The endocannabinoidome-gut microbiome-brain axis as a novel therapeutic target for autism spectrum disorder

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“Introduction: Autism spectrum disorder (ASD) is characterized by disruption of the gut-brain axis, which leads to behavioral, psychiatric, metabolic and gastrointestinal symptoms. Effective ASD treatments are limited. Research highlights the roles of the endocannabinoidome (eCBome) and gut microbiome (GM), both crucial for brain and gut function. This review summarizes research on therapeutic targets within the eCBome-GM-brain axis for ASD and related comorbidities.

Discussion: Evidence suggests that reduced levels of eCBome mediators, like oleoylethanolamide and anandamide, and altered cannabinoid type 1 and type 2 (CB1 and CB2) receptors activity may contribute to ASD symptoms, making them promising targets. Modulating the eCBome-GM-brain axis with inhibitors of fatty acid amide hydrolase (FAAH), transient receptor potential vanilloid 1, and monoacylglycerol lipase (MAGL) may improve repetitive, stereotypical, and sensory behaviors, and alleviate sociability impairments, depression and anxiety. However, inhibition of FAAH and MAGL may also induce ADHD-like behaviors, which can be reversed by CB1 inverse agonists. Targeting metabotropic glutamate receptor 5 to increase levels of the eCBome mediator 2-arachidonoylglycerol (2-AG) may benefit ASD-related behaviors. eCBome mediators such as 2-AG, 1/2-palmitoylglycerol and palmitoylethanolamide may also help manage ASD- and GI-related symptoms, and systemic inflammation. Other potential therapeutic targets that deserve further investigation are eCBome-related receptors G-protein-coupled receptor 55 and peroxisome proliferator-activated receptors-alpha and -gamma, and the cyclooxygenase-2/prostaglandin E2 pathway, which may address hyperactivity and repetitive behaviors. Additionally, mucin-degrading genera like Akkermansia and Ruminococcus may improve ASD-related GI symptoms such as hypersensitivity and inflammation. Selective antibiotics against specific Clostridium strains may improve irritability and aggression. In ASD with ADHD and OCD, treatments may involve modulating the CB1 and CB2 receptor, and bacterial families like Ruminococcaceae and Lachnospiraceae. Lastly, modulating the abundance of anti-inflammatory genera like Prevotella and Anaeroplasma, and taxa associated with gut health such as Roseburia may also offer therapeutic value.

Conclusion: The eCBome-GM-brain axis is a promising target for ASD treatment, meriting further clinical and preclinical research.”

https://pubmed.ncbi.nlm.nih.gov/40605060/

“In conclusion, the eCBome–GM–brain axis represents a promising, multifaceted therapeutic target for ASD and its comorbidities, warranting further clinical and preclinical research to clarify its therapeutic potential and refine targeted interventions.”

https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-025-01145-7

Oral Cannabis for Taxane-Induced Neuropathy: A Pilot Randomized Placebo-Controlled Study

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“Introduction: Taxane-induced peripheral neuropathy (TIPN) is experienced by most patients with breast cancer, and there is no efficacious treatment. In pre-clinical studies, co-administration of two constituents of cannabis, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), synergistically reduces TIPN. 

Materials and Methods: The goal of this 8-week, double-blind, randomized pilot study, conducted from 2019 to 2021, was to test the feasibility and tolerability of oral cannabis (100 mg CBD: 5 mg THC, TID) relative to placebo on pain resulting from TIPN. Participants with painful TIPN completed daily questionnaires online about their pain, sleep, and medication use, and weekly questionnaires on neuropathy. 

Results: All participants (12 women; 51 ± 6 years) randomized to placebo (n = 6) or active (n = 6) cannabis capsules completed the trial. Participants in both medication groups requested dose reductions (mean ± SEM capsules/day: placebo: 2.4 ± 0.4; active: 2.0 ± 0.4). In a preliminary evaluation of efficacy, measures of pain, pain interference, sleep, and functional well-being significantly improved over time (p < 0.03), but participants receiving cannabis had significantly higher ratings of neuropathy at each week (p < 0.035) and lower ratings of functional well-being in the last 3 weeks of treatment compared with participants receiving placebo (p < 0.02). Similarly, cannabis significantly worsened ratings of sleep and pain interference relative to placebo (p < 0.05). 

