Effectiveness of cannabinoids on subjective sleep quality in people with and without insomnia or poor sleep: A systematic review and meta-analysis of randomised studies

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“Study objectives: This systematic review and meta-analysis assessed the efficacy of cannabinoids compared to placebo for improving sleep quality.

Methods: Searches were conducted in MEDLINE, Embase, and Cochrane databases for randomised controlled trials comparing cannabinoids vs. placebo for improving sleep quality in adults with or without insomnia or poor sleep. The primary outcome was self-reported sleep quality (PROMIS, PSQI, LSEQ, Sleep Diary). Secondary outcomes included actigraphy parameters, anxiety (GAD-7, STAI-T), well-being (WHO-5 index), and insomnia severity (ISI). Additional analyses focused on sleep quality in (1) participants with insomnia or poor sleep, and (2) cannabidiol (CBD) vs. non-CBD interventions. Statistical analysis was performed using RevMan 5.4.1, with p < 0.05 considered significant.

Results: Six trials (1077 patients) were included. Cannabinoids significantly improved sleep quality compared to placebo [SMD 0.53; 95 % CI 0.03-1.02; p = 0.04; I2 = 88 %], particularly in those with insomnia or poor sleep [SMD 0.60; 95 % CI 0.09-1.11; p = 0.02; I2 = 89 %]. Non-CBD cannabinoids demonstrated greater efficacy [SMD 0.82; 95 % CI 0.24-1.40; p = 0.005], whereas CBD-only therapies showed no significant effect [SMD 0.13; 95 % CI -0.38-0.65; p = 0.61].

Conclusion: Cannabinoids, particularly non-CBD formulations, improve sleep quality, justifying further investigation as therapeutic options for insomnia or poor sleep.”

https://pubmed.ncbi.nlm.nih.gov/40929927/

https://www.sciencedirect.com/science/article/abs/pii/S1087079225001091?via%3Dihub

Analgesic and toxicological evaluation of cannabidiol-rich Moroccan Cannabis sativa L. (Khardala variety) extract: Evidence from an in vivo and in silico study

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“The legalization of cannabis for industrial and medicinal purposes has significantly expanded worldwide.

This study delves into the analgesic potential toxicity study of chloroformic extract from the Moroccan Cannabis sativa L. (C. sativa) cultivar, Khardala (KH extract). Our findings reveal that the lethal dose of KH extract is ≥5,000 mg/kg, with mice given 2,000 mg/kg exhibiting neurotoxic symptoms, including piloerection, aggressiveness, and fear, along with marked hepato-renal toxicity indicated by elevated levels of alanine aminotransferase, aspartate aminotransferase, total bilirubin, and creatinine in both male and female subjects.

Importantly, no toxicity was observed at 250 mg/kg and 500 mg/kg doses. Remarkably, at a dose of 500 mg/kg, the KH extract demonstrated a potent analgesic effect superior to cannabidiol (CBD), suggesting a synergistic interaction among the extract’s bioactive compounds, such as CBD, cannabidivarin (CBDV), Delta 9 tetrahydrocannabinol (THC), cannabigerol (CBG), Delta 9 tetrahydrocannabivarin (THCV), and β-caryophyllene. 

In silico analysis supports these findings, showing the strong binding potential of THC, THCV, CBG, and CBDV to delta opioid receptors, with G-scores >-5.0 kcal/mol, highlighting the promising analgesic efficacy of this cannabis cultivar extract.

This study underscores the therapeutic potential of the KH cultivar, positioning it as a promising candidate for pain management therapies.”

https://pubmed.ncbi.nlm.nih.gov/40917785/

“In summary, this study contributes to the growing body of research on C. sativa, highlighting the potential therapeutic applications of KH extract in pain management.”

https://www.degruyterbrill.com/document/doi/10.1515/biol-2025-1141/html

Oromucosal as an Alternative Method for Administration of Cannabis Products in Rodents

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“Oral administration of drugs in laboratory rodents such as rats is conventionally performed using the gavage technique. Despite effectiveness, gavage can induce distress associated with restraint, especially following repeated animal handling.

To mitigate these adverse effects and reduce morbidity associated with traditional methods, we explored oromucosal/buccal administration of cannabidiol (CBD)-enriched Cannabis extract.

