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State Cannabis Legalization and Psychosis-Related Health Care Utilization

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JAMA editors name the journal's best articles of the decade | American Medical Association

“Importance: Psychosis is a hypothesized consequence of cannabis use. Legalization of cannabis could therefore be associated with an increase in rates of health care utilization for psychosis.

Objective: To evaluate the association of state medical and recreational cannabis laws and commercialization with rates of psychosis-related health care utilization.

Design, setting, and participants: Retrospective cohort design using state-level panel fixed effects to model within-state changes in monthly rates of psychosis-related health care claims as a function of state cannabis policy level, adjusting for time-varying state-level characteristics and state, year, and month fixed effects. Commercial and Medicare Advantage claims data for beneficiaries aged 16 years and older in all 50 US states and the District of Columbia, 2003 to 2017 were used. Data were analyzed from April 2021 to October 2022.

Exposure: State cannabis legalization policies were measured for each state and month based on law type (medical or recreational) and degree of commercialization (presence or absence of retail outlets).

Main outcomes and measures: Outcomes were rates of psychosis-related diagnoses and prescribed antipsychotics.

Results: This study included 63 680 589 beneficiaries followed for 2 015 189 706 person-months. Women accounted for 51.8% of follow-up time with the majority of person-months recorded for those aged 65 years and older (77.3%) and among White beneficiaries (64.6%). Results from fully-adjusted models showed that, compared with no legalization policy, states with legalization policies experienced no statistically significant increase in rates of psychosis-related diagnoses (medical, no retail outlets: rate ratio [RR], 1.13; 95% CI, 0.97-1.36; medical, retail outlets: RR, 1.24; 95% CI, 0.96-1.61; recreational, no retail outlets: RR, 1.38; 95% CI, 0.93-2.04; recreational, retail outlets: RR, 1.39; 95% CI, 0.98-1.97) or prescribed antipsychotics (medical, no retail outlets RR, 1.00; 95% CI, 0.88-1.13; medical, retail outlets: RR, 1.01; 95% CI, 0.87-1.19; recreational, no retail outlets: RR, 1.13; 95% CI, 0.84-1.51; recreational, retail outlets: RR, 1.14; 95% CI, 0.89-1.45). In exploratory secondary analyses, rates of psychosis-related diagnoses increased significantly among men, people aged 55 to 64 years, and Asian beneficiaries in states with recreational policies compared with no policy.

Conclusions and relevance: In this retrospective cohort study of commercial and Medicare Advantage claims data, state medical and recreational cannabis policies were not associated with a statistically significant increase in rates of psychosis-related health outcomes. As states continue to introduce new cannabis policies, continued evaluation of psychosis as a potential consequence of state cannabis legalization may be informative.”

https://pubmed.ncbi.nlm.nih.gov/36696111/

“In this retrospective cohort study of commercial and Medicare Advantage claims data, state medical and recreational cannabis policies were not associated with a statistically significant increase in rates of psychosis-related health outcomes.”

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2800728

The impact of phyto- and endo-cannabinoids on central nervous system diseases：A review

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Journal of Traditional and Complementary Medicine

“Background and aim: Cannabis sativa L. is a medicinal plant with a long history. Phyto-cannabinoids are a class of compounds from C. sativa L. with varieties of structures. Endocannabinoids exist in the human body. This article provides an overview of natural cannabinoids (phyto-cannabinoids and endocannabinoids) with an emphasis on their pharmacology activities.

Experimental procedure: The keywords “Cannabis sativa L″, “cannabinoids”, and “central nervous system (CNS) diseases” were used for searching and collecting pieces of literature from PubMed, ScienceDirect, Web of Science, and Google Scholar. The data were extracted and analyzed to explore the effects of cannabinoids on CNS diseases.