Discussion: This study demonstrates that: (1) double-blind, placebo-controlled testing of cannabis capsules in this dose range is feasible and well tolerated in women with TIPN and (2) ratings of pain, neuropathy, and well-being significantly improved over 8 weeks, but cannabis significantly worsened several endpoints relative to placebo. These findings highlight the necessity of placebo control when assessing the therapeutic utility of cannabis. Although there was no signal of efficacy herein, a fully powered study testing a range of cannabis doses for TIPN is warranted, given its impact on most patients with breast cancer, promising pre-clinical data, and the widespread use of cannabis among patients with cancer.”

https://pubmed.ncbi.nlm.nih.gov/40611810/

https://www.liebertpub.com/doi/10.1089/can.2025.0028

Cannabidiol interactions with Δ-9-tetrahydrocannabinol on antinociception after carrageenan-induced inflammatory pain in male and female rats

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“Cannabis products used for pain typically contain Δ-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) in varied amounts, but data on the effects of specific cannabinoid formulations on different pain types are lacking.

This study used the carrageenan-induced inflammatory pain model to test oral Δ9-THC, CBD, or their combination on acute edema and pain hypersensitivity.

Male and female Sprague-Dawley rats (n = 10-14 per sex/group) were pretreated (1 hour) with vehicle (sesame oil), Δ9-THC (1, 3, and 10 mg/kg, p.o.), CBD (10, 30, 100 mg/kg, p.o.), or select doses of Δ9-THC + CBD combinations prior to an intraplantar λ-carrageenan injection into the hind paw.

The nonsteroidal anti-inflammatory drug ketoprofen (10 and 20 mg/kg i.p.) or its vehicle (1:1:18 ethanol:Cremophor EL:saline [Millipor Sigma]) was administered to a separate group as a positive control. Measurements were conducted at baseline and 1, 3, and 5 hours after carrageenan injection. Carrageenan produced edema and hypersensitivity to radiant heat (hyperalgesia) and mechanical pressure (allodynia).

Δ9-THC alone sex- and dose-dependently decreased hyperalgesia and allodynia but not inflammation, with effects of Δ9-THC being greater in females than males, and the lowest Δ9-THC dose was proinflammatory in males. CBD alone did not affect pain sensitivity but had modest anti-inflammatory effects in males. Isobolographic and dose addition analyses indicated Δ9-THC + CBD was subadditive relative to Δ9-THC alone.

These data demonstrate that prophylactic oral Δ9-THC alleviates acute inflammatory pain with sex-dependent effects, and CBD diminishes Δ9-THC antinociception when combined.

The findings suggest oral Δ9-THC is superior to CBD or combined Δ9-THC + CBD for acute inflammatory pain.

SIGNIFICANCE STATEMENT: Despite the popularity of cannabis for pain management, empirical data on how specific cannabinoid formulations affect acute inflammatory pain are limited. This study in rats found that pure Δ-9-tetrahydrocannabinol (Δ9-THC) formulations were most effective at improving inflammatory pain compared to pure cannabidiol or Δ9-THC + cannabidiol combinations, and females were more sensitive than males to the antinociceptive effects of Δ9-THC.”

https://pubmed.ncbi.nlm.nih.gov/40609153/

https://jpet.aspetjournals.org/retrieve/pii/S0022356525398381

Cannabinoid receptor ligands with potential therapeutic applications and mechanisms of action: a versatile natural therapeutic agent

