Category Archives: THC (Delta-9-Tetrahydrocannabinol)

Sex differences in the capacity of minor phytocannabinoids to attenuate nociceptive insults in HIV-1 Tat-expressing mice

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“Objecives: Approximately 80 % of people living with HIV (PLWH) develop chronic pain and preclinical studies support the involvement of the HIV-1 regulatory protein, trans-activator of transcription (Tat). Phytocannabinoids may attenuate pain in PLWH; however, these data are controversial, and the biological mechanisms are difficult to untangle from psychosocial factors in people.

Methods: We have examined the therapeutic capacity of minor phytocannabinoids to attenuate Tat-promoted visceral hyperalgesia (acetic acid writhing assay) and reflexive nociception (warm water tail flick assay) in transgenic mice. We hypothesized that conditional expression of Tat1-86 in male and female mice [Tat(+) mice] would amplify pain responses compared to controls [Tat(-) mice], and that phytocannabinoids could ameliorate these effects.

Results: Irrespective of sex, Tat(+) mice demonstrated greater visceral pain responses than did Tat(-) controls. The phytocannabinoids, cannabigerolic acid (CBGA), cannabidiol (CBD), and cannabinol (CBN), attenuated Tat-induced visceral pain in both males and females. However, the effectiveness of these cannabinoids varied by sex with CBN being more efficacious in males, while cannabigerol (CBG) alleviated visceral pain only in Tat(+) females. Cannabidiolic acid (CBDA) and cannabidivarin (CBDV) were not effective in either sex. CBGA and CBG were also efficacious in the tail flick test among Tat(-) males and females, but demonstrated only small, sex-dependent effects to reverse Tat-induced nociception. CBD and CBN exerted little-to-no efficacy in this test.

Conclusions: These data suggest that phytocannabinoids exert analgesia for HIV-related pain, potentially aiding in the development of personalized pain management strategies.”

https://pubmed.ncbi.nlm.nih.gov/41221301/

“Overall, PLWH are more vulnerable to the development of chronic pain, resulting in physical disability and a reduced quality of life. The current pharmacological treatments for managing HIV-related pain lack efficacy and are associated with the risk of substance abuse. The medicinal use of non-psychoactive cannabis constituents for pain management might greatly benefit this population which is at a greater risk for opioid addiction and substance abuse.”

https://www.degruyterbrill.com/document/doi/10.1515/nipt-2024-0025/html

Combination CBD/THC in the management of chemotherapy-induced peripheral neuropathy: a randomized double blind controlled trial

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“Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) can greatly impair function, leading to disability or truncated treatment in cancer patients. Previous animal studies show that cannabidiol (CBD) and delta-9- tetrahydrocannabinol (THC) can ameliorate CIPN. This study assessed the effect of combined CBD and THC on CIPN symptoms amongst cancer patients treated with taxane- or platinum-based agents.

Materials and methods: This 12-week randomized, double-blind, placebo-controlled trial included participants with nonmetastatic breast, colorectal, endometrial, or ovarian cancer experiencing grade 2-3 CIPN. The active group received CBD (125.3-135.9 mg) combined with THC (6.0-10.8 mg) in gelcaps. The Quality-of-Life Questionnaire-CIPN twenty-item scale (QLQ-CIPN20) sensory subscale was used as the primary outcome. Additional outcomes assessed pain, sleep, and function. Neurologic exams evaluated touch, pressure, and vibration sense. Following the randomized controlled trial, participants were invited to enroll in a 12-week open-label observational study.

Results: Of 230 participants identified, 124 met eligibility, 54 were enrolled, 46 were randomized, and 43 completed 12 weeks of treatment. This was lower than our goal of 100 randomized participants. The mean age was 60 +/- 9 years, 88% were female, 63% had breast cancer. All participants had completed chemotherapy. The primary analysis showed no differences in outcome measures between active and placebo groups, likely due to sample size. Although an increase in bilirubin (one participant in active group, and one in placebo) and alkaline phosphatase (one participant in active group) was seen, this did not exceed the exit criteria. A secondary analysis showed that the active group experienced greater improvement in the QLQ-CIPN20 measures of sensory impairment relative to placebo (-10.4 (95% -20.5, -0.3), p = 0.044). There was also improvement in light touch and vibration sensation of the feet on neurological exam that approached significance. There was no effect on other measures, including pain, and no between-group differences in side effects. The uncontrolled observational study showed similar results.

