Category Archives: THC (Delta-9-Tetrahydrocannabinol)

Chemotherapy-induced cachexia dysregulates hypothalamic and systemic lipoamines and is attenuated by cannabigerol.

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“Muscle wasting, anorexia, and metabolic dysregulation are common side-effects of cytotoxic chemotherapy, having a dose-limiting effect on treatment efficacy, and compromising quality of life and mortality.

Extracts of Cannabis sativa, and analogues of the major phytocannabinoid Δ9-tetrahydrocannabinol, have been used to ameliorate chemotherapy-induced appetite loss and nausea for decades. However, psychoactive side-effects limit their clinical utility, and they have little efficacy against weight loss.

We recently established that the non-psychoactive phytocannabinoid (CBG) stimulates appetite in healthy rats, without neuromotor side-effects. The present study assessed whether CBG attenuates anorexia and/or other cachectic effects induced by the broad-spectrum chemotherapy agent cisplatin.

RESULTS:

CBG (120 mg/kg) modestly increased food intake, predominantly at 36-60hrs (p<0.05), and robustly attenuated cisplatin-induced weight loss from 6.3% to 2.6% at 72hrs (p<0.01). Cisplatin-induced skeletal muscle atrophy was associated with elevated plasma corticosterone (3.7 vs 13.1ng/ml, p<0.01), observed selectively in MHC type IIx (p<0.05) and IIb (p<0.0005) fibres, and was reversed by pharmacological rescue of dysregulated Akt/S6-mediated protein synthesis and autophagy processes. Plasma metabonomic analysis revealed cisplatin administration produced a wide-ranging aberrant metabolic phenotype (Q2Ŷ=0.5380, p=0.001), involving alterations to glucose, amino acid, choline and lipid metabolism, citrate cycle, gut microbiome function, and nephrotoxicity, which were partially normalized by CBG treatment (Q2Ŷ=0.2345, p=0.01). Lipidomic analysis of hypothalami and plasma revealed extensive cisplatin-induced dysregulation of central and peripheral lipoamines (29/79 and 11/26 screened, respectively), including reversible elevations in systemic N-acyl glycine concentrations which were negatively associated with the anti-cachectic effects of CBG treatment.

CONCLUSIONS:

Endocannabinoid-like lipoamines may have hitherto unrecognized roles in the metabolic side-effects associated with chemotherapy, with the N-acyl glycine subfamily in particular identified as a potential therapeutic target and/or biomarker of anabolic interventions. CBG-based treatments may represent a novel therapeutic option for chemotherapy-induced cachexia, warranting investigation in tumour-bearing cachexia models.”

https://www.ncbi.nlm.nih.gov/pubmed/31035309

“Cannabigerol (CBG) is one of the major phytocannabinoids present in Cannabis sativa L. that is attracting pharmacological interest because it is non-psychotropic and is abundant in some industrial hemp varieties. The results indicate that CBG is indeed effective as regulator of endocannabinoid signaling.”
“Cannabigerol displayed significant antitumor activity.” https://link.springer.com/article/10.1007/BF02976895
“Antitumor activity of cannabigerol against human oral epitheloid carcinoma cells. Cannabigerol exhibited the highest growth-inhibitory activity against the cancer cell lines.” https://www.ncbi.nlm.nih.gov/pubmed/9875457

Aging circadian rhythms and cannabinoids.

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Neurobiology of Aging

“Numerous aspects of mammalian physiology exhibit cyclic daily patterns known as circadian rhythms. However, studies in aged humans and animals indicate that these physiological rhythms are not consistent throughout the life span. The simultaneous development of disrupted circadian rhythms and age-related impairments suggests a shared mechanism, which may be amenable to therapeutic intervention.

Recently, the endocannabinoid system has emerged as a complex signaling network, which regulates numerous aspects of circadian physiology relevant to the neurobiology of aging.

Agonists of cannabinoid receptor-1 (CB1) have consistently been shown to decrease neuronal activity, core body temperature, locomotion, and cognitive function. Paradoxically, several lines of evidence now suggest that very low doses of cannabinoids are beneficial in advanced age.

One potential explanation for this phenomenon is that these drugs exhibit hormesis-a biphasic dose-response wherein low doses produce the opposite effects of higher doses. Therefore, it is important to determine the dose-, age-, and time-dependent effects of these substances on the regulation of circadian rhythms and other processes dysregulated in aging.

