“Despite effective antiretroviral therapy (ART), people with HIV (PWH) experience persistent inflammation and metabolic dysfunction, increasing their risk for non-AIDS comorbidities. Accordingly, we evaluated the effects of long-term/low-dose Δ9-tetrahydrocannabinol (THC) supplementation in simian immunodeficiency virus (SIV)-infected, ART-treated rhesus macaques (RMs).
THC significantly increased plasma/jejunum serotonin and indole-3-propionate, enhancing gut-brain communication through up-regulation of serotonin receptors (HTR4/HTR7) and aryl hydrocarbon receptor (Ahr) signaling via a cannabinoid receptor (CBR)-2-mediated mechanism. Furthermore, THC enriched cholesterol-metabolizing Oscillibacter and reduced plasma cholesterol and toxic secondary bile acids (SBAs), thus improving cholesterol and SBA homeostasis.
Furthermore, THC increased β-hydroxybutyrate (BHB) levels via a CBR1-mediated mechanism, suggesting enhanced hepatic fatty acid oxidation for metabolic and cardiovascular health. THC restored ART/SIV-induced elevation of pro-inflammatory and cardiotoxic long-chain acylcholines to preinfection levels. THC-treated RMs maintained viral suppression despite reduced plasma ART levels, suggesting diminished ART-related toxicity.
Our findings demonstrate phytocannabinoids to be a safe adjunct therapy alongside ART to mitigate chronic inflammation and metabolic dysfunction in PWH.”
“Taken as a whole, our findings uncover numerous hitherto unknown mechanisms of cannabinoid action and provide multiple lines of evidence for its utility as an effective and relatively safe adjunct therapy to ART.”
“Background: Tourette Syndrome (TS) is a childhood onset chronic disorder in which motor and vocal tics co-occur. Cannabinoids are a potential therapeutic option for otherwise treatment resistant patients. However, there is an ongoing debate regarding potential side effects. This is particularly important in relation to activities being necessary for daily life such as driving a car.
Case presentation: We present the case of a 28-year-old male with TS and comorbid attention-deficit/hyperactivity disorder (ADHD) who was medicated by his treating physician with an extremely high dose of inhaled medicinal cannabis (MC) of up to 10 g/d. We were interested in the effects of MC on patient’s fitness to drive as well as corresponding serum levels of tetrahydrocannabinol (THC) and its metabolites. Therefore, clinical assessments and computer-based tests (Vienna Test System) were performed at different time points at two consecutive days before and after intake of MC at a dose that was determined by the patient according to clinical need. On day 1, he inhaled a total dose of 3.3 g and 4.1 g MC, respectively, before driving tests were performed. Until the end of the day, he used a total dose of 8.8 g. On day 2, he took no MC before all tests were completed.
Remarkably, according to the German Federal Highway Research Institute guidelines, the patient was considered fit to drive in all domains assessed at all time points at day 1 and 2. Higher doses of MC – and corresponding very high THC serum levels – resulted in best results with respect to patient’s driving ability. THC serum levels ranged from 19 ng/ml (at day 2 without MC intake at this day) to 364 ng/ml (at day 1 after intake of a total of 3.3 g MC at the same day). No clinically relevant side effects occurred.
Conclusions: This case study demonstrates that patients with TS plus comorbid ADHD may be fit to drive even after intake of high doses of MC. In any case, however, every driver, who uses MC, is obliged to check fitness to drive before driving a vehicle.”
“We present the case of a patient with TS using extremely high doses of MC (up to 10 g/d) for several years, who reported marked reductions of his tics and comorbid ADHD symptoms after use of MC. According to driving tests performed, he can be considered as fit to drive both on a day when using 3.3 g MC and 4.1 g MC, respectively, before testing as well as at the following day without additional prior MC use. Remarkably, his fitness to drive was even better on day 1 while taking MC and having THC serum levels of up to 364 ng/ml.”
“Cannabinoids are increasingly being used to manage pain resulting from a variety of conditions.
Both preclinical animal models and human studies have played a crucial role in advancing our knowledge of cannabinoids, their involvement in pain mechanisms, and their potential utility as novel analgesics.
This chapter first reviews basic pain neurobiology and the most common experimental pain paradigms, which provide a basis for our discussion of preclinical, human laboratory, and clinical research characterizing the effectiveness of cannabinoids for managing pain.