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“The endocannabinoid system (ECS) is a complex signaling network essential for regulating various physiological processes in the body. Selective cannabinoid receptor ligands have been developed to modulate specific ECS signaling pathways, offering potential therapeutic benefits. These ligands, with high selectivity and affinity for cannabinoid receptors, demonstrate potential in managing diverse medical conditions. Standardizing dosing is crucial to ensure reliable therapeutic effects, as cannabinoids may exhibit biphasic effects. Combination strategies involving both CB1 and CB2 receptor modulation show promise in managing complex conditions, including chronic pain, autoimmune disorders, and neurodegenerative diseases.”

https://pubmed.ncbi.nlm.nih.gov/40600897/

https://www.tandfonline.com/doi/full/10.1080/10286020.2025.2522396

Neutrophil extracellular traps and cannabinoids: potential in cancer metastasis

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“Cancer is the second leading cause of global mortality after cardiovascular diseases, with breast, lung, colon, and prostate cancers being the most common. WHO projects around 30 million new cancer cases worldwide by 2045, with breast cancer being the most common in women and lung cancer in men.

Metastasis is responsible for nearly 90% of cancer-related deaths. Breast and lung cancers tend to metastasize to the bones, lymph nodes, lungs, liver, and brain. Lungs remains one of the most common organs to which various forms of cancer metastasize.

An important factor in metastasis is NETosis – it can initially help to eliminate cancer cells, but it can also promote metastasis. Phytocannabinoids, compounds derived from Cannabis sativa, and the endocannabinoid system (ECS) offer promising therapeutic potential to inhibit NETosis and consequently cancer development and metastasis.

Although the precise effects of phytocannabinoids on neutrophil functions and NETosis are not fully understood and require further research in the context of cancer, preliminary studies suggest their potential to inhibit NET release in various disease models.

This review consolidates current knowledge and provides new insights into how phytocannabinoids and the ECS may serve as effective therapeutic tools to limit cancer metastasis.”

https://pubmed.ncbi.nlm.nih.gov/40599866/

“Research indicates that metastatic progression is responsible for most deaths caused by breast cancer, with metastatic processes accounting for nearly 90% of cancer-related mortality.”

“Phytocannabinoids, together with the endocannabinoid system (ECS), represent a highly promising therapeutic avenue for attenuating neutrophil effector functions, particularly the process of NETosis.

We believe that these compounds have significant potential as agents capable of effectively inhibiting metastatic progression.

Phytocannabinoids, derived primarily from the Cannabis sativa plant, are a group of organic compounds that interact with the endocannabinoid system (ECS) in the human body.”

“Both phytocannabinoids and the endocannabinoid system (ECS) show significant therapeutic potential in cancer treatment. Research indicates that these agents affect the proliferation, apoptosis, migration, and invasiveness of cancer cells. In addition, they modulate the tumor microenvironment, particularly the cells of the immune system.”

https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1595913/full

Differential metabolic pathways underlie THC- and CBD-mediated inhibition of B-cell activation in both young and aged mice

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“Objective: B lymphocytes play a crucial role in immunity but also contribute to the pathogenesis of various diseases. Cannabis plants produce numerous biologically active compounds, including cannabinoids. The two most studied phytocannabinoids are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). These cannabinoids exert diverse and potent biological effects primarily through the endocannabinoid system (ECS), which also plays a key role in mature B-cell function. Both the immune system and the ECS undergo age-related changes that lead to a clinically significant decline in function.

Methods: This study compares the effects of THC and CBD on B-cell activity in young and aged mice. Murine B lymphocytes were activated using lipopolysaccharide (LPS) and interleukin-4 (IL-4), and the impact of cannabinoid treatments was assessed in terms of cell phenotype, proliferation, antibody secretion, tumor necrosis factor-alpha (TNFα) secretion, extracellular signal-regulated kinase (ERK) phosphorylation, and the cellular metabolome.

Results: Both THC and CBD exhibited dose-dependent inhibitory effects on B-cell activation in young and aged mice. However, we show here, for the first time, that the treatments induce distinct metabolic profiles. Although some metabolites, such as glucose-6-phosphate, pentose phosphate pathway (PPP) and nucleotide metabolites, were reduced by both cannabinoids, THC selectively reduced the levels of a distinct set of amino acids, while only CBD increased the levels of Citrulline and Allantoin. Additionally, the effects of THC and CBD differed between young and aged B cells, suggesting that age-related changes in the ECS may influence cannabinoid sensitivity.

