Category Archives: THC (Delta-9-Tetrahydrocannabinol)

Cannabinoid 1 and mu-opioid receptor agonists synergistically inhibit abdominal pain and lack side effects in mice

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Society for Neuroscience - Publications

“While effective in treating abdominal pain, opioids have significant side effects. Recent legalization of cannabis will likely promote use of cannabinoids as an adjunct or alternative to opioids, despite a lack of evidence.

We aimed to investigate if cannabinoids inhibit mouse colonic nociception, alone or in combination with opioids at low doses.

Experiments were performed on C57BL/6 male and female mice. Visceral nociception was evaluated by measuring visceromotor responses (VMR), afferent nerve mechanosensitivity in flat-sheet colon preparations, and excitability of isolated dorsal root ganglion (DRG) neurons. Blood oxygen saturation, locomotion and defecation were measured to evaluate side effects.

An agonist of cannabinoid 1 receptor (CB1R), arachidonyl-2′-chloroethylamide (ACEA), dose-dependently decreased VMR. ACEA and HU-210 (another CB1R agonist) also attenuated colonic afferent nerve mechanosensitivity. Additionally, HU-210 concentration-dependently decreased DRG neuron excitability, which was reversed by the CB1R antagonist AM-251. Conversely, cannabinoid 2 receptor (CB2R) agonists did not attenuate VMR, afferent nerve mechanosensitivity or DRG neuron excitability.

Combination of sub-analgesic doses of CB1R and µ-opioid receptor (MOR) agonists decreased VMR; importantly, this analgesic effect was preserved after 6 days of twice daily treatment. This combination also attenuated afferent nerve mechanosensitivity and DRG neuron excitability, which was inhibited by neuronal nitric oxide synthase (nNOS) and guanylate cyclase inhibitors. This combination avoided side effects (decreased oxygen saturation and colonic transit) caused by analgesic dose of morphine. Activation of CB1R, but not CB2R, decreased colonic nociception both alone and in synergy with MOR.

Thus, CB1R agonists may enable opioid dose reduction and avoid opioid-related side effects.

SIGNIFICANCE STATEMENTOne of the most cited needs for patients with abdominal pain are safe and effective treatment options. The effectiveness of opioids in the management of abdominal pain is undermined by severe adverse side effects. Therefore, strategies to replace opioids or reduce the doses of opioids to suppress abdominal pain is needed. This study in mice demonstrates that cannabinoid 1 receptor (CB1R) agonists inhibit visceral sensation. Furthermore, a combination of sub-analgesic doses of µ-opioid receptor agonist and CB1R agonist markedly reduce abdominal pain without causing the side effects of high dose opioids. Thus, CB1R agonists, alone or in combination with low-dose opioids, may be a novel and safe treatment strategy for abdominal pain.”

https://pubmed.ncbi.nlm.nih.gov/35790401/


A Randomized, Triple-Blind, Comparator-Controlled Parallel Study Investigating the Pharmacokinetics of Cannabidiol and Tetrahydrocannabinol in a Novel Delivery System, Solutech, in Association with Cannabis Use History

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“Background: An oral route of administration for tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) eliminates the harmful effects of smoking and has potential for efficacious cannabis delivery for therapeutic and recreational applications. We investigated the pharmacokinetics of CBD, Δ9-THC, 11-OH-THC, and 11-nor-9-carboxy-Δ9-THC (THC-COOH) in a novel oral delivery system, Solutech™, compared to medium-chain triglyceride-diluted cannabis oil (MCT-oil) in a healthy population. 

Materials and Methods: Thirty-two participants were randomized and divided into two study arms employing a comparator-controlled, parallel-study design. To evaluate the pharmacokinetics of Δ9-THC, CBD, 11-OH-THC, and THC-COOH, blood was collected at pre-dose (t=0) and 10, 20, 30, and 45, min and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, and 48 h post-dose after a single dose of Solutech (10.0 mg Δ9-THC, 9.76 mg CBD) or MCT (10.0 mg Δ9-THC, 9.92 mg CBD). Heart rate and blood pressure were measured at 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 h. Relationships between cannabis use history, body mass index, sex, and pharmacokinetic parameters were investigated. Safety was assessed before and at 48 h post-acute dose. 

