Rethinking Punitive Responses to Underage Marijuana Use in the Era of Legalization: Insights from an Online Survey

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“Background: As adult nonmedical marijuana use becomes legal in many U.S. states, policymakers have adopted a range of responses to underage marijuana-related behaviors, often emphasizing punitive consequences. The extent to which these approaches align with public preferences remains unclear.

Methods: Data were drawn from an online survey of 1502 U.S. registered voters recruited from a national opt-in online panel. Analyses assessed support for a range of consequences for underage marijuana-related behaviors (i.e., possession, use, sale, and use of false identification), with selected bivariate comparisons across demographic groups.

Results: Respondents supported penalties for using false identification (89%) and selling marijuana (84%); fewer supported penalties for possession (59%) or use (57%). For attempted purchases, parental notification (79%), community service (64%), and drug education (58%) were more commonly endorsed than jail time (18%). Several differences by age, sex, race/ethnicity, and parent status were observed.

Conclusions: Respondents generally expressed greater support for parental notification, community service, and education as a response to underage violations of marijuana laws than for punitive responses. Policies that emphasize supportive, health-oriented responses, alongside stronger adult and industry accountability, may be more consistent with public attitudes and more effective than punitive responses in advancing youth protection goals in legalized contexts.”

https://pubmed.ncbi.nlm.nih.gov/42640046

https://www.tandfonline.com/doi/full/10.1080/10826084.2026.2722321

Multiple binding modes underlie Cannabis sativa cannabinoids recognition by peroxisome proliferator-activated receptor gamma

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“Introduction: Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated nuclear receptor with broad therapeutic relevance across various pathologies, including type 2 diabetes, obesity, cancer, and inflammatory disorders. Cannabinoids are a class of terpene-phenolic compounds from Cannabis sativa L. that have been shown to act as partial agonists of PPARγ. Among them, the acidic forms Δ9-tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA) display higher potency than their decarboxylated counterp arts Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Despite experimental evidence supporting direct PPARγ-cannabinoid interaction, the molecular determinants governing ligand recognition within the binding pocket have not yet been comprehensively investigated.

Methods: A combination of molecular docking and molecular dynamics simulations was employed to characterize the binding modes of THC, CBD, THCA, and CBDA within the PPARγ ligand-binding domain. Docking calculations were performed on a curated set of 70 PPARγ crystal structures co-crystallized with structurally diverse ligands, exploiting thus the conformational variability of the binding pocket. The best-ranked solutions were subjected to 500 ns MD simulations and evaluated on the basis of ligand stability, persistence of polar and aromatic-aromatic interactions with the receptor, and energetic contributions estimated by MM/GBSA. Three candidate binding modes per ligand were selected and their trajectories extended to 1,000 ns.

Results: All four cannabinoids yielded at least one stable binding mode at the microsecond timescale. The cannabinoids THCA and CBDA displayed a greater number of stable binding modes than THC and CBD, a result consistent with the higher potency previously reported for these compounds in experimental studies. This behavior may be attributable to the formation of salt bridges with basic residues in the binding pocket.

Conclusion: Our findings provide a structural framework for understanding cannabinoid recognition by PPARγ. The ability of these compounds to adopt multiple binding modes may contribute to their partial agonist profile, opening new avenues for the rational design of selective PPARγ modulators with improved therapeutic properties.”

https://pubmed.ncbi.nlm.nih.gov/42639023

“This work provides a foundation for future studies addressing the molecular basis of cannabinoid action on PPARγ.

Moreover, these findings could serve as a starting point to explore the allosteric mechanism by which these small lipophilic molecules influence receptor structure and dynamics.

Finally, the strategy described here may also be applied to determine the binding modes of these natural compounds in other members of the nuclear receptor family, including PPARα and PPARδ, as well as to investigate the binding modes of minor cannabinoids, such as cannabichromene and cannabigerol.”

https://www.frontiersin.org/journals/bioinformatics/articles/10.3389/fbinf.2026.1893303/full


Long-term experiences of patients prescribed medicinal cannabis in Australia: a qualitative interview study 

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“There is limited, but emerging, evidence supporting the use of medicinal cannabis (MC) to manage pain, anxiety, spasticity, insomnia and depression. Although Australian legislation changed in 2016 to provide access to unapproved MC products, clinical guidance on prescribing MC is limited because it is still mostly an unapproved therapy accessed under strict conditions. Since legislation changed, little is known about the long-term lived experience of patients being prescribed unapproved MC products in Australia. We aimed to explore, and obtain an in depth understanding of, the long-term experiences of patients prescribed MC.