Conclusions: These findings provide insights into the distinct mechanisms by which THC and CBD regulate immune activation and may open the door for investigating the mechanisms behind cannabinoids effects on the immune system. They also highlight the need for further research into phytocannabinoid-based therapies, particularly in age-specific contexts. Given the immunoregulatory properties of cannabinoids, especially CBD, tailored therapeutic strategies may enhance their clinical applications.”

https://pubmed.ncbi.nlm.nih.gov/40599768/

“These findings emphasize the need for further investigation into phytocannabinoid-based therapies, particularly for age-specific applications. Given the immunoregulatory properties of cannabinoids, especially CBD, tailored therapeutic strategies may be developed to optimize their clinical use.”

https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1605474/full

Revisiting the Gateway Drug Hypothesis for Cannabis: A Secondary Analysis of a Nationwide Survey Among Community Users in Japan

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“Aim: Cannabis has historically been used for medicinal and industrial purposes, but is strictly regulated worldwide due to the psychoactive effects of THC. In Japan, cannabis is frequently labeled a “gateway drug,” yet strong causal evidence for progression to other substances is limited. This study investigates whether cannabis acts as a gateway drug among Japanese users.

Methods: An anonymous online survey was conducted in January 2021 with 3900 individuals reporting lifetime cannabis use in Japan. Participants were recruited via social media. The survey gathered data on demographics, cannabis and other substance use history, order of substance initiation, psychiatric background, and criminal records. A Sankey diagram visualized substance use progression, and odds ratios were calculated to assess the likelihood of using other substances following cannabis use.

Results: Of all respondents, 81.5% were male, with the largest age group being 20-24. Tobacco and alcohol were the most common initial substances, while cannabis was typically the third. Odds for subsequent use of alcohol, tobacco, methamphetamine, and other illicit drugs after cannabis use were 1.25, 0.77, 0.08, and 0.78, respectively, suggesting low probabilities of progression. Nearly half of those who reported cannabis as their third drug did not use other substances afterward.

Conclusion: Cannabis use in Japan typically follows alcohol and tobacco, and rarely leads to further drug use. These findings challenge the gateway hypothesis in the Japanese context. Shared vulnerabilities and strict drug policies may shape these patterns. Further research is warranted to explore the impact of legal changes on drug use behavior.”

https://pubmed.ncbi.nlm.nih.gov/40590180/

Cannabis Use and Outcomes in Patients with Chronic Pancreatitis: A National Inpatient Sample Analysis

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“Background and aims: Cannabis is a commonly used recreational and medicinal substance and has been shown to have anti-inflammatory and analgesic effects. Previous studies have shown that cannabis may reduce disease severity of pancreatitis. We aim to use nationally available data to further investigate the impact of cannabis on outcomes among patients with chronic pancreatitis (CP).

Methods: Nationwide Inpatient Sample (NIS) 2016-2020 was used to identify patients with CP. Patients were stratified based on the presence of cannabis use. Data was collected regarding patient demographics, comorbidities, and Charlson Comorbidity Index (CCI). The outcomes assessed were sepsis, acute kidney injury (AKI), deep vein thrombosis (DVT), pulmonary embolism (PE), intensive care unit (ICU) admission, acute pancreatitis (AP), pancreatic cancer, total charges, and length of stay. The relationships were analyzed using multivariate logistic regression.

Results: Out of 907,790 hospitalized patients in this study; 52,360 (5.8%) were cannabis users. After adjusting for confounding factors, cannabis use was associated with decreased odds of mortality (aOR=0.47, p<0.001), DVT (aOR=0.71, p<0.001), PE (aOR=0.622, p=0.002), ICU admission (aOR=0.705, p<0.001), pancreatic cancer (aOR=0.730, p=0.021). There was no difference in odds of AKI, sepsis or AP between the two groups.

