular mechanisms involved in GSD pathogenesis are. In addition to this, the demonstration that the ES is present in our GSD in vitro model could pave the way to a study of the effects of the natural components of Cannabis Sativa as possible future new molecules that could be useful in the treatment of GSD and other bone diseases.”

https://www.mdpi.com/1422-0067/26/3/1143

The Endocannabinoid System: Implications in Gastrointestinal Physiology and Pathology

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“The endocannabinoid system (ECS), composed of receptors, endocannabinoids, and enzymes that regulate biosynthesis and degradation, plays a fundamental role in the physiology and pathology of the gastrointestinal tract, particularly in the small and large intestine and liver.

Specifically, cannabinoid receptor type 1 (CB1R) and cannabinoid receptor type 2 (CB2R), located principally in the nervous system and immune cells, orchestrate processes such as intestinal motility, intestinal and hepatic inflammation, and energy metabolism, respectively.

The main endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), influence appetite, body weight regulation, and inflammatory states and thus have implications in obesity, non-alcoholic fatty liver disease (NAFLD) and irritable bowel syndrome (IBS).

Recent studies have highlighted the therapeutic potential of targeting the ECS to modulate gastrointestinal and metabolic diseases. In particular, peripheral CB1R antagonists and CB2R agonists have shown efficacy in treating intestinal inflammation, reducing hepatic steatosis, and controlling IBS symptoms. Moreover, the ECS is emerging as a potential target for the treatment of colorectal cancer, acting on cell proliferation and apoptosis.

This review highlights the opportunity to exploit the endocannabinoid system in the search for innovative therapeutic strategies, emphasizing the importance of a targeted approach to optimize treatment efficacy and minimize side effects.”

https://pubmed.ncbi.nlm.nih.gov/39941074/

“In conclusion, these findings suggest that the ECS offers a versatile approach for modulating gastrointestinal physiological aspects and treating conditions such as obesity and its complications, IBS, and CRC. Future research should refine ECS-targeted therapies to maximize their efficacy and minimize adverse effects, unlocking new opportunities for innovative treatments of disordered metabolism, inflammation, and cancer.

Clinical studies show that medical cannabis could be a valuable adjunct to cancer and treatments for inflammation, providing symptom relief and improving patients’ overall quality of life. However, further research is needed to refine treatment protocols and explore their full therapeutic potential.”

https://www.mdpi.com/1422-0067/26/3/1306

Therapeutic potential of cannabinoids in neurological conditions: a systematic review of clinical trials

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“Overview: Cannabinoids have gained increasing attention for their therapeutic potential in treating several neurological conditions, including neurodegenerative diseases, chronic pain, and epilepsy. This review aims to assess the current clinical trials investigating cannabinoids, primarily Tetrahydrocannabinol and Cannabidiol, for neurological disorders. This review will aim to highlight the efficacy, safety, and outcome measures used in these trials.

Methods: Clinical trials were identified using ClinicalTrials.gov, focusing on studies that examined the effects of cannabinoids in treating neurological conditions. All trials that fulfilled the following criteria were included: Phase 1–4, focused on cannabinoids as primary intervention, and measured relevant outcomes such as pain relief, cognitive function, or spasticity reduction. Data on conditions, interventions, primary and secondary outcomes, and trial phases were extracted and analysed.

Results: A total of 47 clinical trials were identified, including different neurological conditions. The most frequently studied conditions were Multiple Sclerosis, Fibromyalgia, and Parkinson’s Disease. Most trials were in Phase 2, with the primary outcome measures focused on pain management, spasticity, and cognitive function. Secondary outcomes included safety and tolerability measures.

Conclusion: The review highlights the broad therapeutic potential of cannabinoids in neurology, with promising results in symptom management for conditions like Multiple Sclerosis and Fibromyalgia. However, the lack of standardized study protocols, dosing, and outcome measures presents challenges for broader clinical implementation.”

“The results of this analysis showed that both CBD and THC have significant potential as therapeutic agents for neurological disorders, particularly in managing pain, motor dysfunction, and behavioural disturbances. However, their different pharmacological profiles and side effect risks mean that each cannabinoid may be better suited to different patient populations and conditions. While THC’s broader range of applications in cognitive and motor symptoms positions it as a more multipurpose treatment option, the psychoactive risks associated with its use should not be ignored. On the other hand, CBD’s safety and non-psychoactive nature make it more preferred option for managing chronic pain, but its therapeutic benefits may be more limited. Future research should focus on addressing the gaps in long-term safety and efficacy data, as well as exploring the full potential of lesser-known cannabinoids and combination therapies to further enhance the treatment of neurological disorders.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1521792/full

Nanoemulsions with cannabidiol reduced autistic-like behaviors and reversed decreased hippocampus viable cells and cerebral cortex neuronal death in a prenatal valproic acid rat model

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“The highly lipophilic nature and low aqueous solubility of cannabidiol (CBD) limit its oral bioavailability, resulting in poor intestinal absorption. To overcome these limitations, we proposed the production of a nanoemulsion with CBD to be included in the therapeutic treatment of autism spectrum disorder.