Result and conclusion: In this paper, schematic diagrams are used to intuitively show the phyto-cannabinoids skeletons’ mutual conversion and pharmacological activities, with special emphasis on their relevant pharmacological activities on central nervous system (CNS) diseases. It was found that the endocannabinoid system and microglia play a crucial role in the treatment of CNS diseases. In the past few years, pharmacological studies focused on Δ9-THC, CBD, and the endocannabinoids system. It is expected to encourage new studies on a more deep exploration of other types of cannabinoids and the mechanism of their pharmacological activities in the future.”

https://pubmed.ncbi.nlm.nih.gov/36685079/

https://www.sciencedirect.com/science/article/pii/S2225411022000761?via%3Dihub

The Endocannabinoid System as a Target for Neuroprotection/Neuroregeneration in Perinatal Hypoxic-Ischemic Brain Injury

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biomedicines-logo

“The endocannabinoid (EC) system is a complex cell-signaling system that participates in a vast number of biological processes since the prenatal period, including the development of the nervous system, brain plasticity, and circuit repair. This neuromodulatory system is also involved in the response to endogenous and environmental insults, being of special relevance in the prevention and/or treatment of vascular disorders, such as stroke and neuroprotection after neonatal brain injury. Perinatal hypoxia-ischemia leading to neonatal encephalopathy is a devastating condition with no therapeutic approach apart from moderate hypothermia, which is effective only in some cases. This overview, therefore, gives a current description of the main components of the EC system (including cannabinoid receptors, ligands, and related enzymes), to later analyze the EC system as a target for neonatal neuroprotection with a special focus on its neurogenic potential after hypoxic-ischemic brain injury.”

https://pubmed.ncbi.nlm.nih.gov/36672536/

“The ubiquitous lipid signaling-based EC system is involved in outstanding regulatory functions throughout the human body, including neural development under physiological conditions and neuroprotection, and repair after pathophysiological processes.In the context of neonatal brain injury, the administration of endogenous or exogenous CBs, or the blockage of EC degradation, has revealed a strong neuroprotective response in different preclinical models after HI. Similarly, the possibility of tissue repair in the developing brain by enhancing the proliferative potential of the SVZ and SGZ neurogenic niches is currently under active investigation. Selective modulation of the EC system in the sites of damage by targeting the enzymes responsible for EC degradation may represent an important therapeutic approach in order to avoid non-desired widespread effects.Despite the clinical use of CB-related drugs that must be taken with caution, the modulation of the EC system to ameliorate the neurological consequences after neonatal HI is currently an exciting field of research with enormous possibilities for clinical translation.”

https://www.mdpi.com/2227-9059/11/1/28

Hemp Protein Hydrolysates Modulate Inflammasome-Related Genes in Microglial Cells

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biology-logo

“A prolonged inflammatory response can lead to the development of neurodegenerative diseases such as Alzheimer’s disease. Enzymatic hydrolysis is a sustainable way to increase the value of protein sources by obtaining peptides that can exert bioactivity.

Hemp (Cannabis sativa L.) protein hydrolysates have been proven to exert anti-inflammatory activity.

In this study, two hemp protein hydrolysate (HPHs), obtained with Alcalase as sole catalyst, or with Alcalase followed by Flavourzyme, were evaluated as inflammatory mediators (TNFα, IL-1β, IL-6, and IL-10), microglial polarization markers (Ccr7, iNos, Arg1, and Ym1), and genes related to inflammasome activation (Nlrp3, Asc, Casp1, and Il18), employing the lipopolysaccharide (LPS)-induced neuroinflammation model in murine BV-2 microglial cells.

A significant decrease of the expression of proinflammatory genes (e.g., Tnfα, Ccr7, inos, and Nlrp3, among others) and increase of the expression anti-inflammatory cytokines in microglial cells was observed after treatment with the test HPHs. This result in the cell model suggests a polarization toward an anti-inflammatory M2 phenotype. Our results show that the evaluated HPHs show potential neuroprotective activity in microglial cells via the inflammasome.”