Using an interpretive qualitative approach, participants were recruited from the Quality-of-Life Evaluation Study, a nationwide longitudinal study of patients with any chronic health condition prescribed orally administered MC oil over 1 year. Semi-structured interviews explored experiences of accessing and using MC during and since completing the Quality-of-Life Evaluation Study. Thematic analysis identified themes and subthemes from the data.

Results

Fifteen participants aged 33–78 years (nine female) who had completed the Quality-of-Life Evaluation Study and renewed MC oil prescriptions within the previous 6 months to manage chronic pain, insomnia, muscle spasticity, anxiety or depression were interviewed. Analysis identified four overarching themes: ‘This isn’t living’; ‘I was looking for a solution’; ‘It wasn’t to get high’; and ‘Everything’s much better’, and eight subthemes covering concerns, barriers, patient autonomy and benefits. Participants commonly used MC to reduce or replace conventional medications taken for their conditions, and viewed MC as a low-risk ‘natural’ alternative. Barriers to accessing MC included difficulties obtaining prescriptions and the cost of MC products. Participants reported symptom improvements that flowed on to benefit relationships, productivity and mental health over the long term. Although initially concerned about side-effects, participants self-managed these effectively, with perceived benefits outweighing side-effects. Participants described roadside drug testing as an ongoing concern.

Conclusions

This group of patients prescribed orally administered MC oil in Australia reported many benefits of MC, but faced ongoing barriers to MC access. Improved awareness and education, simplified prescribing processes, and less prohibitive driving laws could lead to wider acceptance of MC as a therapeutic option and improved patient-centred care.”

https://connectsci.au/py/article/32/4/PY25229/275611/Long-term-experiences-of-patients-prescribed

Cannabinoid neuroprotection and cardiotoxicity in retinal disease: the role of the THC:CBD ratio

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“Cannabinoids, compounds acting on the endocannabinoid system (ECS) and the broader endocannabinoidome, have demonstrated promising neuroprotective effects in retinal neurodegenerative diseases including glaucoma and age-related macular degeneration (AMD).

This review evaluates the evidence for cannabinoid receptor expression and function in the retina, the capacity of cannabinoids to reduce oxidative stress and neuroinflammation, and outcomes in preclinical disease models.

Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) act through cannabinoid receptors 1 and 2 (CB1 and CB2) receptors, as well as non-canonical pathways including transient receptor potential cation channel subfamily V member 1 (TRPV1), G-protein coupled receptor 3 (GPR3), peroxisome proliferator-activated receptor gamma (PPARγ), to confer neuroprotective benefits.

Critically, previously identified neuroprotective effects of cannabis may be substantially masked or reversed by the dramatically rising THC:CBD ratio in commercial strains, which has increased from approximately 10:1 in 2000 to 100:1 in many contemporary products.

This shift means that modern cannabis is biochemically distinct from the preparations used in foundational neuroprotection studies.

CBD-dominant formulations, or preparations maintaining lower THC:CBD ratios, represent a valid therapeutic direction for acute retinal neuroprotection, while the proven safety and efficacy of vitamins such as Age-Related Eye Disease Study 2 (AREDS2) therapy provide a reliable chronic neuroprotective strategy.

While the biological plausibility and animal evidence for CBD/THC protection is good, human trials are needed to validate any use in retinal diseases.”

https://www.academia.edu/3071-4087/2/3/10.20935/AcadNeurosci8479



Integrated network pharmacology and lipidomics provide insights into potential mechanisms underlying the effects of cannabidiol in a rat model of autism

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“Background: Cannabidiol (CBD) has shown potential benefits in managing symptoms associated with autism spectrum disorder (ASD), although its underlying mechanisms of action remain unclear. This study investigated whether CBD improves ASD-like behavior in association with changes in lipid metabolic disturbances and apoptosis-related signaling in a prenatal valproic acid (VPA) rat model.