In this method, male rats were treated daily for 15 days with medium-chain triglycerides (TCM) derived from coconut oil or CBD-enriched Cannabis extract. Each treatment was administered individually while animals were gently immobilized using an affectionate touch technique. The administration involved the use of a micropipette to apply the oily formulation directly into the oral mucosa. The dosage was calculated based on the CBD concentration in the Cannabis extract, standardized at 3 mg/kg/day. To ensure accuracy, animals were weighed daily, allowing for dose adjustments in accordance with weight changes over the treatment period. This method offers non-invasive and stress-reducing treatment, potentially improving animal welfare in experimental settings.

The treatment with CBD-enriched Cannabis extract was safe, and the analysis of the hippocampus of these animals’ showed alterations in the expression levels of GluA1 and GFAP proteins, which are directly associated with glutamatergic receptor functionality and neuroinflammation, respectively. This suggests that Cannabis extract could be applied in pathological conditions where glutamatergic excitotoxicity and astrogliosis are observed.”

https://pubmed.ncbi.nlm.nih.gov/40920655/

https://app.jove.com/t/68104/oromucosal-as-an-alternative-method-for-administration-cannabis

Chitosan nanoparticles-encapsulated cannabis extracts and their antimicrobial potential against skin pathogens

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“Cannabis compounds are well-known for their therapeutic applications in the treatment of various health issues.

These substances, mainly cannabinoids, are known for their antimicrobial properties and ability to interact with various cells through endocannabinoid receptors. However, the limitations of cannabis extract, particularly its viscosity, stickiness, and low bioavailability when applied topically, limit its use in dermatology.

To enhance topical applications for treating bacterial infections and dermatophytosis, cannabis extracts were encapsulated in chitosan nanoparticles, an easily accessible and cost-effective. Cannabis extracts were prepared from three cannabis strains differing in content of major cannabinoids, namely Chocolope (THCA-A), Jonas 1 (CBDA), and Hemp G (CBGA), and subsequently were encapsulated in chitosan nanoparticles. The resulting particles were characterized, and antimicrobial and cytotoxic activity was evaluated. The mean size of particles ranged from 89.1 ± 24.8 nm for empty nanoparticles to 355.6 ± 101.6 nm for particles containing Hemp G extract. Considering the extract:chitosan ratio (1:10 w/w, 1:20 w/w respectively) and the encapsulation efficiency (EE) range from 44.65 ± 4.39% to 94.44 ± 0.93%, total amount of extracts encapsulated in chitosan nanoparticles ranged from 2.96 ± 0.05 to 5.61 ± 0.19% in 1 g of chitosan nanopowder.

Most significant antimicrobial effect was observed against the fungi Nannizzia fulva CCF 6025, where the MIC80 of the pure extract from Jonas 1 variety was 256 μg/mL while the encapsulated extract in chitosan nanoparticles (1:10 w/w extract:chitosan ratio) inhibited growth at a concentration of 256 μg/mL of nanoparticles (corresponding to 13.05 ± 0.13 μg/mL of extract).

Overall, encapsulation reduced the amount of extract required to inhibit the growth of pathogenic microorganisms by up to several times, notably in case of dermatophytes, compared to non-encapsulated extracts. Encapsulation also reduced the cytotoxic effects of the extracts on human keratinocytes. Furthermore, pure high-THCA-A extract and encapsulated extract in chitosan nanoparticles slightly increased cell viability after 72 h exposure in low concentrations compared to control.

These results may suggest the chitosan nanoparticles-encapsulated formulations as a suitable topical delivery form of cannabis extracts, offering a possible adjunctive treatment of dermatophytosis and wound healing.”

https://pubmed.ncbi.nlm.nih.gov/40917837/

https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2025.1644502/full

Appraising the “entourage effect”: Antitumor action of a pure cannabinoid versus a botanical drug preparation in preclinical models of breast cancer

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Biochemical Pharmacology

“Breast cancer is the second leading cause of death among women. Although early diagnosis and development of new treatments have improved their prognosis, many patients present innate or acquired resistance to current therapies. New therapeutic approaches are therefore warranted for the management of this disease.

