A Randomized Controlled Trial of the Safety and Efficacy of Dronabinol for Agitation in Alzheimer’s Disease

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“Importance: Agitation in Alzheimer’s disease (AD) is a great source of distress for patients and caregivers and a major public health burden. Current treatments are only modestly effective and many have safety issues including mortality risk. Novel therapeutic options are needed.

There is preliminary evidence for the safety and efficacy of dronabinol (tetrahydrocannabinol, THC) for agitation in AD.

Objective: Assess the safety and efficacy of dronabinol (THC) to decrease agitation in AD.

Design: THC-AD was a 3-week randomized parallel double-blind placebo-controlled clinical trial, conducted between 2017 and 2024.

Setting: 5 inpatient and outpatient academic clinical research centers in the Eastern U.S.

Participants: Volunteer sample of 75 participants meeting inclusion criteria for agitation of AD (International Psychogeriatric Association Provision Criteria) with Neuropsychiatric Inventory Clinician Version Agitation or Aggression (NPI-C A/A) domains total score of 4 or greater. Major exclusion criteria included seizure disorder, delirium, and non-AD dementia.

Interventions: 3 weeks dronabinol vs. placebo titrated up to target dose of 10 mg daily in divided twice-daily.

Main outcomes and measures: Prespecified co-primary agitation outcomes were the Pittsburgh Agitation Scale (PAS) and NPI-C A/A total score.

Results: The majority of participants were female and were taking concomitant psychotropic medications (antidepressants and antipsychotics) at baseline. Study participants were moderately agitated at baseline, were diverse in ethnic background (9% Black, 11% Hispanic/Latina/Latino), and had severe cognitive impairment evidenced by MMSE or SIB-8. 84% completed the 3-week trial.

Dronabinol decreased agitation on both primary outcomes greater than placebo to a clinically relevant extent. The fitted between-arm difference in PAS decline/week was -0.74 (SE 0.3, p = 0.015, effect size = 0.53) and for NPI-C A/A the decline was not significant at -1.26 (SE 0.67, p = 0.094, effect size = 0.36). No secondary outcomes differed between treatment arms including sleep, activities of daily living, Cohen-Mansfield Agitation Inventory (CMAI), cognition, intoxication, or use of ‘as-needed’ lorazepam or trazodone. Dronabinol treatment was not associated with greater intoxication nor with other adverse events (AEs) except for somnolence.

Conclusions and relevance: Adjunctive dronabinol treatment was safe and effective for treating agitation in AD.”

https://pubmed.ncbi.nlm.nih.gov/41350162

“Highlights

•What is the primary question addressed by this study?

Is dronabinol (synthetic THC) a safe and effective treatment for reducing agitation in individuals with Alzheimer’s disease?

•What is the main finding of this study?

In a 3-week randomized, placebo-controlled trial of 75 participants with moderate to severe Alzheimer’s disease, dronabinol significantly reduced agitation as measured by the Pittsburgh Agitation Scale (effect size = 0.53) and showed a trend toward improvement on the NPI-C Agitation/Aggression domain. The medication was well tolerated, with somnolence as the only notable side effect and no increased risk of delirium, falls, or intoxication.

•What is the meaning of the finding?

These results suggest that dronabinol may be a relatively safe and effective pharmacologic option for managing agitation in Alzheimer’s disease.”

https://www.ajgponline.org/article/S1064-7481(25)00506-8/abstract

Characterization and antifungal properties against Botrytis cinerea of bacteria isolated from hemp seed oil

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“Botrytis cinerea is a pathogen infecting Cannabis sativa L. plants, causing economic losses, and can develop resistance to chemical fungicides, the use of which is restricted in cannabis production. Thus, developing biocontrol methods is imperative.

Seven bacterial strains were isolated from hemp seed oil, characterized, and examined for the potential to control a B. cinerea isolate from cannabis.

