Category Archives: THC (Delta-9-Tetrahydrocannabinol)

Associations of Low-Level Prenatal Alcohol and Cannabis Exposure With Adolescent Cognitive Trajectories

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“Background: No studies have examined the differential and combined effects of prenatal alcohol and cannabis exposure (PAE/PCE) on longitudinal trajectories of adolescent cognitive development. Further, previous alcohol research is mixed, with some evidence for negative PAE effects on cognition and other studies reporting null or positive associations. This study examined associations between PAE, PCE, and growth trajectories of adolescent cognition in a large, diverse sample.

Methods: N = 11,029 adolescents from the Adolescent Brain Cognitive Development℠ Study completed the NIH Toolbox cognitive battery at baseline (Mage = 9.95), two-year follow-up (Mage = 11.95), and four-year follow-up (Mage = 14.07). Retrospective parent report of PAE and PCE was assessed at baseline. Univariate growth trajectories were estimated for cognitive measures: Pattern Comparison, Picture Sequence Memory, Oral Reading, Flanker Task, and Picture Vocabulary. Cross-product terms for PAE and PCE tested combined use.

Results: Most mothers reported no prenatal alcohol (n = 8257; 74%) or cannabis (n = 10,812; 94%) use. Overall, use was low: across pregnancy, women reporting any alcohol use averaged 33.31 drinks, and those reporting any cannabis use averaged 33.00 use occasions. Before including covariates, there were negative main effects of PCE and positive main effects of PAE on intercepts for all five cognitive domains. There was little evidence for PCE/PAE effects on slopes for cognition. After adding covariates, no negative effects of PCE remained. Small positive PAE effects on intercepts for multiple domains persisted. Cross-product terms for combined exposure were not significant.

Conclusions: Little evidence emerged for negative effects of low PAE, PCE, or combined exposure on adolescents’ cognitive development after accounting for sociodemographic factors. Light drinking in families with social features positively associated with cognitive ability may result in few negative consequences. This study is the first to demonstrate weak evidence for adverse differential and combined low-level PAE and PCE effects on the development of adolescent cognition.”

https://pubmed.ncbi.nlm.nih.gov/41947378

“Little evidence emerged for negative effects of low level prenatal alcohol, cannabis, or combined exposure on adolescents’ cognitive development after accounting for sociodemographic factors.”

https://onlinelibrary.wiley.com/doi/10.1111/acer.70297

Cannabis Use and the Risk of Incident Venous Thromboembolism Among People With HIV: A Longitudinal Cohort Study in the United States

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“People with HIV (PWH) are at an increased risk of venous thromboembolism (VTE), and cannabis use is common in this population. However, evidence of cannabis impact on VTE risk has been conflicting and not well evaluated in PWH.

Using data from five Centers for AIDS Research Network of Integrated Clinical Systems sites (2009-2020), we assessed the association between cannabis use and VTE risk.

Among 13,646 PWH, 30% reported current cannabis use. In adjusted Cox models, neither former (adjusted hazard ratio [aHR] 0.78, 95% confidence interval (CI) 0.57-1.07) nor current (aHR 0.74, 95% CI 0.51-1.06) cannabis use showed a significant increase in VTE incidence compared with never use. Additionally, no dose-dependent relationship was observed between cannabis use frequency and VTE.

Among PWH, cannabis use does not appear to be associated with an elevated risk of VTE.

Further research is needed to elucidate the relationship between cannabis and VTE risk in this population.”

https://pubmed.ncbi.nlm.nih.gov/42017672

https://journals.lww.com/janac/abstract/9900/cannabis_use_and_the_risk_of_incident_venous.255.aspx

The greater the pleiotropic effects, the greater the benefits – cannabis as a “biopsychosocial” drug: a mixed-methods study on chronic non-cancer pain

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“Background: Against the background of widely inconsistent data from randomized controlled trials (RCT), the use of cannabis-based medicines (CBM) from the perspective of patients with chronic non-cancer pain (CNCP) was described.

Methods: Based on a purposive/convenient sampling, patients were recruited from the Pain Clinic of Hannover Medical School who had been using CBM prescribed by a doctor for at least 6 months. The patients discussed their experiences with CBM in semi-structured individual interviews. The interview transcripts were coded and analyzed using a modified grounded theory approach with the help of MAXQDA®. In addition, the Treatment Satisfaction Questionnaire with Medication (TSQM) was used.