Discussion: The primary analysis showed no between-group difference in CIPN symptoms. The secondary analysis indicated that CBD with THC could improve sensory impairment and might increase touch and vibration sense, although these findings require confirmation in a future, more fully powered study. Nonetheless, our results show that combination CBD/THC can be safely delivered to participants with CIPN and suggest that these cannabinoids should be further investigated for this indication.”

https://pubmed.ncbi.nlm.nih.gov/41211445/

“Overall, this study suggests that combination CBD/THC could help with the sensory impairment seen in CIPN. Since the disorder is prevalent and incurs significant hardship, even a modest sensory improvement could enhance patients’ quality of life, given the lack of alternatives.”

https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1590168/full

The impact of tetrahydrocannabinol on central pain modulation in chronic pain: a randomized clinical comparative study of offset analgesia and conditioned pain modulation in fibromyalgia

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“Tetrahydrocannabinol (THC) has shown efficacy in alleviating chronic pain, particularly in disorders characterized by central sensitization. Offset analgesia (OA) and conditioned pain modulation (CPM) are key biomarkers used to evaluate central pain modulation.

This study aimed to compare the effects of THC on OA and CPM in fibromyalgia syndrome (FMS), a prototypical condition of central sensitization.

Methods

In a randomized, double-blind, placebo-controlled crossover design, 23 FMS patients participated in two experimental sessions. Each session included the McGill Pain Questionnaire, visual analogue scale (VAS) assessments, and evaluations of OA and CPM, conducted both before and after sublingual administration of either THC (0.2 mg/kg) or placebo.

Results

THC significantly reduced spontaneous pain ratings on the McGill scale compared to both baseline and placebo (P = 0.01 and P = 0.02, respectively). THC also significantly enhanced OA relative to baseline and placebo (P = 0.04 and P = 0.008), while no effect was observed on CPM (P = 0.27). Notably, baseline OA magnitude significantly predicted THC-induced pain relief (R² = 0.404, P = 0.003), whereas CPM did not show a significant association (P = 0.121).

Conclusions

This is the first study to evaluate THC’s distinct effects on central pain modulation using both OA and CPM. THC selectively enhanced OA without influencing CPM, highlighting differential neural mechanisms underlying these paradigms. Furthermore, OA predicted treatment response, suggesting its potential as a biomarker for personalized cannabinoid-based therapies in FMS and other central sensitization disorders.”

https://pubmed.ncbi.nlm.nih.gov/41199355/

“Cannabis, particularly its psychoactive component delta-9-tetrahydrocannabinol (THC), has attracted increasing attention as a therapeutic option for chronic pain management. Clinically, THC has been shown to reduce pain intensity, improve quality of life and attenuate hyperalgesia in various chronic pain conditions, including neuropathic pain and fibromyalgia “

“THC is thought to exert its analgesic effects in part by modulating disrupted pain networks. Specifically, THC interacts with the endocannabinoid system.”

“To conclude, this study corroborates the possible effectiveness of THC in alleviating experimental and spontaneous pain in FMS, a study case of central sensitization, and shows an enhancement of OA responses after THC treatment in FMS patients compared to baseline and placebo.”

“This, in turn, reinforces the potential of OA as a reliable marker of pain modulation in FMS and may pave the way for personalized cannabinoid-based therapies for chronic pain in the future.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-025-00348-x

Cannabinoids Shape Synaptic Activity and Adult Neurogenesis in the Zebrafish Pallium

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“The endocannabinoid system regulates neuronal activity and plasticity, but its role in non-mammalian vertebrates remains poorly understood.

In zebrafish (Danio rerio), the pallium processes cognitive functions such as memory, learning, and emotional behavior. This region expresses cannabinoid receptors and undergoes continuous neuronal remodeling through adult neurogenesis.

Here, we investigate whether cannabinoid receptor type 1 (CB1R) modulates synaptic activity and adult neurogenesis in zebrafish pallial circuits.

Using immunofluorescence and single-cell mRNA analysis, we mapped CB1R expression in the pallium and found it to be distributed in a scattered pattern within the dorsomedial (Dm) and dorsolateral (Dl) regions, predominantly in glutamatergic neurons.

Electrophysiological recordings showed that acute application of rimonabant, a CB1R antagonist, reduced the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) without altering intrinsic or other synaptic properties, suggesting a tonic role for CB1R in modulating synaptic transmission. Additionally, prolonged rimonabant treatment (13 days) significantly reduced ERK phosphorylation, a marker of neuronal activity, further supporting the involvement of CB1R in maintaining basal synaptic activity in the pallium.

To assess whether cannabinoid signaling shapes adult neurogenesis, we analyzed the proliferation of neural stem cells (NSCs) and maturation of adult-born neurons.