Three isolates, Bacillus mojavensis HOB3, Paenibacillus sp. HOB6 and Bacillus subtilis HOB7 exhibited significant inhibition of B. cinerea. These isolates were further evaluated for their biosurfactant activity using two liquid media, Lysogeny Broth (LB) and hydrocarbon-amended Bushnell and Haas (BH). The oil-spreading and drop-collapse assays revealed growth-medium-dependent variation in surface activity associated with biosurfactant presence. The BH cell-free extract (BH-CFE) of B. subtilis HOB7 showed the highest estimated biosurfactant presence and antifungal activity against B. cinerea, but both activities were absent when using the LB cell-free extract (LB-CFE) of B. subtilis HOB7.

Thus, a potential relationship between antifungal activity and biosurfactant production was suggested. Genome mining of the strains identified gene clusters encoding compounds with antifungal activity, including the biosurfactants polymyxin B, fusaricidin B, fengycin, and surfactin.

To our knowledge, this is the first report of the isolation of hemp seed oil bacteria with potential biocontrol properties against fungal phytopathogens.”

https://pubmed.ncbi.nlm.nih.gov/41349011

https://cdnsciencepub.com/doi/10.1139/cjm-2025-0241

“Polymyxin B, fusaricidin B, fengycin, and surfactin are all natural lipopeptides (or cyclic non-ribosomal peptides) produced by bacteria of the Paenibacillus and Bacillus genera. They act as biosurfactants and have various antimicrobial properties, particularly as antibiotics and fungicides.” 

UK Medical Cannabis Registry: a case series analysing clinical outcomes of medicinal cannabis therapy for fibromyalgia

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“Introduction: Fibromyalgia is a common condition characterised by widespread chronic pain, associated with comorbid mental health disorders and reduced quality of life. Preclinical data suggest cannabis-based medicinal products (CBMPs) may have potential benefits in fibromyalgia, but there is a paucity of high-quality clinical evidence. This study aims to assess the change in patient-reported outcome measures (PROMs) and incidence of adverse events (AEs) in patients treated with CBMPs for fibromyalgia.

Methods: This case series analysed data from the UK Medical Cannabis Registry (UKMCR). The primary outcome was change in PROMs [Fibromyalgia Symptom Severity, Fibromyalgia Widespread Pain Index, EQ-5D-5L, Generalised Anxiety Disorder-7, and Single-Item Sleep Quality Scale] from baseline to follow-up at 1, 3, 6, 12, and 18 months. Statistical significance was defined as p < 0.050.

Results: Four hundred ninety-seven patients were included. The mean age was 44.66 ± 12.02 years, 341 patients (68.61%) were female, and the majority of patients were unemployed (n = 268, 53.92%). There was an improvement in all PROMs (p < 0.010) from baseline to all follow-up periods. Higher CBD doses (> 25.00 mg/day) and previous cannabis use were associated with increased odds of improvement on fibromyalgia-specific scales (p < 0.050). 227 patients (45.67%) reported 2100 AEs (422.54%). Most AEs were mild-to-moderate (n = 1792, 85.33%). The most common AE was fatigue (n = 153, 30.78%).

Conclusions: There was an association between treatment with CBMPs and improvements in pain, anxiety, sleep, and general quality of life. The high incidence of AEs in relation to other patient cohorts from the UKMCR may relate to the central sensitisation mechanism of fibromyalgia. Key Points • This study found that CBMPs were associated with short to medium-term improvements in pain, anxiety, sleep, and general quality-of-life in patients with fibromyalgia. • More randomised controlled trials are warranted to consolidate the literature, but this large analysis provides real-world data to inform their rollout.”

https://pubmed.ncbi.nlm.nih.gov/41343025

Cannabinoids in the landscape of cancer

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“Introduction: Cannabinoids are a group of terpenophenolic compounds derived from the Cannabis sativa L. plant. There is a growing body of evidence from cell culture and animal studies in support of cannabinoids possessing anticancer properties.