https://pubmed.ncbi.nlm.nih.gov/36671742/

“Neuroinflammation can lead to the development of neurodegenerative diseases. Food-derived peptides released by the action of enzymes have been proven to modulate several physiological processes. In this study, peptides obtained from hemp protein were evaluated as anti-inflammatory agents employing a cell model, measuring the responses of inflammatory mediators, microglial polarization markers, and genes related to inflammasome activation, as markers of inflammation and the potential counteraction exerted by the peptides, related to neurodegenerative processes. Results showed a neuroprotective effect based on anti-inflammatory activity of the peptides, via the inflammasome. The use of these peptides in the diet could help to prevent inflammation and promote a healthy aging of humans.”

https://www.mdpi.com/2079-7737/12/1/49

Cannabidiol Rescues TNF-α-Inhibited Proliferation, Migration, and Osteogenic/Odontogenic Differentiation of Dental Pulp Stem Cells

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biomolecules-logo

“Strategies to promote dental pulp stem cells (DPSCs) functions including proliferation, migration, pro-angiogenic effects, and odontogenic/osteogenic differentiation are in urgent need to restore pulpitis-damaged dentin/pulp regeneration and DPSCs-based bone tissue engineering applications. Cannabidiol (CBD), an active component of Cannabis sativa has shown anti-inflammation, chemotactic, anti-microbial, and tissue regenerative potentials. Based on these facts, this study aimed to analyze the effect of CBD on DPSCs proliferation, migration, and osteogenic/odontogenic differentiation in basal and inflammatory conditions. Highly pure DPSCs with characteristics of mesenchymal stem cells (MSCs) were successfully isolated, as indicated by the results of flowcytometry and multi-lineage (osteogenic, adipogenic, and chondrogenic) differentiation potentials. Among the concentration tested (0.1-12.5 µM), CBD (2.5 μM) showed the highest anabolic effect on the proliferation and osteogenic/odontogenic differentiation of DPSCs. Pro-angiogenic growth factor VEGF mRNA expression was robustly higher in CBD-treated DPSCs. CBD also prompted the migration of DPSCs and CBD receptor CB1 and CB2 expression in DPSCs. TNF-α inhibited the viability, migration, and osteogenic/odontogenic differentiation of DPSCs and CBD reversed these effects. CBD alleviated the TNF-α-upregulated expression of pro-inflammatory cytokines TNF-α, interleukin (IL)-1β, and IL-6 in DPSCs. In conclusion, our results indicate the possible application of CBD on DPSCs-based dentin/pulp and bone regeneration.”

https://pubmed.ncbi.nlm.nih.gov/36671503/

“We tested the effect of CBD on DPSCs functions required for dentin and pulp revitalization and bone regeneration, including viability, migration, osteogenic/odontogenic differentiation, pro-angiogenic potential, and anti-inflammatory effects in vitro experiments. Our results showed the anabolic effect of CBD in these functions of DPSCs both in the basal and inflammatory situations suggesting the possible application of CBD or/and DPSCs on oral tissue regeneration including dentin/pulp and bone. Our results warrant in situ studies using dentin/pulp and bone regeneration models to further confirms these anabolic roles of CBD.”

https://www.mdpi.com/2218-273X/13/1/118

Recreational cannabis and opioid distribution

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“Twenty-one U.S. states have passed recreational cannabis laws as of November 2022. Cannabis may be a substitute for prescription opioids in the treatment of chronic pain. Previous studies have assessed recreational cannabis laws’ effects on opioid prescriptions financed by specific private or public payers or dispensed to a unique endpoint.

Our study adds to the literature in three important ways: by (1) examining these laws’ impacts on prescription opioid dispensing across all payers and endpoints, (2) adjusting for important opioid-related policies such as opioid prescribing limits, and (3) modeling opioids separately by type. We implement two-way fixed-effects regressions and leverage variation from eleven U.S. states that adopted a recreational cannabis law (RCL) between 2010 and 2019.