Results: Acute consumption of Solutech provided a significantly greater maximum concentration (Cmax), larger elimination and absorption rate constants, faster time to Cmax and lag time, and half-life for all analytes compared to MCT-oil (p<0.001). In addition, cannabis use history had a significant influence on the pharmacokinetic parameters of CBD, Δ9-THC, 11-OH-THC, and THC-COOH. On average, participants with later age of first use had higher Δ9-THC, CBD, and THC-COOH Cmax and later time-to-Cmax and half-life for Δ9-THC, CBD, THC-COOH, and 11-OH-THC than those with earlier age of first use (p≤0.032). Those with more years of recreational cannabis use had higher area under the curve for Δ9-THC and CBD, Cmax for CBD, and longer 11-OH-THC half-life than those with less (p≤0.048). 

Conclusion: This study demonstrated that consumption of Solutech enhanced most pharmacokinetics parameters measured compared to MCT-oil. Participant’s cannabis use history, including their age of first use and number of years using cannabis significantly impacted pharmacokinetic parameters investigated. Acute consumption of both products was found to be safe and well tolerated. The results suggest that Solutech may optimize bioavailability from cannabis formulations.”

https://pubmed.ncbi.nlm.nih.gov/35787693/

https://www.liebertpub.com/doi/10.1089/can.2021.0176

Vascular responses disrupted by fructose-induced hyperinsulinemia improved with delta-9- tetrahydrocannabinol

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“Objectives: In recent years, cannabinoids have been shown to have beneficial effects on diabetic vascular complications.

Vascular complications due to fructose-induced hyperinsulinemia (HI) and diabetic vascular complications have similar mechanisms.

The aim of this experimental study was to observe whether the cannabinoid agonist delta-9-tetrahydrocannabinol (THC) has an ameliorating effect on fructose-induced HI and vascular responses in the aortic ringof rats with HI.

Methods: A total of 24 rats were categorized into 4 groups: control (standard food pellets and water), HI (water containing 10% fructose provided for 12 weeks), THC (1.5 mg/kg/day intraperitoneal administration for 4 weeks), and THC+HI.Body weight was measured again on the last day of the study and the serum insulin level was measured with an enzyme-linked immunosorbent assay. The acetylcholine (ACh) maximum relaxant effect in aortic rings pre-contractedwith noradrenaline (NA) was evaluated.

Results: The body weight of THC and THC+HI groups was lower compared with that of the controls (p<0.01). Increasedinsulin level as a result of fructose consumption decreased with THC administration (p<0.01) while the glucose level increased in all other groups compared with the control group (p<0.01, p<0.05). The NA Emax value decreased in thegroup receiving THC treatment (p<0.01). The increased ACh pD2 value in the HI groups also decreased in the THCtreatment group (p<0.0001). The decreased maximum inhibition value in the HI group increased significantly with THC administration (p<0.001).

Conclusion: THC demonstrated beneficial effects on fructose-induced HI. THC improved ACh-induced endothelialdependent relaxation in HI rat aortic rings.”

http://acikerisim.demiroglu.bilim.edu.tr:8080/xmlui/handle/11446/4516

https://internationalbiochemistry.com/jvi.aspx?un=IJMB-83703&volume=

The protective effects of Δ 9 -tetrahydrocannabinol against inflammation and oxidative stress in rat liver with fructose-induced hyperinsulinemia

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“Objectives: A large amount of fructose is metabolized in the liver and causes hepatic functional damage. Δ9 -tetrahydrocannabinol (THC) is known as a therapeutic agent for clinical and experimental applications. The study aims to investigate the effects of THC treatment on inflammation, lipid profiles and oxidative stress in rat liver with hyperinsulinemia.