Methods: Male offspring from VPA-exposed rats received CBD (10 mg/kg, intraperitoneal, twice daily) for 7 days starting on postnatal day 21. Behavioral testing evaluated hyperactivity, social interaction, and repetitive behaviors. Hippocampal lipid profiles were quantified by UPLC-MS/MS. Candidate mechanisms were examined through a joint pathway analysis integrating lipidomics with curated target information, followed by targeted gene/protein validation (qPCR, Western blotting) and molecular docking.

Results: CBD treatment improved VPA-induced hyperactivity and repetitive behaviors and social interaction deficits. Lipidomics demonstrated remodeling of hippocampal lipid abnormalities after CBD treatment, with changes across major classes, including phosphatidylcholines, lysophosphatidylcholines, and sphingomyelins. Joint pathway analysis pinpointed potential targets-LDHA, LDHB, PKM, PTGS2, and EPHX2-linked to energy-related pathways (pyruvate metabolism, glycolysis/gluconeogenesis, propanoate metabolism) and arachidonic acid metabolism. CBD also modulated apoptosis-related protein dysregulation, with potential involvement of Akt-related signaling. Docking results suggested possible binding between CBD and the selected targets.

Conclusion: These results suggest that CBD improves ASD-like behaviors alongside hippocampal lipid metabolism remodeling and modulation of apoptosis-related signaling in VPA-exposed rats, providing preliminary insights into potential mechanisms underlying the effects of CBD in ASD models.”

https://pubmed.ncbi.nlm.nih.gov/42632396

“CBD improved ASD-like behaviors in VPA-induced rats.”

https://www.sciencedirect.com/science/article/abs/pii/S0165178126004658?via%3Dihub

Effects of stir-fried Hemp (Cannabis sativa L.) seed polysaccharides on blood deficiency syndrome in rats based on metabolomics and gut microbiota

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“This study evaluated the therapeutic potential of raw hemp seed polysaccharides (HSP) and stir-fried hemp seed polysaccharides (FHSP) in a rat model of blood-deficiency syndrome induced by cyclophosphamide and acetylphenylhydrazine.

Both HSP and FHSP are acidic heteropolysaccharides primarily composed of arabinose, galacturonic acid, and galactose, but differ in molecular weight, monosaccharide ratios, and microstructure. Methylation and GC-MS analyses indicated that HSP and FHSP shared similar major glycosidic linkage types, predominantly including →5)-Araf-(1→, Galp-(1→, →4)-GalAp-(1→, and →6)-Galp-(1→, but differed in their relative molar proportions.

In vivo experiments showed that both HSP and FHSP significantly improved hematological parameters (RBC, WBC, HGB, and HCT), regulated cytokine levels (EPO, G-CSF, TNF-α, and IL-6), and alleviated splenic damage. Compared with HSP, FHSP produced more pronounced improvements in several evaluated indicators under the present experimental conditions.

Mechanistic analyses suggested that the beneficial effects of FHSP may be associated with the JAK1-STAT1 signaling pathway, amelioration of splenic metabolic dysfunction involving arachidonic acid, glutathione, riboflavin, and arginine and proline metabolism, and modulation of the gut microbial community.

These findings suggest that FHSP has potential for alleviating blood deficiency syndrome and provide new insights into the further development and application of hemp seed polysaccharides.”

https://pubmed.ncbi.nlm.nih.gov/42629028

https://www.sciencedirect.com/science/article/abs/pii/S0963996926014754?via%3Dihub

The beneficial properties of CBDA in diet-induced neuroinflammation

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“Cannabidiolic acid (CBDA) is a phytocannabinoid found in the Cannabis plant. Understanding the effects of CBDA is essential to uncover its full potential and possible health benefits.

The study was conducted on rats receiving standard rat chow (control) and a high-fat diet (HFD).

Half of the animals in each group were administered CBDA intragastrically. The total lipid fractions and arachidonic acid (AA) contents were measured in the frontal and posterior cortex, hippocampus, and subcortical nuclei using gas-liquid chromatography. The expression of proteins involved in neurodegenerative diseases and insulin signaling pathway proteins in the frontal and posterior cortex was measured using Immunoblotting. RT-PCR was used to assess the expression of pro-inflammatory pathway proteins in the same regions. Additionally, untargeted and targeted metabolomic analyses were performed on cerebrospinal fluid (CSF).