We find that RCLs lead to a reduction in codeine dispensed at retail pharmacies. Among prescription opioids, codeine is particularly likely to be used non-medically. Thus, the finding that RCLs appear to reduce codeine dispensing is potentially promising from a public health perspective.”

https://pubmed.ncbi.nlm.nih.gov/36653623/

https://onlinelibrary.wiley.com/doi/10.1002/hec.4652

“When recreational cannabis is legal, codeine demand drops”

https://news.cornell.edu/stories/2023/01/when-recreational-cannabis-legal-codeine-demand-drops

Chemical constituents of industrial hemp roots and their anti-inflammatory activities

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BMC-Springer-Nature-MIDM - Greehey Children's Cancer Research Institute

“Objective: Although the chemical constituents of the aerial parts of Cannabis have been extensively studied, phytochemicals of Cannabis roots are not well characterized. Herein, we investigated the chemical constituents of industrial hemp (Cannabis sativa L.) roots and evaluated the anti-inflammatory activities of phytochemicals isolated from the hemp roots extract.

Methods: An ethyl acetate extract of hemp roots was subjected to a combination of chromatographic columns to isolate phytochemicals. The chemical structures of the isolates were elucidated based on spectroscopic analyses (by nuclear magnetic resonance and mass spectrometry). The anti-inflammatory effects of phytochemicals from hemp roots were evaluated in an anti-inflammasome assay using human monocyte THP-1 cells.

Results: Phytochemical investigation of hemp roots extract led to the identification of 32 structurally diverse compounds including six cannabinoids (1-6), three phytosterols (26-28), four triterpenoids (22-25), five lignans (17-21), and 10 hydroxyl contained compounds (7-16), three fatty acids (29-31), and an unsaturated chain hydrocarbon (32). Compounds 14-21, 23, 27, and 32 were identified from the Cannabis species for the first time. Cannabinoids (1-5) reduced the level of cytokine tumor necrosis-alpha (by 38.2, 58.4, 47.7, 52.2, and 56.1%, respectively) and 2 and 5 also decreased the interleukin-1β production (by 42.2 and 92.4%, respectively) in a cell-based inflammasome model. In addition, non-cannabinoids including 11, 13, 20, 25, 29, and 32 also showed selective inhibition of interleukin-1β production (by 23.7, 22.5, 25.6, 78.0, 24.1, 46.6, and 25.4%, respectively) in THP-1 cells.

Conclusion: The phytochemical constituent of a hemp roots extract was characterized and compounds from hemp roots exerted promising anti-inflammatory effects.”

https://pubmed.ncbi.nlm.nih.gov/36642726/

“The medicinal uses of Cannabis roots for a variety of maladies are supported by empirical practice and emerging scientific evidence.

Several pre-clinical studies reported that cannabis root extracts exert various pharmacological effects including anti-inflammatory, estrogenic, liver protective, and anti-cancer activities.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-022-00168-3

Cannabidiol for the Treatment of Brain Disorders: Therapeutic Potential and Routes of Administration

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SpringerLink

“The use of cannabidiol (CBD) for treating brain disorders has gained increasing interest. While the mechanism of action of CBD in these conditions is still under investigation, CBD has been shown to affect numerous different drug targets in the brain that are involved in brain disorders. Here we review the preclinical and clinical evidence on the potential therapeutic use of CBD in treating various brain disorders. Moreover, we also examine various drug delivery approaches that have been applied to CBD. Due to the slow absorption and low bioavailability with the current oral CBD therapy, more efficient routes of administration to bypass hepatic metabolism, particularly pulmonary delivery, should be considered. Comparison of pharmacokinetic studies of different delivery routes highlight the advantages of intranasal and inhalation drug delivery over other routes of administration (oral, injection, sublingual, buccal, and transdermal) for treating brain disorders. These two routes of delivery, being non-invasive and able to achieve fast absorption and increase bioavailability, are attracting increasing interest for CBD applications, with more research and development expected in the near future.”

https://pubmed.ncbi.nlm.nih.gov/36635488/

https://link.springer.com/article/10.1007/s11095-023-03469-1

Cannabidiol inhibits lung proliferation in monocrotaline-induced pulmonary hypertension in rats

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Biomedicine & Pharmacotherapy