Methods: Sprague-Dawley rats were divided into groups: control, fructose (10% fructose in drinking water for 12 weeks), THC (1.5 mg/kg/day for the last 4 weeks, intraperitoneally) and fructose+THC groups. Biochemical parameters were measured spectrophotometrically. ELISA method was used for insulin measurement. Apoptosis and inflammation markers were detected by the streptavidin-biotin peroxidase method.

Key findings: The consumptions of food and fluid are inversely proportional to fructose and non-fructose groups. Insulin levels were the highest in fructose group. The reduced glutathione-S-transferase level significantly increased in fructose + THC group compared with fructose group. Total cholesterol level in the fructose + THC group was higher than the fructose group. Caspase-3 and NF-κβ immunopositive cell numbers increased in fructose + THC rats compared with fructose group. The number of IL-6 immunopositive cell decreased in fructose + THC group compared with fructose group.

Conclusions: According to the result, long-term and low-dose THC administration may reduce hyperinsulinemia and inflammation in rats to some extent.”

https://pubmed.ncbi.nlm.nih.gov/30427077/

“Taken together, the findings from this study demonstrate that fructose consumption induces hyperinsulinemia, oxidative stress and inflammation in rats. The long-term and low-dose THC administration may prevent hyperinsulinemia and inflammation to some extent.”

https://academic.oup.com/jpp/article/71/3/408/6122105?login=false


Receptor-targeted nanoparticles modulate cannabinoid anticancer activity through delayed cell internalization

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Scientific Reports

“Δ9-tetrahydrocannabinol (Δ9-THC) is known for its antitumor activity and palliative effects.

However, its unfavorable physicochemical and biopharmaceutical properties, including low bioavailability, psychotropic side effects and resistance mechanisms associated to dosing make mandatory the development of successful drug delivery systems.

In this work, transferring (Tf) surface-modified Δ9-THC-loaded poly(lactide-co-glycolic) nanoparticles (Tf-THC-PLGA NPs) were proposed and evaluated as novel THC-based anticancer therapy. Furthermore, in order to assess the interaction of both the nanocarrier and the loaded drug with cancer cells, a double-fluorescent strategy was applied, including the chemical conjugation of a dye to the nanoparticle polymer along with the encapsulation of either a lipophilic or a hydrophilic dye.

Tf-THC PLGA NPs exerted a cell viability decreased down to 17% vs. 88% of plain nanoparticles, while their internalization was significantly slower than plain nanoparticles. Uptake studies in the presence of inhibitors indicated that the nanoparticles were internalized through cholesterol-associated and clathrin-mediated mechanisms.

Overall, Tf-modification of PLGA NPs showed to be a highly promising approach for Δ9-THC-based antitumor therapies, potentially maximizing the amount of drug released in a sustained manner at the surface of cells bearing cannabinoid receptors.”

https://pubmed.ncbi.nlm.nih.gov/35079042/

“The potential therapeutic applications of marijuana, firstly reported in 1997 by the National Institutes of Health (NIH, USA), are attributed to a great extent to its main component, Δ9-tetrahydrocannabinol (Δ9-THC)1. This cannabinoid continues to attract special attention in oncology due to its palliative effects and antitumor activity; Δ9-THC has been reported to inhibit tumor angiogenesis and cell growth in malignant tissues, leading to cell death.”

“Δ9-THC has been reported to inhibit tumor angiogenesis and cell growth in malignant tissues.”

“Overall, Tf-modification of PLGA NPs seemed a highly promising approach for Δ9-THC-based antitumor therapies, aiming at a prolonged action of the carrier at the target cell surface. Moreover, the translation of this strategy to the delivery of alternative active pharmaceutical ingredients with pharmacological targets on the surface of cells could lead to advances in related therapies.”

https://www.nature.com/articles/s41598-022-05301-z

In Vitro Effect of Δ9-Tetrahydrocannabinol and Cannabidiol on Cancer-Associated Fibroblasts Isolated from Lung Cancer

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ijms-logo

“There is evidence that demonstrates the effect of cannabinoid agonists inhibiting relevant aspects in lung cancer, such as proliferation or epithelial-to-mesenchymal transition (EMT).