The results showed that a decrease in arachidonic acid levels and pro-inflammatory precursor proteins after CBDA treatment in high-fat-fed rats was simultaneous with improved insulin signaling, particularly in the posterior cortex.

Inactivation of glycogen synthase kinase 3 (GSK-3β) in this region was concomitant with changes in neurodegenerative biomarkers in the cortex and CSF. Metabolomic studies revealed a significant diminishment in creatinine, phenylalanine, and sarcosine levels in the HFD+CBDA group, suggesting it plays an important role in neurological disorders.

The results suggest that CBDA has anti-inflammatory properties by reducing the synthesis of lipid inflammatory mediators, which are concomitant with improved insulin signaling and probably reduced neurodegeneration.

Thus, CBDA could be considered as a part of future clinical treatment for many inflammatory conditions.”

https://pubmed.ncbi.nlm.nih.gov/42627619

“Our study demonstrated a preliminary analysis of the impact of CBDA on the inflammatory profile of the brain under conditions of excess calories from fat. The results suggest an anti-inflammatory role for this cannabinoid, particularly in inhibiting the synthesis of lipid inflammatory mediators.”

https://link.springer.com/article/10.1007/s10787-026-02358-4

Cannabidiol and skeletal muscle insulin resistance: translational implications for exercise and rehabilitation medicine

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“Insulin Resistance (IR) is a central pathophysiological mechanism underlying obesity, type 2 diabetes mellitus, metabolic syndrome, and metabolic dysfunction-associated steatotic liver disease, with significant implications for skeletal muscle function, exercise capacity, and rehabilitation outcomes. Because skeletal muscle represents the primary site of insulin-stimulated glucose disposal, muscle insulin resistance is a key determinant of both metabolic health and physical performance.

Cannabidiol (CBD), a non-intoxicating phytocannabinoid derived from Cannabis sativa, has attracted increasing scientific interest due to its anti-inflammatory, antioxidant, and pleiotropic signaling properties.

This narrative review aims to examine the relationship between CBD and insulin resistance, with a particular focus on skeletal muscle biology and its relevance for exercise and rehabilitation medicine.

A structured literature search was conducted using major biomedical databases, including PubMed, Scopus, and Web of Science, to identify relevant preclinical and clinical studies. Evidence was synthesized narratively, with emphasis on skeletal muscle insulin resistance, endocannabinoid system signaling, potential mechanisms of CBD action, and clinical outcomes.

Preclinical data suggest that CBD may influence several pathways involved in skeletal muscle insulin resistance, including chronic low-grade inflammation, oxidative stress, lipotoxicity, and ceramide accumulation. However, current human studies remain limited and do not demonstrate consistent improvements in glycemic control or insulin sensitivity with CBD alone. Furthermore, evidence regarding its effects on muscle function, exercise performance, or rehabilitation outcomes is lacking.

In conclusion, CBD represents a biologically plausible but clinically unproven modulator of skeletal muscle insulin resistance. At present, it should be considered an experimental adjunct rather than an established therapeutic strategy. Future research should focus on well-designed clinical trials integrating metabolic and functional endpoints to determine its potential role alongside exercise-based interventions in rehabilitation medicine.”

https://pubmed.ncbi.nlm.nih.gov/42615071

https://www.pagepressjournals.org/bam/article/view/15541

Anticonvulsant effects, safety, and sex-dependent molecular signatures of cannabidiol treatment in a preclinical model of audiogenic epilepsy

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“Roughly one-third of patients with epilepsy remain drug resistant, underscoring the need for novel therapeutic strategies. Although cannabidiol (CBD) has recently been approved for specific epileptic encephalopathies, its anticonvulsant mechanisms and the influence of biological sex on treatment response remain incompletely understood.

In this preclinical study, we evaluated the efficacy, tolerability, pharmacokinetics, and molecular effects of CBD in the GASH/Sal hamster, a genetic model of audiogenic generalized tonic-clonic seizures.