Results: Theoretical saturation was reached after 32 interviews. Open and selective coding revealed the overarching phenomenon of “subjective pain experience under CBM therapy”, with one of the main themes being the “effect of CBM”. This revealed the categories “effect on pain” and “psychological” and “somatic effect”. The most important concepts were “pain intensity”, “pain management”, “stress management”, “musculoskeletal system”, and “sleep quality.” Constructing a theoretical framework 4 groups of responses to CBM treatment were identified. The focus is either on (I) pain reduction, (II) pain coping, (III) reduced stress or (IV) multidimensional aspects. When this classification was applied to topic of quality of life (QOL), the greatest effectiveness and highest overall satisfaction were found in group (IV). Mixed methods showed a continuous increase in the perceived effectiveness of CBM on pain-centered complaints from group (I) to (IV).

Conclusions: In line with the biopsychosocial understanding of chronic pain, it appears that those CNCP patients who benefit most from CBM are those who show the most far-reaching effects on both a physical and psychological level. The pleiotropic effects of CBM may be responsible for this. Based on these results, interdisciplinary prospective research appears sensible and necessary to further and systematically investigate this clinically relevant topic.”

https://pubmed.ncbi.nlm.nih.gov/42015327

https://link.springer.com/article/10.1186/s42238-026-00440-w

Analgesic Effect of Cannabinoids for Fibromyalgia: A Systematic Review and Meta-Analysis

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“Background: Fibromyalgia is a kind of complex chronic pain syndrome that exerts a profound impact on patients’ lives. Current pharmacological treatments for fibromyalgia often yield suboptimal results. Cannabinoids have emerged as a potential therapeutic alternative to these treatments.

Objectives: Our study aimed to assess the analgesic efficacy of cannabinoids in treating fibromyalgia.

Study design: A systematic review and meta-analysis.

Methods: We conducted a comprehensive literature search using PubMed (MEDLINE), EMBASE, ISI Web of Knowledge, Cochrane Library, and Clinicaltrials.gov to analyze randomized controlled trials and observational studies that investigated the analgesic efficacy of cannabinoids in individuals diagnosed with fibromyalgia. The primary outcome was the effect of cannabinoids on pain intensity, quantified by the standardized mean difference (SMD) in pain levels before and after the treatment. We registered our review protocol in PROSPERO (CRD42024495525). The quality of the evidence was evaluated using the Grade of Recommendations Assessment, Development, and Evaluation (GRADE) method.

Results: Twelve clinical studies, consisting of 2 randomized controlled trials and 10 observational studies, (14 comparisons, 1,248 patients) were selected. Cannabinoids reduced pain intensity with statistical significance (SMD = -1.41, 95% CI = -1.98 to -0.84, P < 0.001), which was associated with a low GRADE rating. Both short-term (< 3 months, SMD = -1.37, 95% CI = -2.32 to -0.43, P = 0.004) and longer-term (≥ 3 months, SMD = -1.43, 95% CI = -2.22 to -0.65, P < 0.001) follow-ups showed statistically significant pain score reduction. Patients also experienced statistically significant improvements in sleep quality, anxiety, depression and quality of life (P-values < 0.05). Common adverse effects included dizziness, dry mouth, and drowsiness, while serious adverse effects were rare.

Limitations: Our analyses revealed that the results demonstrated considerable heterogeneity, which was attributed to variations in study designs, interventions, and outcome measurements across the included studies. These factors could potentially influence the validity of the findings. Thus, the results should be interpreted with these variations in mind.

Conclusion: Cannabinoids may provide analgesic benefits for patients with fibromyalgia. Cannabinoid use was also associated with improvements in sleep, anxiety, depression and quality of life. However, the findings should be interpreted with caution due to the quality of the evidence, heterogeneity, and small amount of available data from randomized controlled trials.”

https://pubmed.ncbi.nlm.nih.gov/42013320

The cannabidiol (CBD): Tetrahydrocanabinol (THC) concentration ratio is critical for neuroprotection and recovery following traumatic brain injury

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“An optimal ratio of cannabidiol (CBD) to tetrahydrocanabinol (THC) was hypothesized to protect against neuropathological consequences following traumatic brain injury (TBI).

Varied CBD:THC extract concentrations were compared with hemp CBD lacking THC (CBD0). Neurons, glia, and parvalbumin interneurons (PV-INs) were evaluated.

Weight loss was observed following high doses of THC dominant cannabis, THC100:1. Neuroscores and vestibulomotor performance were restored most with CBD:THC300:1-10:1. However, THC dominant treatments resulted in early onset to spontaneous seizures post-TBI.