Most of these studies are based on evidence observed in in vitro models developed on cancer cell lines. These studies do not consider the complexity of the tumor microenvironment (TME). One of the main components of the TME is cancer-associated fibroblasts (CAFs), cells that are relevant in the control of proliferation and metastasis in lung cancer.

In this work, we evaluated the direct effects of two cannabinoid agonists, tetrahydrocannabinol (THC) and cannabidiol (CBD), used alone or in combination, on CAFs and non-tumor normal fibroblasts (NFs) isolated from adenocarcinoma or from healthy lung tissue from the same patients.

We observed that these compounds decrease cell density in vitro and inhibit the increase in the relative expression of type 1 collagen (COL1A1) and fibroblast-specific protein 1 (FSP1) induced by transforming growth factor beta (TGFβ). On the other hand, we studied whether THC and CBD could modulate the interactions between CAFs or NFs and cancer cells. We conditioned the culture medium with stromal cells treated or not with THC and/or CBD and cultured A549 cells with them.

We found that culture media conditioned with CAFs or NFs increased cell density, induced morphological changes consistent with EMT, inhibited cadherin-1 (CDH1) gene expression, and induced an increase in the relative expression of cadherin-2 (CDH2) and vimentin (VIM) genes in A549 cells. These changes were inhibited or decreased by THC and CBD administered alone or in combination. In another series of experiments, we conditioned culture media with A549 cells treated or not with THC and/or CBD, in the presence or absence of TGFβ. We observed that culture media conditioned with A549 in the presence of TGFβ induced an increase in the expression of COL1A1 and VIM, both in CAFs and in non-tumor NFs. Both THC and CBD ameliorated these effects.

In summary, the results presented here reinforce the usefulness of cannabinoid agonists for the treatment of some relevant aspects of lung cancer pathology, and demonstrate in a novel way their possible effects on CAFs as a result of their relationship with cancer cells. Likewise, the results reinforce the usefulness of the combined use of THC and CBD, which has important advantages in relation to the possibility of using lower doses, thus minimizing the psychoactive effects of THC.”

https://pubmed.ncbi.nlm.nih.gov/35743206/

https://www.mdpi.com/1422-0067/23/12/6766


Promoting Oligodendrocyte Differentiation from Human Induced Pluripotent Stem Cells by Activating Endocannabinoid Signaling for Treating Spinal Cord Injury

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SpringerLink

“Transplantation of oligodendrocyte progenitor cell (OPC) at the injury site is being developed as a potential therapeutic strategy for promoting remyelination and locomotor function recovery after spinal cord injury (SCI). To this end, the development of expandable and functional human OPCs is crucial for testing their efficacy in SCI.

In mice and rats, the endocannabinoid signaling system is crucial for the survival, differentiation, and maturation of OPCs. Similar studies in humans are lacking currently. Endocannabinoids and exogenous cannabinoids exert their effects mainly via cannabinoid receptors (CB1R and CB2R). We demonstrated that these receptors were differentially expressed in iPSC-derived human NSCs and OPCs, and they could be activated by WIN55212-2 (WIN), a potent CB1R/CB2R agonist to upregulate the endocannabinoid signaling during glial induction.

WIN primed NSCs generated more OLIG2 + glial progenitors and migratory PDGFRα + OPC in a CB1/CB2 dependent manner compared to unprimed NSCs. Furthermore, WIN-induced OPCs (WIN-OPCs) robustly differentiated into functional oligodendrocytes and myelinate in vitro and in vivo in a mouse spinal cord injury model. RNA-Seq revealed that WIN upregulated the biological process of positive regulation of oligodendrocyte differentiation. Mechanistically, WIN could act as a partial smoothed (SMO) inhibitor or activate CB1/CB2 to form heteromeric complexes with SMO leading to the inhibition of GLI1 in the Sonic hedgehog pathway.