Extensive preclinical research has demonstrated that cannabinoids, the active ingredients of Cannabis sativa, trigger antitumor responses in different models of cancer.

Most of these studies have been conducted with pure compounds, mainly Δ9-tetrahydrocannabinol (THC). The cannabis plant, however, produces hundreds of other compounds with their own therapeutic potential and the capability to induce synergic responses when combined, the so-called “entourage effect”.

Here, we compared the antitumor efficacy of pure THC with that of a botanical drug preparation (BDP).

The BDP was more potent than pure THC in producing antitumor responses in cell culture and animal models of ER+/PR+, HER2+ and triple-negative breast cancer. This increased potency was not due to the presence of the 5 most abundant terpenes in the preparation. While pure THC acted by activating cannabinoid CB2 receptors and generating reactive oxygen species, the BDP modulated different targets and mechanisms of action. The combination of cannabinoids with estrogen receptor- or HER2-targeted therapies (tamoxifen and lapatinib, respectively) or with cisplatin, produced additive antiproliferative responses in cell cultures. Combinations of these treatments in vivo showed no interactions, either positive or negative.

Together, our results suggest that standardized cannabis drug preparations, rather than pure cannabinoids, could be considered as part of the therapeutic armamentarium to manage breast cancer.”

“It is well documented that cannabinoids, the active ingredients of the hemp plant Cannabis sativa, produce antitumor responses in preclinical models of cancer, by tackling different stages of cancer progression such as uncontrolled cancer cell proliferation and survival, angiogenesis and metastasis. The vast majority of these studies has been performed with pure compounds, mainly Δ9-tetrahydrocannabinol (THC). The cannabis plant, however, produces hundreds of additional compounds (other cannabinoids, terpenoids, flavonoids, polyphenols, etc.) that have been much less studied but show promising therapeutic properties (anti-proliferative, anti-inflammatory, immune-stimulant, etc.), and/or the potential capability of enhancing some THC actions, the so-called “entourage effect”.

https://www.sciencedirect.com/science/article/abs/pii/S0006295218302387

UHPLC-Q-TOF-MS profiling and multifaceted antioxidant, antihyperglycemic and anticancer potential of Cannabis sativa sugar leaves: An unexplored source of cannabidiol, terpenes and polyphenols

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Pharmacological Research - Natural Products

“Cannabis sativa is one of the most extensively researched plant species that holds promising therapeutic and ethnomedicinal significance.

Various parts of the species including fan leaves, flowers and trichomes are well documented for their richness in cannabidiol (CBD) and tetrahydrocannabidiol (THC) contents. However, an overlooked part of C. sativa, the sugar leaves, which are wasted during harvesting has plethora of CBD and THC and yet to investigated.

In this study we investigated the ethanol extract of sugar leaves of C. sativa (CSLE) for chemical composition through UHPLC-Q-TOF-MS analysis and pharmacological potential by using various in vitro antioxidant, antidiabetic, nitric oxide inhibition and anticancer studies. Furthermore, in silicomolecular docking analysis was performed for 10 selected compounds against α-glucosidase and α-amylase.

The UHPLC-Q-TOF-MS profiling of CSLE revealed the tentative identification of 37 compounds including CBD, THC, terpenes and flavonoids. The cytotoxicity studies presented highest activity against breast cancer cell lines (MDA-MB-231, IC50= 18.12 ± 1.13 µg/mL) followed by lung, liver and colorectal cancer cell lines.

Similarly, CSLE showed significant antidiabetic activity by inhibiting α-glucosidase (IC50= 3.13 ± 2.78 µg/mL) and α-amylase. The in vitro antioxidant assays gave highest activity in ABTS followed by DPPH method as well as potentially inhibited nitric oxide (NO) formation. The computational analysis revealed good docking interaction of CBD, THC, selected terpene and flavonoids against α-glucosidase and α-amylase.