This review highlights 3 fields-biological aging, circadian rhythms, and endocannabinoid signaling-to critically assess the therapeutic potential of endocannabinoid modulation in aged individuals. If the hormetic properties of exogenous cannabinoids are confirmed, we conclude that precise administration of these compounds may bidirectionally entrain central and peripheral circadian clocks and benefit multiple aspects of aging physiology.”

https://www.ncbi.nlm.nih.gov/pubmed/31035036

https://www.sciencedirect.com/science/article/pii/S0197458019300867?via%3Dihub

Pre- and post-conditioning treatment with an ultra-low dose of Δ9-tetrahydrocannabinol (THC) protects against pentylenetetrazole (PTZ)-induced cognitive damage.

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Behavioural Brain Research

“Preconditioning, a phenomenon where a minor noxious stimulus protects from a subsequent more severe insult, and post-conditioning, where the protective intervention is applied following the insult, offer new insight into the neuronal mechanism(s) of neuroprotection and may provide new strategies for the prevention and treatment of brain damage. We have previously reported that a single administration of an extremely low dose of Δ(9)-tetrahydrocannabinol (THC; the psychoactive ingredient of marijuana) to mice induced minor long-lasting cognitive deficits.

In the present study we examined the possibility that such a low dose of THC will protect the mice from more severe cognitive deficits induced by the epileptogenic drug pentylenetetrazole (PTZ). THC (0.002 mg/kg, a dose that is 3-4 orders of magnitude lower than the doses that induce the conventional effects of THC) was administered 1-7 days before, or 1-3 days after the injection of PTZ (60 mg/kg). The consequences of this treatment were studied 3-7 weeks later by various behavioral tests that evaluated different aspects of memory and learning.

We found that a single administration of THC either before or after PTZ abolished the PTZ-induced long-lasting cognitive deficits.

Biochemical studies indicated a concomitant reduction in phosphorylated-ERK (extracellular signal-regulated kinase) in the cerebella of mice 7 weeks following the injection of THC.

Our results suggest that a pre- or post-conditioning treatment with extremely low doses of THC, several days before or after brain injury, may provide safe and effective long-term neuroprotection.”

https://www.ncbi.nlm.nih.gov/pubmed/21315768

https://www.sciencedirect.com/science/article/pii/S0166432811001094?via%3Dihub

Structural Insights into CB1 Receptor Biased Signaling.

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“The endocannabinoid system has emerged as a promising target for the treatment of numerous diseases, including cancer, neurodegenerative disorders, and metabolic syndromes. Thus far, two cannabinoid receptors, CB1 and CB2, have been discovered, which are found predominantly in the central nervous system (CB1) or the immune system (CB2), among other organs and tissues. CB1 receptor ligands have been shown to induce a complex pattern of intracellular effects. The binding of a ligand induces distinct conformational changes in the receptor, which will eventually translate into distinct intracellular signaling pathways through coupling to specific intracellular effector proteins. These proteins can mediate receptor desensitization, trafficking, or signaling. Ligand specificity and selectivity, complex cellular components, and the concomitant expression of other proteins (which either regulate the CB1 receptor or are regulated by the CB1 receptor) will affect the therapeutic outcome of its targeting. With an increased interest in G protein-coupled receptors (GPCR) research, in-depth studies using mutations, biological assays, and spectroscopic techniques (such as NMR, EPR, MS, FRET, and X-ray crystallography), as well as computational modelling, have begun to reveal a set of concerted structural features in Class A GPCRs which relate to signaling pathways and the mechanisms of ligand-induced activation, deactivation, or activity modulation. This review will focus on the structural features of the CB1 receptor, mutations known to bias its signaling, and reported studies of CB1 receptor ligands to control its specific signaling.”

https://www.ncbi.nlm.nih.gov/pubmed/31013934

https://www.mdpi.com/1422-0067/20/8/1837

The New Runner’s High? Examining Relationships Between Cannabis Use and Exercise Behavior in States with Legalized Cannabis