The alternating T-maze showed the CBD10:1 group had the highest spontaneous alternation rates whereas TBI + vehicle, CBD0, CBD1:1, and THC100:1 groups had the lowest. The novel object recognition memory task showed CBD300:1 treated animals had the best performance, while TBI or THC100:1 treated groups had the worst. The forced swim test (FST) revealed immobility time was highest after TBI and lowest after THC20:1 or THC100:1 treatment post-TBI. The elevated plus maze (EPM) revealed the CBD0 group spent the most time in closed arms. Both tests indicate that reduced anxiety was THC dependent. In the absence of TBI, THC20:1 treatment resulted in the highest mobility.

All combinations resulted in reduced injury post-TBI but CBD10:1 and THC20:1 afforded the most protection and THC100:1 the least. Reduced GFAP labeling was highest with CBD dominant cannabis supporting its neuroprotective role against inflammation. Rescue of diminished bilateral PV-INs was observed within the hippocampus and medial prefrontal cortex (mPFC) with CBD dominant treatment (CBD300, CBD0) supporting their anticonvulsant effect. Loss of PV-INs with THC dominant treatment supports their proconvulsant effect. Thus, CBD and THC have different beneficial therapeutic effects indicating an optimal concentration ratio is critical for neuropathological therapeutics.

SIGNIFICANCE STATEMENT: There is currently no optimal treatment that can prevent behavioral and cellular pathology as well as onset of spontaneous seizures associated with traumatic brain injury (TBI). We hypothesized that an optimal ratio of CBD:THC is required to protect against neuropathological consequences following TBI. Six extracts with varied CBD:THC ratio concentrations were compared with hemp CBD lacking THC. CBD dominant cannabis with critical THC dosing afforded the most neuroprotection and behavioral recovery, whereas THC dominant cannabis stimulated spontaneous seizure onset. CBD and THC had different beneficial therapeutic effects indicating an optimal concentration ratio is critical for neuropathological therapeutics. Absorbable medical carriers will offer delivery treatment options to optimize both short- and long-term drug efficacy relating to neuropathological disorders.”

https://pubmed.ncbi.nlm.nih.gov/41997410

https://www.sciencedirect.com/science/article/pii/S0014488626001196?via%3Dihub

Cannabis use by people with HIV is associated with an anti-inflammatory immunometabolic phenotype in monocyte-derived macrophages

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“Chronic neuroinflammation is associated with comorbidities in people with HIV (PWH) on antiretroviral therapy (ART).

While cannabis use is associated with reduced neuroinflammation and neurocognitive impairment (NCI) in PWH, the underlying mechanisms are unknown. 

To address this gap in knowledge, we analyzed monocyte-derived macrophages (MDMs) from a cohort of 50 PWH and 33 people without HIV (mean age: 61.9 years), categorized by frequency of cannabis use (naïve/low, moderate, daily). We performed immunocytochemistry, RNA sequencing, and qPCR on MDMs and quantified related biomarkers in donor plasma.

In this cohort study, daily cannabis use in PWH was associated with less global neurocognitive deficits, and with an anti-inflammatory immunometabolic-phenotype in MDMs characterized by (1) a metabolic shift from glycolysis to oxidative phosphorylation, (2) higher mitochondrial numbers, (3) altered cytokine profiles (pro-inflammatory downregulation, anti-inflammatory upregulation), and (4) higher brain-derived neurotrophic factor (BDNF) expression. These cellular changes were corroborated by a plasma biomarker profile in PWH including (1) lower levels of growth differentiation factor 15 and soluble triggering receptor expressed on myeloid cells 2, and (2) higher mature BDNF/precursor BDNF ratios that correlated with better cognition.

Thus, cannabis use may mitigate NCI in PWH by immunometabolically reprogramming MDM function towards an anti-inflammatory and neuroprotective state.”

https://pubmed.ncbi.nlm.nih.gov/41998680

“Cannabis use by people with HIV (PWH) is associated with neuroprotective and anti-inflammatory effects”

https://link.springer.com/article/10.1186/s12974-026-03779-2

Impact of Preoperative Marijuana Use on Functional Recovery and Complications After Spinopelvic Fusion in Adult Spinal Deformity

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“Background and objectives: With the rising prevalence of marijuana use and increasing rates of complex spinal deformity surgeries, understanding the impact of cannabis on perioperative outcomes is crucial. Previous studies yield mixed results on fusion success, complications, and opioid use in spine surgery, but none have focused on long-segment spinopelvic fusions.