Acute phytocannabinoid exposure resulted in a reduction in NSC proliferation, specifically in the anterior Dm. To assess the neurogenic outcome, the cannabinoid treatment was administered during neuronal maturation (12-24 days after BrdU labeling).

We observed an increase in the number of 25-day-old neurons (BrdU+, HuC/D+) in both Dm and Dl regions. This effect was reverted by the CB1R antagonist rimonabant.

These results indicate that cannabinoid signaling modulates synaptic activity and neuronal integration, highlighting a conserved control of neurogenesis by the endocannabinoid system across vertebrates.”

https://pubmed.ncbi.nlm.nih.gov/41200796/

https://onlinelibrary.wiley.com/doi/10.1111/jnc.70289

“Delta-9-Tetrahydrocannabinol (∆9-THC) Induce Neurogenesis and Improve Cognitive Performances of Male Sprague Dawley Rats”

https://link.springer.com/article/10.1007/s12640-017-9806-x


Recent development of plant-derived and synthetic cannabinoids as novel antimicrobial agents

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“Antimicrobial resistance remains a critical global health threat, driving the urgent need for novel therapeutic agents. Cannabinoids, bioactive secondary metabolites derived from Cannabis sativa, have gained attention for their promising antimicrobial properties.

This review presents the latest advances in the antimicrobial properties of cannabinoids, emphasizing their activity against multidrug-resistant pathogens, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and selected Gram-negative bacteria.

We summarize their antibacterial and antifungal effects, along with insights into structure-activity relationships that reveal the critical roles of functional groups such as the resorcinol moiety and alkyl side chain.

Mechanistic studies suggest that membrane disruption, metabolic interference, and reactive oxygen species generation contribute to their antimicrobial action. Moreover, we summarize the synergistic potential of cannabinoids when used in combination with conventional antibiotics, highlighting both promising outcomes and notable limitations.

Despite these advances, challenges such as poor solubility, limited in vivo data, and regulatory barriers persist. Addressing these gaps through focused medicinal chemistry and translational research will be essential to harness the full potential of cannabinoids as next-generation antimicrobial agents.”

https://pubmed.ncbi.nlm.nih.gov/41200875/

“Natural and synthetic cannabinoids show activity mainly against Gram-positive bacteria and selected fungi.

Synthetic cannabinoid analogues can enhance potency, selectivity, and pharmacokinetic properties while minimizing psychoactive effects.

Rational modifications to cannabinoid scaffolds, such as the resorcinol ring and alkyl side chain, influence antimicrobial efficacy.

Cannabinoids disrupt microbial membranes, increasing permeability, altering membrane potential, and inducing apoptosis.

Cannabinoids interfere with intracellular metabolic and biosynthetic pathways, impairing energy production and cell wall synthesis.”

https://www.tandfonline.com/doi/full/10.1080/17568919.2025.2580915


Synthetic cannabinoid WIN 55,212-2 reduces CHIKV replication, modulates cytokine and chemokine production, and induces ER stress-related transcriptional responses in human monocyte-derived macrophages

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“Chikungunya virus (CHIKV), an emerging arbovirus of the family Togaviridae, causes Chikungunya fever (CHIKF), characterized by excessive inflammation and chronic arthralgia. Macrophages act as viral targets and amplifiers of inflammation, underscoring their crucial role in the pathogenesis of viral infections. Currently, no effective treatment exists for CHIKF, highlighting the need for novel therapeutic approaches.

Cannabinoids, known for their immunomodulatory and antiviral properties, have emerged as potential candidates. Here, we investigated the effects of cannabidiol (CBD) and WIN 55,212-2 (WIN) in CHIKV-infected human monocyte-derived macrophages (MDMs). Pre- and post-treatment efficacy were assessed at 6- and 24-h post-infection (h.p.i).

WIN, but not CBD, significantly reduced CHIKV replication in post-treatment assays, with effects most evident at 24 h.p.i. This antiviral activity occurred without significant changes in mRNA levels of IFNβ1, IFNλ1, and IL27p28, indicating that it did not alter the expression of type I/III interferons. Furthermore, WIN treatment reduced APOBEC3A mRNA levels. Additionally, WIN significantly reduced the production of CCL-2, as well as pro- (IL-6, TNF-α) and anti-inflammatory (IL-10) cytokines, while upregulating IRE1α and sXBP1 transcripts, suggesting modulation of ER stress pathways.