Overall, the findings present the sugar leaves of C. sativa as the undisputed rich source of CBD, THC, terpenes and flavonoids with multifaceted therapeutic potential in diabetes, inflammation and different types of cancers. However, there is need of further investigations on toxicity profile and in-depth pharmacological evaluation through in vivo disease bearing animal models.”

https://www.sciencedirect.com/science/article/abs/pii/S2950199725001429

“The research titled “UHPLC-Q-TOF-MS profiling and multifaceted antioxidant, antihyperglycemic and anticancer potential of Cannabis sativa sugar leaves: An unexplored source of cannabidiol, terpenes and polyphenols” identifies sugar leaves of Cannabis sativa as a potential source for multiple therapeutic compounds, including cannabidiol, terpenes, and polyphenols. Through UHPLC-Q-TOF-MS analysis, the study found that these sugar leaf extracts exhibit antioxidant, antihyperglycemic (anti-diabetic), and anticancer activities against various cancer cell lines. The specific compounds present in the sugar leaves, when combined with other plant compounds like terpenes and flavonoids, demonstrate a phenomenon known as the entourage effect, which could enhance their therapeutic potential.”

Neuroavailable peptides from hempseed protein hydrolysates reduce hippocampal inflammation and glial activation in a scopolamine-induced Alzheimer’s disease

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“Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment, synaptic dysfunction, and neuronal loss. Neuroinflammation, driven by the activation of microglia and astrocytes, is a key contributor to AD pathology, amplifying oxidative stress and amyloid-β toxicity. Modulation of neuroinflammatory pathways thus represents a promising therapeutic strategy.

In this study, we evaluated the effects of a food-grade hempseed protein hydrolysate (HPH20A) on hippocampal inflammation and glial activation in a scopolamine-induced mouse model of AD.

Mice were orally supplemented with HPH20A (10 mg/kg/day) for 12 weeks. Hippocampal tissue was analyzed by RT-qPCR and immunohistochemistry to assess the expression of glial and inflammatory markers. To identify peptides capable of reaching the brain, we employed a double transwell in vitro system simulating intestinal and blood-brain barrier (BBB) transport, followed by LC-TIMS-MS/MS peptidomics, in silico bioactivity prediction, and molecular docking. HPH20A supplementation significantly attenuated the expression of pro-inflammatory markers, including GFAP, IBA1, TREM2, CD68, iNOS, COX2, and IL-6, and increased the anti-inflammatory cytokine IL-10. Peptidomic analysis identified two peptides, NVDTELAHKL and DSETVKRL, consistently present across intestinal, systemic, and brain compartments. These peptides were predicted to exhibit anti-inflammatory activity and demonstrated high-affinity binding to AD-related targets (APP, TREM2, and AChE) in docking simulations.

Taken together, these findings suggest that HPH20A exerts neuroprotective effects by modulating hippocampal inflammation inflammation, potentially through specific bioactive peptides capable of crossing the BBB.

Our results support the potential of hempseed-derived peptides as dietary modulators of neuroinflammation in early stages of neurodegenerative disease.”

https://pubmed.ncbi.nlm.nih.gov/40916308/

https://www.sciencedirect.com/science/article/pii/S0753332225006328?via%3Dihub

Cannabis administration is associated with reduced alcohol consumption: Evidence from a novel laboratory co-administration paradigm

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“Background: Alcohol and cannabis co-use is increasingly prevalent across the U.S., concomitant with trends towards recreational cannabis legalization. While some studies have shown that cannabis co-use is associated with reductions in alcohol consumption (i.e., substitution), others have observed increases in alcohol intake (i.e., complementarity) or no change. This study aims to address this gap in the literature through investigating the effects of legal-market cannabis on alcohol consumption and craving in the laboratory.

Method: Leveraging a within-subjects design, we enrolled non-treatment seeking individuals who use both alcohol and cannabis (n = 61) to complete two laboratory sessions, wherein they were provided an alcohol priming drink alone or after self-administering cannabis. Participants were then given the opportunity to self-administer up to 4 additional drinks. We assessed differences in alcohol self-administration and craving between sessions.

Results: Cannabis self-administration was associated with a significant reduction in number of drinks self-administered. Further, exploratory analyses revealed that individuals who drank less after using cannabis (“substituters”, n = 23) experienced reductions in craving after using cannabis and alcohol compared to alcohol alone, whereas individuals who drank the same number of drinks after using cannabis show minimal differences in craving. There were no significant group differences in blood-THC concentration post-cannabis use.