While a substantial body of literature exists describing these effects, findings are complex and largely mixed, dependent on the cannabinoid administered, route of administration, and pain modality/syndrome tested. Herein, we highlight the need for more rigorous, placebo-controlled research defining the therapeutic efficacy of cannabinoids.
The chapter concludes by emphasizing the need for further investigation of other cannabis constituents (e.g., minor cannabinoids and terpenes), potential interactions between cannabinoids and other analgesic medications, as well as other emerging issues in the intersection between cannabinoids and pain management.”
“Background: Methamphetamine use, which is disproportionately prevalent among people with HIV, increases risk for cardio- and neurovascular pathology through persistent immune activation and inflammation. Preclinical studies indicate that cannabinoids may reduce markers of pro-inflammatory processes, but data from people with chronic inflammatory conditions are limited. We examined potentially interacting associations of lifetime methamphetamine use disorder (MUD), recent cannabis use, and HIV with four plasma markers of immune and inflammatory functions.
Method: Participants with HIV (PWH, n = 86) and without HIV (PWoH, n = 148) provided urine and blood samples and completed neuromedical, psychiatric, and substance use assessments. Generalized linear models examined main and conditional associations of lifetime MUD, past-month cannabis use, and HIV with plasma concentrations of CXCL10/IP-10, CCL2/MCP-1, ICAM-1, and VCAM-1.
Results: PWH displayed higher CXCL10/IP-10 than PWoH. Past-month cannabis use was independently associated with lower CXCL10/IP-10 levels and conditionally lower CCL2/MCP-1, ICAM-1, and VCAM-1 levels among people with lifetime MUD, but only PWoH displayed cannabis-associated lower VCAM-1 levels.
Conclusions: Human plasma sample evidence suggests that cannabis use is associated with lower levels of immune and inflammatory molecules in the context of MUD or HIV. Cannabinoid pathways may be worthwhile clinical targets for treating sequelae of chronic inflammatory conditions.”
“METH use disorder is highly prevalent in PWH, and both can have significant effects on immune function and pro-inflammatory processes that lead to significant central nervous system consequences, despite modern advances in anti-retroviral therapy effectiveness and tolerability. Results from this study support prior findings that METH and HIV disease confer risk for negative outcomes via their influence on chronic inflammatory processes, and we provide novel evidence from human plasma samples that cannabis use is associated with reduced levels of immune and inflammatory molecules in the context of chronic METH use or HIV infection (CCL2/MCP-1, VCAM-1, ICAM-1) and independent of METH use and HIV (CXCL10/IP-10). Associations between cannabis use and lower indices of inflammatory pathology from HIV and MUD point toward cannabinoid pathways as promising therapeutic targets that warrant further study.”
“Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have transformed type 2 diabetes mellitus (T2DM) management by promoting glucosuria, lowering glycated hemoglobin (HbA1c), blood pressure, and weight; however, their use is limited by genitourinary infections and ketoacidosis. Phytocannabinoids-bioactive compounds from Cannabis sativa-exhibit multi-target pharmacology, including interactions with cannabinoid receptors, Peroxisome Proliferator-Activated Receptors (PPARs), Transient Receptor Potential (TRP) channels, and potentially SGLT2.
Objective: To evaluate the potential of phytocannabinoids as novel modulators of renal glucose reabsorption via SGLT2 and to compare their efficacy, safety, and pharmacological profiles with synthetic SGLT2 inhibitors.
Methods: We performed a narrative review encompassing the following: (1) the molecular and physiological roles of SGLT2; (2) chemical classification, natural sources, and pharmacokinetics/pharmacodynamics of major phytocannabinoids (Δ9-Tetrahydrocannabinol or Δ9-THC, Cannabidiol or CBD, Cannabigerol or CBG, Cannabichromene or CBC, Tetrahydrocannabivarin or THCV, and β-caryophyllene); (3) in silico docking and drug-likeness assessments; (4) in vitro assays of receptor binding, TRP channel modulation, and glucose transport; (5) in vivo rodent models evaluating glycemic control, weight change, and organ protection; (6) pilot clinical studies of THCV and case reports of CBD/BCP; (7) comparative analysis with established synthetic inhibitors.