Method: A database search of peer reviewed articles published in English as full texts between January 1970 and April 2021 in Google Scholar, MEDLINE, PubMed and Web of Science was undertaken. References of relevant literature were searched to identify additional studies to construct a narrative literature review of oncological effects of cannabinoids in pre-clinical and clinical studies in various cancer types.

Results: Phyto-, endogenous and synthetic cannabinoids demonstrated antitumour effects both in vitro and in vivo. However, these effects are dependent on cancer type, the concentration and preparation of the cannabinoid and the abundance of receptor targets. The mechanism of action of synthetic cannabinoids, (-)-trans-Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) has mainly been described via the traditional cannabinoid receptors; CB1 and CB2, but reports have also indicated evidence of activity through GPR55, TRPM8 and other ion channels including TRPA1, TRPV1 and TRPV2.

Conclusion: Cannabinoids have shown to be efficacious both as a single agent and in combination with antineoplastic drugs. These effects have occurred through various receptors and ligands and modulation of signalling pathways involved in hallmarks of cancer pathology. There is a need for further studies to characterise its mode of action at the molecular level and to delineate efficacious dosage and route of administration in addition to synergistic regimes.”

https://pubmed.ncbi.nlm.nih.gov/34259916

“Since time immemorial, the Cannabis plant has been used as a source of fibre, herbal remedy, medicinal and for religious purposes. Plant-based, endogenous and synthetic cannabinoid compounds have shown merits in not only alleviating the unwanted side effects of antineoplastic drug regiments, but have also shown promising evidence in decreasing tumour burden.”

“Plant-based, endogenous and synthetic cannabinoid compounds have shown merits in not only alleviating the unwanted side effects of antineoplastic drug regiments, but have also shown promising evidence in decreasing tumour burden, and one in vivo study so far concludes increasing survival rates in mice.

The antitumour effects of cannabinoids trend in modulating processes which include apoptosis and autophagy through first stimulating de novo synthesis of ceramide which induces activation of ER stress-related signalling proteins further leading to the inhibition of the AKT/mTORC1 axis promoting cell cycle arrest and additional mechanisms, such as cell death and aging.

Other pathways involved mechanistically are activation of MAPK/ERK signalling through calcium induction. Strategies that would optimize the anticancer effects of cannabinoids through interference of these signalling cross-talks may prove useful for therapeutic intervention. Nevertheless, we found that these effects were reached differently downstream depending on the type of cancer, the dosage of the compound and which receptor/ligands were activated.

We also found the co-administration of cannabinoids with chemotherapy drugs enhanced the potency of these effects. These synergistic effects should be targeted for translation to clinical application, especially in cancers which are refractory to chemotherapy.

Various extracted forms of cannabinoids from C. sativa have shown varying cytotoxic effects which should be explored in more detail in future studies as majority of the evidence originates from studies investigating mainly ∆9-THC and CBD’s actions. Whilst the emerging evidence of phytocannabinoid anticancer effects are promising, there remains a paucity of clinical evaluation which must be overcome.”

https://link.springer.com/article/10.1007/s00432-021-03710-7

Plant-derived cannabinoids as anticancer agents

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“Substantial preclinical evidence demonstrates the antiproliferative, cytotoxic, and antimetastatic properties of plant-derived cannabinoids (phytocannabinoids) such as cannabidiol and tetrahydrocannabinol. The cumulative body of research into the intracellular mechanisms and phenotypic effects of these compounds supports a logical, judicious progression to large-scale phase II/III clinical trials in certain cancer types to truly assess the efficacy of phytocannabinoids as anticancer agents.”

https://pubmed.ncbi.nlm.nih.gov/35260379

https://www.cell.com/trends/cancer/abstract/S2405-8033(22)00024-3?

Toxicity and carcinogenicity of delta 9-tetrahydrocannabinol in Fischer rats and B6C3F1 mice

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“delta 9-Tetrahydrocannabinol (delta 9-THC) was studied for potential carcinogenicity in rodents because it is the principal psychoactive ingredient in marihuana and it has potential medicinal uses.