Conclusion: Results indicate that for some individuals who drink heavily, cannabis may serve as a substitute for alcohol, and craving reduction is a potential mechanism through which this could occur.”

https://pubmed.ncbi.nlm.nih.gov/40915022/

“Cannabis use was associated with a reduction in alcohol intake.”

https://www.sciencedirect.com/science/article/abs/pii/S0376871625003138?via%3Dihub

Short-term residual effects of smoked cannabis on simulated driving performance

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“Rationale: Between periods of use, chronic cannabis consumers may display residual effects on selective cognitive functions, particularly memory and attention. Whether there are comparable deficits in real-world behaviors, such as driving, has not been thoroughly examined.

Objectives: The current study explored the association between driving simulator performance, cannabis use history, and demographic factors after ≥ 48 h of abstinence. Study I examined simulator performance across a broad range of use within 191 healthy cannabis users. Study II compared performance between participants with the highest cannabis use intensity and a non-cannabis-using comparison group.

Methods: In Study I, 191 healthy cannabis users completed a 25-minute simulated drive, following ≥ 48 h of abstinence. In Study II, a pilot study comprising a subset of 18 frequent cannabis users was compared to 12 non-using controls who completed identical driving measures in a separate study. In both studies, the main outcome was the Composite Drive Score (CDS), a global measure of driving performance comprising key driving-related variables, including standard deviation of lateral position.

Results: In Study I, there was no relationship between CDS, its subtests, measures of cannabis use history, or demographic variables (all ps > 0.10). In Study II, frequent cannabis users and the non-using comparison group did not differ on CDS or performance on its subtests (all ps > 0.40).

Conclusions: The current study did not find evidence of a residual effect of cannabis on simulated driving performance during a short period of cannabis abstinence. Future studies would benefit from inclusion of larger non-cannabis-using comparison groups.”

https://pubmed.ncbi.nlm.nih.gov/40913146/

https://link.springer.com/article/10.1007/s00213-025-06880-1

UK Medical Cannabis Registry: A clinical outcomes analysis for insomnia

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“Insomnia affects approximately 10% of adults globally. Current treatments have their limitations, and there is growing evidence on the therapeutic potential of cannabis-based medicinal products for insomnia.

This study aimed to assess changes in sleep-specific and general patient-reported outcome measures (PROMs) in individuals prescribed cannabis-based medicinal products for insomnia and to assess the incidence of adverse events.

A case series was analysed with patients diagnosed with primary insomnia from the UK Medical Cannabis Registry (UKMCR). The primary outcome examined changes in the Single-Item Sleep Quality Scale (SQS), Generalised Anxiety Disorder-7 (GAD-7), and EuroQol-5 Dimension-5 Level (EQ-5D-5L). Changes in PROMs were assessed from baseline to 1-, 3-, 6-, 12- and 18-months. Adverse events were classified according to the CTCAE version 4.0. The inclusion criteria were met by 124 participants.

SQS scores showed improvement from baseline (2.66 ± 2.41) to 1- (5.67 ± 2.65; p < 0.001), 3- (5.41 ± 2.69; p < 0.001), 6- (4.80 ± 2.89; p < 0.001), 12- (4.24 ± 3.01; p < 0.001) and 18-months (3.81 ± 2.90; p < 0.001). GAD-7 scores improved from baseline to 1-, 3-, 6-, 12- and 18-months (p < 0.050). There were also improvements in EQ-5D-5L dimensions of usual activities, pain/discomfort, anxiety/depression, and index values (p < 0.001). Eleven (8.87%) participants reported a total of 112 (90.32%) adverse events, but none were disabling or life-threatening.

The study demonstrated improvements in subjective sleep quality and other captured PROMs in insomnia patients treated with cannabis-based medicinal products. Although the treatment was generally well-tolerated, randomised controlled trials are needed to confirm the effectiveness and safety of cannabis-based medicinal products.”

https://journals.plos.org/mentalhealth/article?id=10.1371/journal.pmen.0000390

“Study finds cannabis improves sleep where other drugs fail”

https://www.sciencedaily.com/releases/2025/09/250901104658.htm