The partial and temporal inhibition of GLI1 during glial induction is shown to promote OPCs that differentiate faster than control’s. Thus, CB1R/CB2R activation results in more efficient generation of OPCs that can mature and efficiently myelinate.”

https://pubmed.ncbi.nlm.nih.gov/35725998/

https://link.springer.com/article/10.1007/s12015-022-10405-0


Evaluation of cannabinoid receptors type 1-2 in periodontitis patients

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“Background: As effective immune modulators, Endocannabinoids may suppress the inflammatory responses in periodontitis. This study assessed the expression of cannabinoid receptors in gingiva and the impact on periodontitis.

Methods: A cross-sectional study on 20 patients with more than stage II and Grade A periodontitis and a control group consisting of 19 healthy individuals was performed. The gingival biopsies were assessed for the expression of CB1 and CB2 using the quantitative reverse transcription polymerase chain reaction, TaqMan method.

Results: The study sample consisted of 39 subjects, 31 females (79.5%) and 8 males (20.5%), including 20 periodontitis subjects (80% female and 20% male), and control groups (78.9% female and 21.1% male). The mean ages of cases and controls were 33.3 ± 4.7 and 35.7 ± 5.1 years, respectively. The gene expression of CB2 in periodontitis was 27.62 ± 7.96 and in healthy subjects was 78.15 ± 23.07. The CB2 was significantly lower than the control group (p = .008). In comparison, the gene expression index of CB1 in the periodontal group (9.42 ± 3.03) was higher than the control group (6.62 ± 1.13) but did not meet a significant value (p = .671).

Conclusion: The lower expression of CB2 receptors in the periodontitis group may be due to the reduced protective effect of anti-inflammatory agents. These elements include cannabinoids and the imbalance leading to the predominance of pro-inflammatory effects. Therefore, the local effects of cannabinoids as an immunomodulator could be useful for oral inflammatory diseases such as periodontitis.”

https://pubmed.ncbi.nlm.nih.gov/35719011/

“In conclusion, as CB2 receptors are expressed in gingival tissues, particularly immune cells and fibroblasts, they involve in tissue and wound repair. The lower expression of these receptors in periodontitis, could be related to the inflammatory reactions and interrupts wound repair. Therefore, it seems that the use of cannabinoid CB2 agonists in the form of mouth wash contributes to the healing of periodontitis.”

https://onlinelibrary.wiley.com/doi/10.1002/cre2.608

Inhibition of mitochondrial permeability transition pore and antioxidant effect of Delta-9-tetrahydrocannabinol reduces aluminium phosphide-induced cytotoxicity and dysfunction of cardiac mitochondria

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Pesticide Biochemistry and Physiology

“Previous studies have demonstrated that phosphine gas (PH3) released from aluminium phosphide (AlP) can inhibit cytochrome oxidase in cardiac mitochondria and induce generation of free radicals, oxidative stress, alteration in antioxidant defense system and cardiotoxicity.

Available evidence suggests that cannabinoids have protective effects in the reduction of oxidative stress, mitochondrial and cardiovascular damages.

The objective of this study was to evaluate the effect of trans-Δ-9-tetrahydrocannabinol (THC) on AlP-induced toxicity in isolated cardiomyocytes and cardiac mitochondria.

Rat heart isolated cardiomyocytes and mitochondria were cotreated with different concentrations of THC (10, 50 and 100 μM) and IC50 of AlP, then cellular and mitochondrial toxicity parameters were assayed. Treatment with AlP alone increased the cytotoxicity, depletion of cellular glutathione (GSH), mitochondrial reactive oxygen species (ROS) generation, lipid oxidation, mitochondria membrane potential (ΔΨm) collapse and mitochondrial swelling, when compared to control group. However, incubation with THC (10, 50 and 100 μM) attenuated the AlP-induced changes in all these parameters in a THC concentration-dependent manner.