Conclusions: Our study found that cannabis use is associated with reduced disease severity and better outcomes among patients hospitalized with CP. Further studies are needed to confirm our findings and explore the role of cannabinoids in pancreatitis.”

https://pubmed.ncbi.nlm.nih.gov/40580529/

https://jgld.ro/jgld/index.php/jgld/article/view/6066

Cannabis sativa extract and fertility: Preclinical evaluation in male and female Wistar rats

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“Currently, there are reservations regarding the medicinal use of Cannabis sativa extract and its potential to impact fertility. Certain cannabinoids, such as Δ9-tetrahydrocanabinol (THC), can modulate both male and female sex hormones, potentially leading to alterations in fertilization viability.

This study aims to evaluate the effects of standardized Cannabis sativa extract (CSE) and its respective placebos on fertility and early embryonic development in Wistar rats, including both male and female subjects.

The animals were divided into 7 groups, each consisting of 20 animals, and different doses of a Cannabis sativa extract (160.32mg/mL) were administered to assess fertility outcomes. Male and female fertility assessments were conducted according to the guidelines outlined in the “Guide for the Conduct of Non-Clinical Toxicology and Pharmacological Safety Studies Required for Drug Development,” including clinical exams, biochemical analyses, macroscopic evaluations, relative organ weight measurements, sperm production, and morphology assessments, as well as morphometric and histopathological analyses of the testes.

The results indicated that none of the tested doses (0.28, 2.8, 28, or 56mg/kg/bw) significantly affected sex hormone levels in either male or female rats. Additionally, no alterations were observed in male organ morphology and sperm characteristics. In female rats, fertility was unaffected, and blastocyst implantation was not impaired across all doses, even up to 7 days post-pregnancy confirmation.

No direct toxic effects on the embryo were observed.

In conclusion, treatment with Cannabis sativa extract did not result in any significant changes in fertility or pregnancy feasibility in either male or female rats.”

https://pubmed.ncbi.nlm.nih.gov/40582628/

Preclinical evaluation of cannabidiolic acid as a neuroprotective agent in TDP-43 transgenic mice, an experimental model of amyotrophic lateral sclerosis

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“Plant-derived cannabinoids, including Δ9-THC, cannabinol, and Sativex-like combinations, have shown neuroprotection in preclinical ALS models. However, minor phytocannabinoids like cannabidiolic acid (CBDA) remain unexplored.

This study evaluated the neuroprotective effects of CBDA, cannabidivarin, CBD, Δ9-THC, and Δ9-tetrahydrocannabidivarin in Prp-hTDP-43(A315T) transgenic male mice from early symptomatic (day 65) to advanced stages (day 90).

CBDA proved the most effective, improving motor coordination (rotarod test) and reducing neuronal cell death, gliosis, microglial reactivity, and pro-inflammatory mediators in the spinal cord. A dose-response study confirmed that 10 mg/kg CBDA improved motor performance and preserved motor neurons, while lower doses were less effective and higher doses caused toxicity. Flow cytometry revealed a shift from an M1 proinflammatory to an M2 anti-inflammatory phenotype in microglial cells after CBDA treatment, mirroring effects in BV2 cells exposed to LPS.

Comparing CBDA with riluzole (standard ALS therapy), CBDA showed superior neuroprotection, except for rotarod performance, where no improvement was observed. A combination of CBD and riluzole failed to enhance efficacy and even weakened microglial response benefits.

In conclusion, CBDA was the most effective of the five phytocannabinoids studied and outperformed riluzole in ALS models. These findings support further clinical evaluation of CBDA for ALS treatment.”

https://pubmed.ncbi.nlm.nih.gov/40580876/

“CBDA was most active as neuroprotectant than CBD, CBDV, THC and THCV in ALS mice.”

https://www.sciencedirect.com/science/article/pii/S0753332225004822?via%3Dihub