Overall, these findings identify WIN as a potential modulator of CHIKV replication and macrophage inflammatory response, acting through host-direct mechanisms that warrant further investigation.”

https://pubmed.ncbi.nlm.nih.gov/41197267/

“WIN 55,212-2 post-treatment reduced CHIKV replication and inflammation in MDMs by downregulating proinflammatory cytokines and chemokines and inducing ER stress via the PERK–IRE1α/sXBP1 pathway (Fig. 7B). Inhibiting these pathways partially restored viral load, suggesting their involvement in the antiviral effect. WIN 55,212-2 also decreased CHIKV nsP2 mRNA levels, without direct virucidal activity. These findings indicate that WIN functions as a dual-agent, both antiviral and immunomodulatory,”

https://www.sciencedirect.com/science/article/abs/pii/S1567576925017825?via%3Dihub

“WIN 55,212-2 is a synthetic cannabinoid and a potent full agonist of the cannabinoid receptors CB1 and CB2. Though it mimics the effects of tetrahydrocannabinol (THC), the compound has a distinctly different chemical structure. It has been extensively studied for its potential therapeutic effects due to its anti-inflammatory, analgesic, and neuroprotective properties. The compound is illegal in some countries, including the United States, where it is classified as a Schedule I controlled substance.”


The Development and Therapeutic Potential of Classical and Next-Generation Cannabinoid Ligands

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“The endogenous cannabinoid system (ECS) is a complex network that plays a crucial role in various physiological processes, and its modulation through cannabinoid ligands has garnered significant interest in pharmacological research.

Cannabinoid receptors, primarily CB1 and CB2, are G-protein-coupled receptors that can interact with many different types of ligands, including orthosteric agonists and antagonists and allosteric and biased modulators.

This review provides an updated perspective on cannabinoid receptor ligand development, beginning with natural ligands such as phytocannabinoids and endocannabinoids. These compounds provided the initial inspiration for the design of the first synthetic classical cannabinoids which were later refined into structurally distinct non-classical cannabinoids.

Beyond these traditional orthosteric ligands, we explore the expanding field of allosteric and biased modulators, which offer refined control over receptor signaling and present opportunities to reduce side effects associated with direct receptor activation. We also highlight the significance of covalent ligands and labeled chemical probes in elucidating cannabinoid receptor structure, localization, and function.

Advances in imaging and chemoproteomic techniques have further enhanced our ability to visualize receptor dynamics and identify novel interaction partners. Finally, we examine the clinical landscape of cannabinoid-based therapeutics, from approved drugs to ongoing clinical trials, and discuss the remaining challenges and future directions in ECS-targeted drug development.

This review aims to provide a comprehensive overview of current trends and emerging strategies in cannabinoid ligand research.”

https://pubmed.ncbi.nlm.nih.gov/41192631/

“The endogenous cannabinoid system has broad therapeutic relevance. “

“Natural and synthetic cannabinoids finely regulate the endogenous cannabinoid system.”

https://www.sciencedirect.com/science/article/pii/S1043661825004475?via%3Dihub

History of cannabis use and cognitive function in older adults: findings from the UK biobank

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“Background: Cannabis is a commonly used psychoactive drug, but its cognitive effects remain unclear, particularly in older adults. This study examined associations between past and present cannabis use and cognitive function among dementia-free older adults.

Methods: Cross-sectional and longitudinal data were drawn from the UK Biobank, including adults aged ≥60 years. Cannabis use patterns were self-reported, and cognitive function was assessed via computerized tests of attention, executive function, processing speed, visual memory and working memory. Multivariable linear regression models adjusted for demographic, health and lifestyle-related covariates.

Results: Cross-sectional analyses included 67 713 participants; longitudinal analyses included 52 002 participants with two cognitive assessments (mean age 67.2 ± 4.4 years; 46.1% male). Lifetime cannabis users (17%) performed better across all cognitive domains: attention (B = 0.071), executive function (B = 0.047), processing speed (B = 0.363), visual (B = 0.062) and working memory (B = 0.181). Current use was associated with better working memory (B = 0.169). Mixed and contradictory results were found for early onset, duration and frequency of use with cognitive outcomes. Longitudinally, past use was associated with less decline in executive function, while longer duration of use predicted steeper decline in processing speed.

Conclusions: Cannabis use is not uniformly harmful to cognition in older adults. Past use was linked to better performance and slower decline in some cognitive domains. However, specific usage patterns, such as longer duration, were associated with poorer outcomes in other domains. These findings highlight the need for further research to clarify underlying mechanisms and guide evidence-based recommendations regarding cannabis use in aging populations.”

https://pubmed.ncbi.nlm.nih.gov/41189327/

“Cannabis use in older adults is not uniformly associated with cognitive decline; former users showed better cognitive perform.”