There was no evidence that delta 9-THC was carcinogenic in rats or mice.”

https://pubmed.ncbi.nlm.nih.gov/8812248

https://www.sciencedirect.com/science/article/abs/pii/S0272059096900482?via%3Dihub


Computational GWAS Meta Meta Analysis Revealing Cross Talk Between Cannabis CNR1 and DRD2 Receptors Optimizing Long-Term Outcomes for Cannabis Use Disorder (CUD) By Enhancing Dopamine Homeostasis Promoting High-Quality Cannabis Medicinals

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“This paper presents a shared perspective from scientists and clinicians seeking to harness the therapeutic potential of cannabis while addressing Cannabis Use Disorder (CUD) through reproducible scientific findings.

Rather than blocking CNR1 receptors, which may induce hypodopaminergia, we propose a pro-dopaminergic strategy using a natural nutraceutical formulation designed to enhance dopamine release and upregulate D2 receptor mRNA, thereby increasing D2 receptor density.

Given the failure of CNR1 antagonists such as Rimonabant, we argue for an opposite approach: restoring dopamine balance through CNR1 stimulation rather than inhibition.”

https://pubmed.ncbi.nlm.nih.gov/41333412

https://www.researchsquare.com/article/rs-8140327/v1


Supercritical CO2 extraction of hemp seeds: A multivariate perspective on the influence of processing parameters on oil composition, antioxidant activity, and enzyme inhibition

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“Hemp seeds are valued for their unique nutritional and health benefits.

This study examined the impact of supercritical (sc)CO2 extraction conditions on hemp seed oil yield, composition, antioxidant activity, and enzyme inhibition using a multivariate approach. While pressure (300-500 bar) had minimal effects, temperature (40-60 °C) and ethanol addition (0.6-1.5 %) significantly influenced oil yield.

The levels of fatty acids, tocopherols, carotenoids, chlorophylls, phenolics, and flavonoids varied independently of extraction pressure and temperature, but their extractability generally increased with ethanol concentration. The co-solvent addition also enhanced radical scavenging activity but diminished the metal-reducing and chelating properties.

Hemp seed oils inhibited enzymes linked to chronic diseases like diabetes, skin disorders, and Alzheimer’s.

Multivariate analysis grouped samples by fatty acid profile, pigment content, and bioactivity. This work provides novel insights into how scCO2 conditions affect the chemical and biological properties of hemp seed oils.”

https://pubmed.ncbi.nlm.nih.gov/41341704

“Cannabis sativa L. (hemp) seeds have been consumed as animal feed or for human nutrition for thousands of years. The whole hemp seeds are comprised of fiber, proteins, and contain more than 30 % oil.

Hemp seed oil is abundant in polyunsaturated fatty acids (PUFAs) and exhibits a favorable omega-6 to omega-3 fatty acid (ω6/ω3) ratio of 3:1. This ratio is regarded as optimal in human nutrition, as it can significantly reduce the incidence of cardiovascular pathologies.”

“This study highlighted that scCO2 extraction is a promising method for obtaining high-quality oil from de-hulled hemp seeds, with tunable parameters influencing both yield and bioactivity.”

https://www.sciencedirect.com/science/article/pii/S2590157525011435?via%3Dihub

A single dose of cannabidiol modulates the relationship between hippocampal glutamate and learning-related prefrontal activation in individuals at Clinical High Risk of Psychosis

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“Background: Cannabidiol (CBD) is being studied as a potential intervention for the people at clinical high risk for psychosis (CHR), though the mechanisms underlying its effects are not fully understood. Previous studies indicate that a single dose of CBD can normalize alterations in memory-related brain activation and modulate hippocampal glutamate levels in the early stages of psychosis. This study aimed to examine the acute effects of CBD on the relationship between hippocampal glutamate levels and brain activation during verbal memory in individuals at CHR.