“Cannabidiol (CBD) is a safe and well-tolerated plant-derived drug with anti-proliferative properties. Pulmonary hypertension (PH) is a rapidly progressive and still incurable disease. CBD diminishes monocrotaline (MCT)-induced PH, including reduced right ventricular systolic pressure, pulmonary vascular hypertrophy, and right ventricular remodeling. The aim of our study was to investigate the effect of chronic administration of CBD (10 mg/kg once daily for 21 days) on selected remodeling parameters in the lung of MCT-induced PH rats. In MCT-induced PH, we found an increase in profibrotic parameters, e.g., transforming growth factor β1 (TGF-β1), galectin-3 (Gal-3), procollagen I, collagen I, C-propeptide, matrix metalloproteinase 9 (MMP-9) and an increased number of mast cells. In our study, we observed that the TGF-β1, Gal-3, procollagen I, collagen I, C-propeptide, and mast cell levels in lung tissue were decreased after CBD administration to MCT-treated rats. In summary, CBD treatment has an anti-proliferative effect on MCT-induced PH. Given the beneficial multidirectional effects of CBD on PH, we believe that CBD can be used as an adjuvant PH therapy, but this argument needs to be confirmed by clinical trials.”

https://pubmed.ncbi.nlm.nih.gov/36634588/

https://www.sciencedirect.com/science/article/pii/S0753332223000227?via%3Dihub

Cannabidiol repairs behavioral and brain disturbances in a model of fetal alcohol spectrum disorder

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Pharmacological Research

“Fetal alcohol spectrum disorder (FASD) includes neuropsychiatric disturbances related to gestational and lactational ethanol exposure. Available treatments are minimal and do not modulate ethanol-induced damage. Developing animal models simulating FASD is essential for understanding the underlying brain alterations and searching for efficient therapeutic approaches. The main goal of this study was to evaluate the effects of early and chronic cannabidiol (CBD) administration on offspring exposed to an animal model of FASD. Ethanol gavage (3g/kg/12h, p.o.) was administered to C57BL/6J female mice, with a previous history of alcohol consumption, between gestational day 7 and postnatal day 21. On the weaning day, pups were separated by sex, and CBD administration began (30mg/kg/day, i.p.). After 4-6 weeks of treatment, behavioral and neurobiological changes were analyzed. Mice exposed to the animal model of FASD showed higher anxiogenic and depressive-like behaviors and cognitive impairment that were evaluated through several experimental tests. These behaviors were accompanied by alterations in the gene, cellular and metabolomic targets. CBD administration normalized FASD model-induced emotional and cognitive disturbances, gene expression, and cellular changes with sex-dependent differences. CBD modulates the metabolomic changes detected in the hippocampus and prefrontal cortex. Interestingly, no changes were found in mitochondria or the oxidative status of the cells. These results suggest that the early and repeated administration of CBD modulated the long-lasting behavioral, gene and protein alterations induced by the FASD model, encouraging the possibility of performing clinical trials to evaluate the effects of CBD in children affected with FASD.”

https://pubmed.ncbi.nlm.nih.gov/36642113/

“The results of the present study reveal that the early and chronic administration of CBD repairs the emotional and cognitive alterations observed in male and female mice exposed to the animal model of FASD. Likewise, CBD modulates sex-dependently the gene expression changes and metabolomic targets affected by the model exposure. Interestingly, the data suggest the absence of mitochondrial and oxidative targets in CBD-induced modulation, pointing out that lipid and protein metabolism could be another pathway involved in the cellular reparation observed after CBD chronic administration. The modulation of Pparβ/δ gene expression could be one of the multiple targets involved in CBD’s induced cellular reparation and behavioral modulation. However, further studies are required to explore the real implication of this target in CBD’s mechanism of action in this model of FASD. Taken together, these results strongly stimulate the possibility of performing clinical trials to evaluate the effects of CBD in children affected with FASD.”

https://www.sciencedirect.com/science/article/pii/S1043661823000117?via%3Dihub