“These results offer preliminary evidence that cannabis use may not be uniformly detrimental to cognitive health in aging.”

https://academic.oup.com/ageing/article/54/11/afaf319/8313927?login=false

Cannabis sativa extracts reduce inclusion formation in a cell model of alpha-synuclein aggregation

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“Parkinson’s disease (PD) is classified as a synucleinopathy due to the accumulation of protein inclusions rich in the alpha-synuclein (aSyn) protein. Identifying effective pharmacological therapies is important to slow the progression and minimize the symptoms of these diseases.

Cannabis sativa has a diverse chemical profile depending on its genotype, including several classes of substances, such as cannabinoids, flavonoids, terpenes, and alkaloids.

In this study, we evaluated the effects of four C. sativa extracts with different phytocannabinoid chemical profiles in two cellular models that reproduce alterations in cellular homeostasis common during the cellular phase of PD and other synucleinopathies. We used Saccharomyces cerevisiae strains transformed with plasmid DNA and genetically modified human cells (H4), both expressing aSyn.

The results showed that all the extracts were antioxidants, decreasing intracellular oxidation levels and increasing the number of daughter cells in yeast cells, but did not prevent mitochondrial damage. Besides, the extracts reduced the number of intracellular inclusions in H4 cells and increased the number of cells without inclusions.

Phytochemical characterization revealed extracts rich in Tetrahydrocannabinol – THC (69.88 %), Cannabidiol – CBD (52.64 %), and Cannabinol – CBN (47.38 % and 58.64 %), and we concluded that, regardless of these percentages, all C. sativa extracts showed protective biological activity against toxicity caused by alpha-synuclein production, both in yeast cells and H4 cells.”

https://pubmed.ncbi.nlm.nih.gov/41187864/

“Four Cannabis sativa extracts rich in different phytocannabinoids (THC, CBD, and CBN) demonstrated antioxidant potential independent of their chemical profiles. A decrease in the intracellular oxidative environment in the Saccharomyces cerevisiae model with aSyn indicates that the extracts (E-THC, E-CBD, E-CBN and E-CBN+) may contribute to maintaining cellular redox homeostasis, minimizing potential effects related to the development of Parkinsonism.”

https://www.sciencedirect.com/science/article/abs/pii/S0367326X25005945?via%3Dihub

Cannabinoids rescue migraine symptoms caused by central CGRP administration in mice

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“This study investigates the therapeutic potential of a combined dose of cannabidiol (CBD) and tetrahydrocannabinol (THC) at a 100:1 ratio (100 mg/kg CBD and 1 mg/kg THC) in mitigating central calcitonin gene-related peptide (CGRP)-induced migraine symptoms in a mouse model.

The 100:1 ratio of CBD to THC was administered intraperitoneally, 60 minutes prior to starting all the assays, followed by intracerebroventricular CGRP administration, 30 minutes later, with behavior assays conducted 30 minutes after CGRP injection. To determine whether pretreatment of CBD:THC could counteract CGRP-induced light aversion, we utilized the light/dark assay, which also recorded motility behavior. To investigate whether CBD:THC pretreatment could alleviate CGRP-induced spontaneous pain, we used the automated squint assay.

Our findings show that pretreatment with 100:1 CBD:THC rescued light aversion caused by centrally administered CGRP in CD1 mice. Additionally, CBD:THC pretreatment rescued the increased resting time in darkness, decreased transitions between light and dark zones, and partially rescued the decreased rearing behavior induced by centrally administered CGRP. Moreover, an open field assay confirmed that centrally administered CGRP did not induce anxiety in a light independent assay. Finally, our findings from the automated squint assay indicate that pretreatment with 100:1 CBD:THC partially rescued centrally administered CGRP-induced spontaneous pain.

Collectively, these results demonstrate that a combination of CBD and THC can alleviate light aversion and pain symptoms induced by a centrally-acting migraine trigger.”

https://pubmed.ncbi.nlm.nih.gov/41182862/

“The medicinal properties of the plant Cannabis can be traced back thousands of years, with some of its earliest records dating to Chinese medicine around 2700 BC, and Indian medicine around 900 BC. During the late 19th to early 20th centuries, many Western physicians considered Cannabis to be the “most satisfactory” remedy for migraine, and, for eight decades, it was the primary treatment for migraine in mainstream Western medical literature.”

https://journals.sagepub.com/doi/10.1177/03331024251392103