The current study aimed to evaluate the effect of CBD-rich corn oil nanoemulsion treatment in male rats born to females exposed to valproic acid (VPA) during pregnancy on autistic-like behaviors and hippocampal histology. Offspring rats were treated orally twice daily with CBD nanoemulsions at different doses (1 and 2 mg/animal). The endpoints evaluated were anxiety, grooming time, exploratory activity, sociability, the social preference index, and hippocampal and cerebral cortex histology. All formulations were characterized as nanoemulsions and showed a reduced vesicle size (107.6 – 72.6 nm), low PDI (0.290-0.432), negative zeta potential (-40.6 mv), and good stability. Prenatal exposure to VPA increased anxiety and grooming time, and reduced exploratory activity, sociability, and the social preference index in the animals. Furthermore, VPA-exposed animals exhibited elevated neuronal death and a reduction in viable cells in the hippocampus.

In conclusion, CBD nanoemulsion treatment reversed autistic-like behaviors, potentially by protecting against hippocampal neuronal death.”

https://pubmed.ncbi.nlm.nih.gov/39936657/

https://www.scielo.br/j/aabc/a/jkp56mWRhknfsvMytM7qzWc/?lang=en

Cannabidiol-loaded hydrogel microneedle patches inhibit TRIM14/TRAF3/ NF-κB axis for the treatment of psoriasis

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“Psoriasis is a common chronic skin disease characterized by hyperproliferation of keratinized cells and infiltration of inflammatory cells that affects many patients worldwide. There is no cure for psoriasis, and its pathogenesis has not yet been fully elucidated. Alterations in some TRIM family proteins have been demonstrated to be involved in the exacerbation of psoriasis, however, the molecular mechanism of TRIM14 in psoriasis is unknown.

Here, we show that TRIM14 is highly expressed in psoriasis patients and is closely associated with the progression of psoriasis. A possible mechanism is that TRIM14 binds to TRAF3 and mediates the autophagic degradation of TRAF3 through the selective autophagy receptor NDP52, activating the NF-κB pathway.

In addition, cannabidiol (CBD) can effectively inhibit the proliferation of keratinocytes, possibly by inhibiting the expression of TRIM14 and attenuating the continuous activation of the NF-κB pathway in psoriasis.

CBD-loaded hydrogel microneedle patches significantly improved the symptoms of keratoderma thickening, erythema and desquamation in psoriatic mice and reduced the levels of inflammatory factors in psoriatic skin tissue and blood, as well as the spleen index compared with Tacrolimus cream (positive control).

In summary, TRIM14, which is highly expressed in psoriasis patients, may be a potential target and provide new ideas for the treatment of psoriasis. In addition, the CBD hydrogel microneedle patch developed for TRIM14 has obvious therapeutic effects and provides a new option for future drug therapy for psoriasis patients.”

https://pubmed.ncbi.nlm.nih.gov/39933682/

https://linkinghub.elsevier.com/retrieve/pii/S0141813025013741

Amyotrophic Lateral Sclerosis, the Endocannabinoid System, and Exogenous Cannabinoids: Current State and Clinical Implications

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“A unifying mechanistic cause for amyotrophic lateral sclerosis (ALS) remains uncertain. Multiple pathophysiological processes appear to occur simultaneously.

Cannabinoids, including delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG), and others found in cannabis, and cannabis extracts (CEs), appear to have activity in these pathogenic pathways, which have led to increasing interest in cannabinoids as therapeutic agents for ALS.

The use of cannabinoids as a treatment strategy is substantiated by preclinical evidence suggesting a role for the endocannabinoid system (ECS) in ALS and other neurodegenerative disorders.

Preclinical data indicate that cannabis and CEs have powerful antioxidative, anti-inflammatory, and neuroprotective effects in the SOD1G93A mouse model of ALS. The use of CEs in SOD1G93A murine models has been shown to prolong neuronal cell survival, which leads to delayed onset of the disease state, and slows progression of the disease.

Although research in humans remains limited, a few studies suggest that cannabis and CBD, in humans, provide benefits for both motor symptoms, including rigidity, cramps, and fasciculations, and non-motor symptoms including sleep quality, pain, emotional state, quality of life, and depression. There remains a need for further, well-designed clinical trials to validate further the use of an individual cannabinoid, or a combination of cannabinoids, as a disease-modifying therapy for ALS.”

https://pubmed.ncbi.nlm.nih.gov/39936266/

https://onlinelibrary.wiley.com/doi/10.1002/mus.28359

The Neuroprotective Effect of Alcoholic Extract of Cannabis Sativa on Neuronal Density of Spinal Cord Alpha Motoneurons after Sciatic Nerve Injury in Rats

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“Introduction: Injuries of the peripheral nerve system affect the neurons cell body leading to axon injury.

Cannabis sativa plant has anti oxidant and anti apoptotic effects. Therefore the aim of present study was to study the neuroprotective effect of alcoholic extract of cannabis sativa leaves on neuronal density of alpha motoneurons in spinal cord after sciatic nerve injury in rats.