Methods: This retrospective cohort study analyzed 155 adult patients undergoing posterior spinal fusion from the pelvis to L2 or higher between 2015 and 2023. Patients were stratified by preoperative marijuana use (n = 34 users vs n = 121 nonusers). Baseline demographics, surgical parameters, clinical outcomes [Oswestry Disability Index (ODI), visual analog scale], radiographic measures (pelvic tilt, lumbar lordosis, and sagittal vertical axis), and complications were compared using t-tests, χ2 tests, and logistic regression, with P < .05 considered significant.

Results: Marijuana users had higher preoperative opioid dependence (64.7% vs 42.9%, P = .025), more previous spine surgeries (52.9% vs 19.0%, P < .001), and elevated preoperative ODI scores (56.9 vs 52.8, P = .038), but demonstrated greater ODI improvement (43.7 vs 37.1, P = .003). No significant differences were observed in visual analog scale changes, radiographic corrections, hospital stay (8.8 vs 8.9 days, P = .920), transfusions (2.2 vs 1.5 units, P = .240), medical complications (eg, deep vein thrombosis/pulmonary embolism: 4 vs 21, P = .599), or mechanical complications (eg, pseudarthrosis: 10 vs 36, P > .999, and hardware failure: 12 vs 53, P = .434).

Conclusion: In this cohort, preoperative marijuana use was not associated with statistically significant differences in complication rates or inferior outcomes after long-segment spinopelvic fusion. Users experienced enhanced functional recovery, although this finding must be interpreted in the context of their higher baseline disability. Given the modest sample size, these findings should be viewed as preliminary; prospective studies with standardized cannabis exposure metrics are needed to confirm these results.”

https://pubmed.ncbi.nlm.nih.gov/41982324

https://journals.lww.com/neurosurgpraconline/fulltext/2026/06000/impact_of_preoperative_marijuana_use_on_functional.8.aspx

Dynamic Mechanism for Subtype Selectivity of Endocannabinoids

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“Endocannabinoids are naturally occurring lipid-like molecules that bind to cannabinoid receptors (CB1 and CB2) and regulate many of human bodily functions via the endocannabinoid system.

There is a tremendous interest in developing selective drugs that target the CB receptors.

However, the biophysical mechanisms responsible for the subtype selectivity for endocannabinoids have not been established. Recent experimental structures of CB receptors show that endocannabinoids potentially bind via membrane using the lipid access channel in the transmembrane region of the receptors. Furthermore, the N-terminus of the receptor could move in and out of the binding pocket thereby modulating both the pocket volume and its residue composition.

On the basis of these observations, we propose two hypotheses to explain the selectivity of the endocannabinoid, anandamide for CB1 receptor. First, the selectivity arises from distinct enthalpic ligand-protein interactions along the ligand binding pathway formed due to the movement of N-terminus and subsequent shifts in the binding pocket composition. Second, selectivity arises from the volumetric differences in the binding pocket allowing for differences in ligand conformational entropy.

To quantitatively test these hypotheses, we perform extensive molecular dynamics simulations (∼0.9 milliseconds) along with Markov state modeling and deep learning-based VAMPnets to provide an interpretable characterization of the anandamide binding process to cannabinoid receptors and explain its selectivity for CB1.

Our findings reveal that the distinct N-terminus positions along lipid access channels between TM1 and TM7 lead to different binding mechanisms and interactions between anandamide and the binding pocket residues. To validate the critical stabilizing interactions along the binding pathway, relative free energy calculations of anandamide analogs are used. Moreover, the larger CB2 pocket volume increases the entropic effects of ligand binding by allowing higher ligand fluctuations but reduced stable interactions. Therefore, the opposing enthalpy and entropy effects between the receptors shape the endocannabinoid selectivity.

Overall, the CB1 selectivity of anandamide is explained by the dominant enthalpy contributions due to ligand-protein interactions in stable binding poses. This study shed lights on potential selectivity mechanisms for endocannabinoids that would aid in the discovery of CB selective drugs.”

https://pubmed.ncbi.nlm.nih.gov/41962866

“By situating these results within the broader landscape of pharmacological and structural evidence, we provide a cohesive mechanistic framework for endocannabinoid selectivity that can inform the rational design of CB1-selective therapeutics.”

https://www.jbc.org/article/S0021-9258(26)00304-2/fulltext

Effect of cannabinol, tetrahydrocannabivarin and cannabidiol on voluntary alcohol consumption

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“Aims: Previous studies have demonstrated that the endocannabinoid system plays a significant role in the development of alcohol use disorder (AUD), and CB1 receptor antagonists/inverse agonists show promise as a novel AUD pharmacotherapy. However, these compounds failed in clinical trials due to the severe psychiatric side effects. Non-psychoactive phytocannabinoids may have a better safety profile and could be used as an alternative approach to treat AUD. The aim of this study was to test the potential of three phytocannabinoids in reducing alcohol consumption: CB1 receptor partial agonist cannabinol (CBN), neutral antagonist tetrahydrocannabivarin (THCV) and negative allosteric modulator cannabidiol (CBD).