Results: In silico studies identify high-affinity binding of several phytocannabinoids within the SGLT2 substrate pocket. In vitro, CBG and THCV modulate SGLT2-related pathways indirectly via TRP channels and CB receptors; direct IC50 values for SGLT2 remain to be determined. In vivo, THCV and CBD demonstrate glucose-lowering, insulin-sensitizing, weight-reducing, anti-inflammatory, and organ-protective effects. Pilot clinical data (n = 62) show that THCV decreases fasting glucose, enhances β-cell function, and lacks psychoactive side effects. Compared to synthetic inhibitors, phytocannabinoids offer pleiotropic benefits but face challenges of low oral bioavailability, polypharmacology, inter-individual variability, and limited large-scale trials.
Discussion: While preclinical and early clinical data highlight phytocannabinoids’ potential in SGLT2 modulation and broader metabolic improvement, their translation is impeded by significant challenges. These include low oral bioavailability, inconsistent pharmacokinetic profiles, and the absence of standardized formulations, necessitating advanced delivery system development. Furthermore, the inherent polypharmacology of these compounds, while beneficial, demands comprehensive safety assessments for potential off-target effects and drug interactions. The scarcity of large-scale, well-controlled clinical trials and the need for clear regulatory frameworks remain critical hurdles. Addressing these aspects is paramount to fully realize the therapeutic utility of phytocannabinoids as a comprehensive approach to T2DM management.
Conclusion: Phytocannabinoids represent promising multi-target agents for T2DM through potential SGLT2 modulation and complementary metabolic effects. Future work should focus on pharmacokinetic optimization, precise quantification of SGLT2 inhibition, and robust clinical trials to establish efficacy and safety profiles relative to synthetic inhibitors.”
“phytocannabinoids may complement or even extend the benefits of current SGLT2 inhibitors, offering a holistic, multi-mechanistic approach to complex metabolic disease management.”
“Background/Objective: Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting adverse effect of various chemotherapeutic agents. Previous work demonstrated that cannabis alleviates symptoms of oxaliplatin-induced CIPN. To evaluate the effects of cannabis components, cannabidiol (CBD) and tetrahydrocannabinol (THC), on CIPN-related symptoms.
Methods: We reviewed a patient-reported outcomes dataset from “Tikun Olam,” a major medical cannabis provider. Of 1493 patients, 802 reported at least one CIPN symptom at baseline, including a burning sensation, cold sensation, paresthesia (prickling) and numbness, and 751 of them met the study inclusion criteria. Patients were categorized into THC-high/CBD-low and CBD-high/THC-low groups. Symptom changes after six months of cannabis use were analyzed using K-means clustering and logistic regression, incorporating interactions between baseline symptoms and THC and CBD doses. Linear regression assessed changes in activities of daily living (ADL) and quality of life (QOL).
Results: Both groups reported symptom improvement. The THC-high group showed significantly greater improvement in burning sensation and cold sensation (p = 0.024 and p = 0.008). Improvements in ADL and QOL were also significantly higher in the THC group (p = 0.029 and p = 0.006). A significant interaction between THC and CBD was observed for symptom improvement (p < 0.0001).
Conclusions: Cannabis effectively reduces CIPN symptoms and improves QOL and ADL. Higher THC doses were more effective than lower doses, with combined CBD and THC doses yielding greater symptom relief.”
“Cannabis products demonstrated efficacy in alleviating symptoms associated with CIPN and resulted in a reduction in the number of reported symptoms. Improvements in symptoms and in QOL and ADL questionnaire responses were observed when queried after six months of cannabis use. Higher doses of THC showed greater efficacy than lower doses, while gradually increasing doses of both CBD and THC alone and in combination correlated better with symptom improvement.
The observed dose–response relationship of both THC and CBD highlights the need for prospective controlled trials to establish optimal cannabinoid ratios for specific symptom clusters, such as burning or cold sensations. Future studies should also aim to evaluate the long-term safety and efficacy of cannabis in oncology patients, as well as explore mechanistic pathways linking cannabinoid receptor activation to neuroprotection and anti-inflammatory effects in CIPN.
Personalized treatment strategies, incorporating cannabinoid pharmacogenetics and symptom-driven dose titration, should be further investigated to better integrate medical cannabis into standard supportive oncology care.”