Animals received intraperitoneal CBD (200 mg/kg) either acutely or chronically for 14 days. CBD concentrations were measured in serum and brain, while seizure severity, latency, and neuroethological parameters were assessed following acoustic seizure induction. Safety was evaluated through body weight, hematological, and biochemical analyses, and gene expression profiling was performed in the inferior colliculus, the primary epileptogenic focus. CBD achieved measurable systemic and brain exposure after both acute and chronic administration, despite substantial inter-individual variability and no significant sex differences in drug concentrations.

CBD reduced audiogenic seizure severity in a time-dependent manner, with greater protection after chronic treatment.

CBD also prolonged latency to seizure onset in both sexes (earlier in females). Although complete seizure suppression was more frequent in females than males (37.5% vs. 12.5% after chronic treatment), direct sex comparisons did not reach statistical significance.

Notably, higher serum and brain CBD concentrations were associated with lower seizure severity. Chronic CBD administration was well tolerated in both sexes, affecting selected hematological parameters without altering body weight or liver function. Gene expression profiling revealed that transcriptional organization of the inferior colliculus was driven predominantly by biological sex rather than by seizure induction or CBD treatment. Marked sex-dependent differences were observed in serotonergic, endocannabinoid, purinergic, and Sigmar1-related neuroprotective pathways. Within this molecular context, seizure stimulation modulated Trpv1 and Slc29a1, whereas chronic CBD induced pathway-specific, sex-dependent changes involving 5-Htr1a, Adora1, and Cnr1, without eliciting widespread transcriptional remodeling.

Collectively, these findings identify CBD as a well-tolerated anticonvulsant in the GASH/Sal model and suggest that pharmacokinetic exposure and the sex-specific molecular organization of the epileptogenic focus contribute to variability in treatment response, highlighting the importance of considering biological sex in cannabinoid-based epilepsy research.”

https://pubmed.ncbi.nlm.nih.gov/42630256

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2026.1745696/full


Beyond inflammation: Cannabinoid receptors as metabolic checkpoints in glial reprogramming during neurodegeneration

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“Cannabinoid receptors have traditionally been regarded as regulators of neuroinflammation. However, their anti-inflammatory effects alone are insufficient to fully elucidate their complicated roles in neurodegenerative diseases (NDDs).

Mounting evidence identifies disruptions in energy metabolism as key drivers of neurodegeneration, which has prompted a re-evaluation of the cannabinoid receptor system within the context of brain energy metabolism and pathophysiological processes. Accumulated findings from several independent preclinical studies have offered novel insights into the potential involvement of cannabinoid receptors in energy metabolism, mitochondrial function, and glial metabolic reprogramming.

This review focuses on the metabolic regulatory potential of classical cannabinoid receptors, including cannabinoid receptor type 1 (CB1R) and cannabinoid receptor type 2 (CB2R), with particular attention to mitochondrial CB1 receptors (mtCB1), as well as non-classical targets such as G protein-coupled receptor 55 (GPR55), G protein-coupled receptor 119 (GPR119), and peroxisome proliferator-activated receptors (PPARs). Additionally, the review explores the mechanisms by which astrocytes maintain neuronal support through cell-type-specific metabolic specialization and how metabolic reprogramming in microglia modulates neuroinflammatory phenotypes.

Although the current evidence is predominantly derived from preclinical models and several mechanistic links remain to be experimentally validated, we propose a novel conceptual model, namely the cannabinoid receptor-glial metabolic reprogramming-neuronal metabolic support failure axis, in which the breakdown of metabolic checkpoints is viewed as a crucial event in disease progression.

At the therapeutic level, we advocate shifting from conventional anti-inflammatory approaches to metabolic repair strategies, while also exploring emerging directions in the development of cannabinoid-based medications targeting metabolism.

Collectively, a deep understanding of the complex metabolic regulatory functions of cannabinoid receptors is critical for developing next-generation treatment strategies for NDDs.”

https://pubmed.ncbi.nlm.nih.gov/42624021

“Shift from anti-inflammation to metabolic repair for cannabinoid NDD therapy.”

https://www.sciencedirect.com/science/article/abs/pii/S1567576926011458?via%3Dihub