Methods: Male Wistar rats were subjected to a long-term voluntary alcohol drinking procedure that lasted for several months. Thereafter, rats were given three once daily administrations of CBN, THCV, or CBD. Their side-effect profile was examined by recording changes in water consumption, body weight and locomotor activity. Ultrasonic vocalisations were recorded in alcohol-naïve group-housed rats to monitor if treatment induced discomfort, distress, or other changes in emotional states.

Results: Our data demonstrated that all phytocannabinoids reduced voluntary alcohol consumption; however, the compounds differed in their effectiveness and side-effect profile. Treatment with CBN and THCV reduced alcohol intake and alcohol preference and had a mild sedative effect. CBD had a minor effect on alcohol consumption, did not affect alcohol preference, reduced the locomotor activity and lowered the positive emotional states of rats. None of the compounds caused discomfort or distress.

Conclusions: We conclude that CBN and THCV may have potential in treating AUD.”

https://pubmed.ncbi.nlm.nih.gov/41947574

“Cannabis plants have long been used both medicinally and recreationally, mainly due to the psychoactive compound delta9-tetrahydrocannabinol (THC, a partial agonist of the CB1 receptor). However, the health benefits of these plants may be attributable to over a hundred of other, non-psychoactive compounds or their metabolites, collectively termed phytocannabinoids.”

“In summary, the present study demonstrated that CBN and THCV were more effective in reducing the maintenance of voluntary alcohol consumption and had a better safety profile compared to CBD. The effect of all three phytocannabinoids on alcohol consumption may be related to their action on the CB1 receptor.”

https://academic.oup.com/alcalc/article/61/3/agag019/8607733

The iron fist of nature: Cannabinoid derivatives alter iron homeostasis and activate ferroptotic pathways in glioblastoma cells

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“Glioblastoma multiforme is the most commonly diagnosed type of brain tumor, with a poor prognosis and a high rate of recurrence. Because of its highly aggressive nature and the lack of efficient treatment options, novel therapeutic strategies are needed.

Ferroptosis is an iron-dependent, unique type of cell death, which provides an alternative way to eradicate cancer cells that are resistant to apoptosis and other cell death mechanisms.

CP55-940 (CP) and WIN 55212-2 (WIN) are synthetic cannabinoid receptor agonists with various biological activities, including neuroprotective and anticancer effects; however, their mechanism of action has not been fully uncovered.

In the present study, the potential of CP and WIN in glioblastoma cells was investigated.

Cell viability was determined with the MTT assay. Labile iron pool and reactive oxygen species generation were visualized with confocal microscopy. Malondialdehyde assay was performed to detect lipid peroxidation. Gene expressions of ferroptotic hallmarks, glutathione peroxidase-4, and transferrin receptor 1 were determined by RT-qPCR. Protein expression levels of iron-responsive element-binding protein 2, solute carrier family 7 member 11, and glutathione peroxidase-4 were analyzed by western blotting.

Results demonstrated that CP and WIN significantly induce ferroptotic pathways in glioblastoma cells via increased oxidative stress, labile iron pool, and lipid peroxidation. Furthermore, it was determined for the first time that both compounds significantly upregulate the transferrin receptor 1 gene expression.

In conclusion, the present study demonstrated for the first time that cannabinoid derivatives CP and WIN alter iron regulation and initiate ferroptosis in glioblastoma cells, rendering them potential candidates in therapy.

SIGNIFICANCE STATEMENT: We explored the ferroptotic activity of cannabinoid derivatives (CP and WIN) in glioblastoma cells for the first time. Additionally, we report for the first time that cannabinoid derivatives alter cellular iron levels, causing increased labile iron pool via upregulating the transferrin gene significantly.”

https://pubmed.ncbi.nlm.nih.gov/41962357

https://jpet.aspetjournals.org/article/S0022-3565(26)00518-5/abstract

“CP 55,940 is a synthetic cannabinoid which mimics the effects of naturally occurring THC (one of the psychoactive compounds found in cannabis). CP 55,940 was created by Pfizer in 1974 but was never marketed. It is currently used as a research tool to study the endocannabinoid system.”

“WIN 55,212-2 is a chemical described as an aminoalkylindole derivative, which produces effects similar to those of cannabinoids such as tetrahydrocannabinol (THC) but has an entirely different chemical structure.”