“Objective: Emerging evidence suggests lipid metabolism dysregulation contributes to autism spectrum disorders (ASD), with the endocannabinoid system (cannabinoid receptors CB1R/CB2R) implicated in lipid homeostasis. This study investigated whether CB1R/CB2R activation improves hippocampal lipid metabolism and ASD-like behaviors in a valproic acid (VPA)-induced ASD rat model.
Methods: Male offspring from dams exposed to VPA (600 mg/kg, i.p.) received the CB1R agonist ACPA (0.1 mg/kg) or the CB2R agonist AM1241 (3 mg/kg) from postnatal days 21-27. ASD-like behaviors (marble burying, self-grooming, social interaction, open-field tests) and hippocampal lipid profiles (UPLC-MS/MS) were analyzed.
Results: VPA-exposed rats displayed heightened repetitive behaviors, social deficits, and hyperactivity, all significantly alleviated by ACPA and AM1241. Lipidomics revealed marked reductions in hippocampal phosphatidylcholines, lysophosphatidylcholines, fatty acids, sphingomyelins, ceramides, and phosphatidylethanolamines in VPA rats. Both agonists restored lipid levels to near normal, comparable to controls.
Conclusions: CB1R/CB2R activation ameliorates behavioral abnormalities and rectifies hippocampal lipid dysregulation in VPA-induced ASD models, highlighting cannabinoid receptors as potential therapeutic targets for ASD-associated metabolic disturbances.”
“This study provides new evidence linking ASD-like behaviors, lipid metabolism abnormalities, and endocannabinoid system regulation. Our results demonstrated that CB1R and CB2R activation alleviated VPA-induced ASD-like behaviors and restored disrupted lipid profiles in the hippocampus, suggesting a potential therapeutic approach for ASD. Further research should explore the molecular mechanisms underlying CB1R- and CB2R-mediated lipid regulation and their implications for ASD treatment strategies.”
“Aims: Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of hospital-acquired pneumonia with resistance against beta-lactam antibiotics. New, potent antibiotics against MRSA with other mechanisms of action are thus urgently needed. Recently, cannabinoids have been evaluated for antimicrobial activity in the ongoing search for new anti-infective agents, but their anti-biofilm effect has not been extensively studied. In this study, five main phytocannabinoids – canndibidiol (CBD), delta-9-tetrahydrocannabinol (THC), cannabinol (CBN), cannabigerol (CBG), and cannabichromene (CBC) were examined for their activity against a MRSA biofilm.
Methods and results: The anti-biofilm activity was assessed by crystal violet staining, resazurin metabolic assay, reactive oxygen species (ROS) assay, and propidium iodide membrane integrity test. The minimum inhibitory concentrations of all tested cannabinoids were between 1-2 µg/mL. CBN showed the most potent anti-MRSA biofilm activity, significantly reducing biofilm biomass and bacterial viability. It also induced the highest intracellular ROS levels. In contrast, CBD was the least effective among the tested cannabinoids in most of the anti-biofilm assays, yet it caused the greatest membrane damage to bacteria within the biofilm.
Conclusions: This study showed that despite being chemically similar, the cannabinoids demonstrated different potency and potentially different mechanisms of action against MRSA. More research is needed to investigate how they act on this pathogen and its biofilm.”
“Background: Cannabis constituents, including Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), show distinct pharmacological profiles with therapeutic relevance for neurological and psychiatric conditions. THC exerts euphoric effects primarily via CB1 receptor activation, while CBD displays non-euphoric properties affecting various pathways.
Aims: This study evaluated the effects of THC, CBD, and their combination on brain functional connectivity (FC) and cerebral blood flow (CBF) using multimodal neuroimaging.
Methods: Adult male Sprague Dawley rats received intraperitoneal doses of 10 mg/kg THC, 150 mg/kg CBD, 10.8:10 mg/kg THC:CBD, or vehicle. Resting-state blood oxygenation level dependent magnetic resonance imaging and arterial spin labelling assessed FC and CBF, approximately 2 h after drug administration. Graph-theory metrics and seed-based analyses identified connectivity and perfusion alterations, while plasma analyses determined cannabinoid concentrations.