Methods: In this experimental research, animals were divided into four groups; A: control, B: compression, C: compression+ treatment with 25 mg/kg alcoholic extract, D: compression + treatment with 50 mg/kg extract (n=8). At first, sciatic nerve compression in B, C and D groups was achieved for 60 seconds using locker pincers. Alcoholic extract was injected intra peritoneally in the first and second weeks after compression. Then 28 days after compression, under profusion method, the lumbar spinal cord was sampled and the numerical density in each group was compared with the compression group. The data was analyzed with the use of Minitab 14 software and ANOVA statistical test.

Results: Neuronal density showed a meaningful difference in the compression and control groups(P<0.001). Neuronal density in treatment groups(25, 50 mg/kg) also had a meaningful increase(P<0.001) as compared to the compression group.

Conclusion: Alcoholic extract of cannabis sativa leaves has a neuroprotective effect on spinal cord alpha motoneurons after injury. This could be due to growth and regeneration factors present in the alcoholic extract of cannabis sativa leaves that induce regeneration process in injured neurons or prevent degeneration.”

https://www.oalib.com/research/2894368

Entourage effects of nonpsychotropic cannabinoids on visceral sensitivity in experimental colitis

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“Abdominal pain is the most disabling symptom of inflammatory bowel diseases, but current treatments are limited, leading patients to seek alternatives such as cannabis.

Cannabis contains over 100 cannabinoids which, unlike tetrahydrocannabinol, are biologically active compounds often without psychotropic effects (ie, nonpsychotropic cannabinoids [npCBs]). These npCBs have analgesic and anti-inflammatory properties and may show potentiating effects when administered in combination, referred to as the entourage effect.

Here, we investigated the analgesic effects of cannabichromene, cannabidiol (CBD), cannabidivarin, and cannabigerol (CBG), individually and in combination, using the mouse model of dextran sulfate sodium colitis-induced visceral hypersensitivity (VHS).

We then explored antinociceptive targets through patch-clamp electrophysiology on dorsal root ganglia neurons and recombinant channels. We found that a single injection of 10 mg/kg of either CBD or CBG reduced both VHS and c-Fos activation in the spinal dorsal horn. Moreover, a combination of npCBs consisting of 5 mg/kg CBD with 1 mg/kg of cannabichromene, cannabidivarin, and CBG-all at subtherapeutic dosages-reduced VHS, without altering colitis. Electrophysiological recordings revealed that the antinociceptive mixture of npCBs acts through voltage-gated sodium and calcium channels, particularly Cav2.2, but not Cav3.2 and Kv channels.

These results suggest that CBD, CBG, and a mixture of npCBs given at subtherapeutic doses may be beneficial in managing VHS associated with inflammatory bowel disease.

SIGNIFICANCE STATEMENT: Cannabis is increasingly used as an alternative treatment for managing pain associated with chronic conditions. Nonpsychotropic cannabinoids, such as cannabidiol, interact with ionotropic and voltage-gated ion channels. In our study, we demonstrated that cannabidiol, cannabigerol, and a combination of nonpsychotropic cannabinoids, administered at subtherapeutic doses, effectively alleviated visceral hypersensitivity associated with inflammatory bowel disease.”

https://pubmed.ncbi.nlm.nih.gov/39921943/

https://jpet.aspetjournals.org/article/S0022-3565(25)09725-3/abstract

UK Medical Cannabis Registry: An Analysis of Clinical Outcomes of Medicinal Cannabis Therapy for Cancer Pain

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“Cancer pain (CP) is a prevalent condition with limited pharmacotherapeutic options. Cannabis-based medicinal products (CBMPs) have shown analgesic effects, but their efficacy in CP remains contentious.

This study aims to evaluate the change in patient-reported outcome measures (PROMs) and adverse events (AEs) in CP patients treated with CBMPs.

A case series was conducted using prospectively collected clinical data from the UK Medical Cannabis Registry. Primary outcomes were the changes in the Brief Pain Inventory (BPI), pain visual analogue scale (Pain-VAS), EQ-5D-5L, Generalized Anxiety Disorder-7 (GAD-7), Patient Global Impression of Change (PGIC) and Single-Item Sleep Quality Scale (SQS) questionnaires from baseline to 1, 3, and 6 months. AEs were recorded and graded. p < 0.050 was considered statistically significant. One hundred and sixty-eight participants were included.

CBMPs were associated with improvements in all pain-specific PROMs at all follow-up periods (p < 0.050).

Improvements in GAD-7, SQS, and EQ-5D-5L index scores were also observed (p < 0.050). Twenty-nine AEs (17.26%) were reported by five patients (2.98%), mostly mild-to-moderate (72.41%). Although the observational design means causality cannot be established, the findings support the development of future randomized controlled trials into CP management with CBMPs.”

https://pubmed.ncbi.nlm.nih.gov/39921589/

“This study found that initiation of CBMPs is associated with improvements in pain-specific and general health-related quality of life outcomes in CP patients over six months, with a relatively low incidence of mild-to-moderate AEs and no life-threatening AEs.”

https://www.tandfonline.com/doi/full/10.1080/15360288.2025.2457101