Methods: A total of thirty-three participants (n = 33) at CHR were randomly assigned to receive a single 600 mg dose of CBD (CHR-CBD) or a placebo capsule (CHR-PLB). Age-matched healthy controls (HC) (n = 19) received no study drugs. Participants underwent MRI scanning while performing a verbal learning task, and proton magnetic resonance spectroscopy to measure hippocampal glutamate levels. Effect of group x hippocampal glutamate interactions on brain activation was tested.

Results: CHR-PLB showed positive correlation between hippocampal glutamate levels and dorsolateral prefrontal cortex (dlPFC) (Pcorr. = 0.0039) activation compared to HC during both verbal encoding and recall. Under a single dose of CBD, the glutamate-dlPFC activation relationship was negative and significantly different compared to placebo in CHR individuals (Pcorr. = 0.0001) during both verbal encoding and recall. The reversed correlation in CBD group was also observed in the parahippocampal gyrus (Pcorr. = 0.0022) and amygdala (Pcorr. = 0.0019) during verbal recall.

Conclusions: These findings suggest that CBD may normalise disrupted hippocampal-prefrontal glutamatergic coupling in CHR, highlighting its potential to target the neurochemical mechanisms underlying cognitive impairment.”

https://pubmed.ncbi.nlm.nih.gov/41337954

“To the best of our knowledge, this is the first study to demonstrate that a single dose of CBD may partially attenuate the altered relationship between hippocampal glutamate levels and activation in the prefrontal cortex, amygdala, and parahippocampal regions in individuals at CHR.”

“Single dose of CBD modulates hippocampal glutamate-prefrontal activation coupling in CHR.”

https://www.sciencedirect.com/science/article/abs/pii/S0925492725001507?via%3Dihub

Endocannabinoid system and mood responses to acute aerobic exercise in adult cancer patients versus healthy controls: a pilot study

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“Purpose: To investigate the endocannabinoid system (ECS) and affective state responses to acute aerobic exercise in adult cancer patients versus their healthy peers.

Methods: Participants engaged in 30 min of quiet rest followed by 30 min of exercise. Exercise involved 5-min warm-up/cool-down procedures and 20 min of moderate-intensity training (64-76% of age-predicted maximal heart rate) on a treadmill or cycle. Blood samples and 10 Visual Analog Scales (VAS) were collected before and after each condition. Participants were also asked after exercise: ‘Did you experience a Runner’s high’. Blood samples were analysed for endocannabinoids: N-arachidonoylethanolamine (AEA; anandamide), 2-arachidonoylglycerol (2-AG) and 1-arachidonoylglycerol (1-AG), and endocannabinoid-like lipid mediators: palmitoylethanolamide (PEA), oleoylethanolamide (OEA) and stearoylethanolamide (SEA).

Results: Cancer patients had lower circulating AEA, OEA and log SEA versus controls across all timepoints (all p < 0.06). In the total cohort, exercise increased AEA, log 1-AG, OEA, PEA and log SEA (all p = 0.05) while log 2-AG did not change. Of 10 VAS, only Happiness increased with exercise in the total cohort (p = 0.02). There were no group x time effects or associations between ECS and VAS responses to exercise. Five patients per group (50%) reported experiencing a Runner’s high.

Conclusions: Exercise increased endocannabinoids and endocannabinoid-like lipid mediators in the total cohort. However, cancer patients exhibited lower AEA, OEA and SEA concentrations versus their peers, indicating potential ECS dysfunction.

Additional research is required to investigate the effect of various modalities and dosages of exercise on ECS markers and the clinical interpretation of these adaptations across a range of cancer populations.”

https://pubmed.ncbi.nlm.nih.gov/41331388

https://link.springer.com/article/10.1007/s00520-025-10221-5

“Exercise activates the endocannabinoid system”

https://pubmed.ncbi.nlm.nih.gov/14625449

“The Endocannabinoid System: A Target for Cancer Treatment.”

https://pmc.ncbi.nlm.nih.gov/articles/PMC7037210