Results: THC increased whole-brain FC and clustering coefficient, with elevated CBF in cortical and subcortical regions. CBD decreased FC metrics without affecting CBF, while THC:CBD induced moderate increases in both. Seed-based analysis revealed THC-driven increases in cortical-hippocampal and cortical-striatal connectivity, attenuated in the THC:CBD group. A multivariate combined analysis of FC and CBF revealed a divergent pattern of changes induced by each drug.
Conclusions: In conclusion, we show that THC and CBD induce distinct neurophysiological profiles in rats, with THC increasing both connectivity and perfusion, moderated by CBD when combined. These findings corroborate existing knowledge about the effects of cannabinoids on the brain, while also supporting the potential of preclinical functional neuroimaging to delineate cannabinoid-induced endophenotypes, offering insights for therapeutic development.”
“Growing evidence supports the therapeutic potential of cannabis and its constituent phytocannabinoids in treating a range of neurological and psychiatric conditions.”
“In summary, we have demonstrated that acute THC administration resulted in increases in FC and regional CBF, acute CBD administration resulted in an overall reduction in FC with negligible effect on CBF, and the combination drug THC:CBD resulted in effects similar to, but lower than THC alone. Our application of functional neuroimaging has thus identified differential pharmacodynamic signatures for THC and CBD in anaesthetised adult male rats. Further work should encompass an investigation of the effects of sub-chronic administration of phytocannabinoids on brain activity in animal models with relevance to selected disease indications to investigate changes on FC in a perturbed system, more applicable to the disease state. “
“This study aimed to design a THC-rich hydrogel to deliver cannabis derivatives topically. We developed hydrogels using polyvinyl alcohol (PVA) mixed with propylene glycol (PG), vegetable glycerin (VG), or both to facilitate the dissolution of delta-9-tetrahydrocannabinol (THC).
The hydrogels showed a brown color, confirming the presence of the cannabinoid. They exhibit a porous structure and better mechanical properties than PVA alone. Indeed, the hydrogel containing PG, VG, or both showed elastic deformation behaviors with lower water content. FTIR analysis demonstrated the presence of THC with two specific peaks at 1,575 and 1,619 cm-1, confirming the presence of THC in the hydrogels.
Human dermal fibroblast cultures onto the surface of all hydrogels confirmed the safety of the THC-rich hydrogel as the cell adhesion was comparable to the control (no THC). Furthermore, cells adhering to the hydrogels could proliferate, showing increased cell viability at 48 and 72 h, with a higher proliferation obtained with the THC-rich PVA-PG-VG hydrogels.
Such cell behavior could be due to the release of the THC in the culture medium, as demonstrated by ultra-high performance liquid chromatography (UPLC), showing the presence of THC in the culture medium, ranging from 203 to 290 μg after 24 h of incubation of the hydrogels containing PG and VG or both. In comparison, the released THC from the PVA hydrogel was higher, reaching 852 μg. It is interesting to note that the THC release at 24, 48, and 72 h was slower with the hydrogels containing PG, VG, and both, compared to PVA alone.
Overall, the present study has designed safe THC-rich PVA-PG-VG hydrogels as a functional delivery system for the topical use of cannabinoids to control tissue diseases, such as inflammation.”
“Cannabis has long been used to relieve symptoms such as pain, fever, anxiety, and diarrhea in the context of numerous diseases. Furthermore, cannabis products were reported to reduce inflammatory diseases. Over the past decades, it has been demonstrated that cannabinoids have anti-inflammatory effects, as ascertained by the decrease in the secretion of inflammatory mediators. The human body is subjected to various conditions (stress, autocrine/endocrine changes, exposure to exogenous stimuli, etc.) leading to organ and tissue inflammatory disorders, such as those in the skin and the oral cavity. Such tissue inflammation could be controlled using cannabis products.”
“Altogether, our results demonstrated the possible combination of PVA with PG and VG to generate useful THC-rich hydrogels for cannabinoid delivery. Because THC is lipophilic, our study suggests the possible delivery of THC when in topical contact with the tissues, including skin and oral mucosa, as the cells have lipid-rich membranes. Our THC-rich PVA-PG-VG hydrogels, therefore, may have the potential as a drug carrier for topical use to treat tissue inflammation.”