Interestingly, the obtained results showed remarkably significant protective effects of THC by attenuation the different parameters of cytotoxicity, mitochondrial toxicity and oxidative stress induced by ALP in isolated cardiomyocytes and cardiac mitochondria. It is the first report showing the protective effects of THC against AlP-induced toxicity, and these effects are related to antioxidant potential and inhibition of mitochondria permeability transition (MPT) pore.

Based on these results, it was hypothesized that THC may be used as a potential therapeutic agent for the treatment of AlP-induced mitochondrial dysfunction and cardiotoxicity.”

https://pubmed.ncbi.nlm.nih.gov/35715056/

“AIP-induced mitochondrial dysfunction and oxidative stress in mitochondria.•

THC inhibits AIP-induced mitochondrial dysfunction in isolated mitochondria.•

THC reverses AIP-induced mitochondrial swelling in isolated mitochondria.•

THC inhibits AIP-induced MMP (ΔΨm) collapse in isolated mitochondria.•

THC ameliorates AIP-induced cytotoxicity and oxidative stress in cardiomyocytes.”

https://www.sciencedirect.com/science/article/abs/pii/S0048357522000840?via%3Dihub

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Chronic Pain and the Endocannabinoid System: Smart Lipids – A Novel Therapeutic Option?

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Karger Publishers Further Expands into Open Access and Open Science | STM Publishing News

“The development of a high-end cannabinoid-based therapy is the result of intense translational research, aiming to convert recent discoveries in the laboratory into better treatments for patients. Novel compounds and new regimes for drug treatment are emerging. Given that previously unreported signaling mechanisms for cannabinoids have been uncovered, clinical studies detailing their high therapeutic potential are mandatory. The advent of novel genomic, optogenetic, and viral tracing and imaging techniques will help to further detail therapeutically relevant functional and structural features. An evolutionarily highly conserved group of neuromodulatory lipids, their receptors, and anabolic and catabolic enzymes are involved in a remarkable variety of physiological and pathological processes and has been termed the endocannabinoid system (ECS). A large body of data has emerged in recent years, pointing to a crucial role of this system in the regulation of the behavioral domains of acquired fear, anxiety, and stress-coping. Besides neurons, also glia cells and components of the immune system can differentially fine-tune patterns of neuronal activity. Dysregulation of ECS signaling can lead to a lowering of stress resilience and increased incidence of psychiatric disorders. Chronic pain may be understood as a disease process evoked by fear-conditioned nociceptive input and appears as the dark side of neuronal plasticity. By taking a toll on every part of your life, this abnormal persistent memory of an aversive state can be more damaging than its initial experience. All strategies for the treatment of chronic pain conditions must consider stress-related comorbid conditions since cognitive factors such as beliefs, expectations, and prior experience (memory of pain) are key modulators of the perception of pain. The anxiolytic and anti-stress effects of medical cannabinoids can substantially modulate the efficacy and tolerability of therapeutic interventions and will help to pave the way to a successful multimodal therapy. Why some individuals are more susceptible to the effects of stress remains to be uncovered. The development of personalized prevention or treatment strategies for anxiety and depression related to chronic pain must also consider gender differences. An emotional basis of chronic pain opens a new horizon of opportunities for developing treatment strategies beyond the repeated sole use of acutely acting analgesics. A phase I trial to determine the pharmacokinetics, psychotropic effects, and safety profile of a novel nanoparticle-based cannabinoid spray for oromucosal delivery highlights a remarkable innovation in galenic technology and urges clinical studies further detailing the huge therapeutic potential of medical cannabis (Lorenzl et al.; this issue).”

https://pubmed.ncbi.nlm.nih.gov/35702403/

“The evidence that full-spectrum cannabis preparations have medical benefits with less unwanted central effects stimulated the development of an oromucosal spray containing full-spectrum water-soluble cannabis. This remarkable innovation in galenic technology advocates clinical studies further and enables the realization of the very promising therapeutic potentials. Medicinal cannabis has a favorable safety and tolerability profile”

https://www.karger.com/Article/FullText/522432