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“Results indicated that the majority (81.7%) of participants endorsed using cannabis concurrently with exercise. In addition, the majority of participants who endorsed using cannabis shortly before/after exercise reported that doing so enhances their enjoyment of and recovery from exercise, and approximately half reported that it increases their motivation to exercise.” https://www.frontiersin.org/articles/10.3389/fpubh.2019.00099/abstract
“Cannabis doesn’t make you a lazy pothead, in fact, it might actually motivate you to workout: study. A new study published in the medical journal Frontiers in Public Health has found that consuming cannabis may help motivate users to exercise and improve their workouts.” https://leaderpost.com/cannabis-health/cannabis-doesnt-make-you-a-lazy-pothead-in-fact-it-might-actually-motivate-you-to-workout-study/wcm/bb0beff4-eea0-417a-8812-c5ba10841b34
“Study finds marijuana motivates people to exercise, smashing lazy stoner stereotype. Most people who use marijuana report that consuming before or after exercising improves the experience and aids in recovery, according to a new study. And those who do use cannabis to elevate their workout tend to get a healthier amount of exercise.” https://www.bostonglobe.com/news/marijuana/2019/04/16/study-finds-marijuana-motivates-people-exercise-smashing-lazy-stoner-stereotype/FHHsXxyTrTHrSisso0GC3H/story.html
“A published scientific study claims using weed before workout either “increases motivation” to exercise or “enhances recovery from exercise.”

“Exercise activates the endocannabinoid system.”   https://www.ncbi.nlm.nih.gov/pubmed/14625449

Future Aspects for Cannabinoids in Breast Cancer Therapy.

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“Cannabinoids (CBs) from Cannabis sativa provide relief for tumor-associated symptoms (including nausea, anorexia, and neuropathic pain) in the palliative treatment of cancer patients.

Additionally, they may decelerate tumor progression in breast cancer patients.

Indeed, the psychoactive delta-9-tetrahydrocannabinol (THC), non-psychoactive cannabidiol (CBD) and other CBs inhibited disease progression in breast cancer models.

The effects of CBs on signaling pathways in cancer cells are conferred via G-protein coupled CB-receptors (CB-Rs), CB1-R and CB2-R, but also via other receptors, and in a receptor-independent way.

THC is a partial agonist for CB1-R and CB2-R; CBD is an inverse agonist for both.

In breast cancer, CB1-R expression is moderate, but CB2-R expression is high, which is related to tumor aggressiveness. CBs block cell cycle progression and cell growth and induce cancer cell apoptosis by inhibiting constitutive active pro-oncogenic signaling pathways, such as the extracellular-signal-regulated kinase pathway.

They reduce angiogenesis and tumor metastasis in animal breast cancer models. CBs are not only active against estrogen receptor-positive, but also against estrogen-resistant breast cancer cells. In human epidermal growth factor receptor 2-positive and triple-negative breast cancer cells, blocking protein kinase B- and cyclooxygenase-2 signaling via CB2-R prevents tumor progression and metastasis.

Furthermore, selective estrogen receptor modulators (SERMs), including tamoxifen, bind to CB-Rs; this process may contribute to the growth inhibitory effect of SERMs in cancer cells lacking the estrogen receptor.

In summary, CBs are already administered to breast cancer patients at advanced stages of the disease, but they might also be effective at earlier stages to decelerate tumor progression.”

 https://www.ncbi.nlm.nih.gov/pubmed/30987191
https://www.mdpi.com/1422-0067/20/7/1673

Δ9-tetrahydrocannabinol attenuates oxycodone self-administration under extended access conditions.

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Neuropharmacology

“Growing nonmedical use of prescription opioids is a global problem, motivating research on ways to reduce use and combat addiction.

Medical cannabis (“medical marijuana”) legalization has been associated epidemiologically with reduced opioid harms and cannabinoids have been shown to modulate effects of opioids in animal models.

This study was conducted to determine if Δ9-tetrahydrocannabinol (THC) enhances the behavioral effects of oxycodone.

Together these data demonstrate additive effects of THC and oxycodone and suggest the potential use of THC to enhance therapeutic efficacy, and to reduce the abuse, of opioids.”

https://www.ncbi.nlm.nih.gov/pubmed/30980837

“Δ9-tetrahydrocannabinol (THC) enhances the antinociceptive effects of oxycodone. Vaporized and injected THC reduces oxycodone self-administration. Cannabinoids may reduce opioid use for analgesia. Cannabinoids may reduce nonmedical opioid use.”  

https://www.sciencedirect.com/science/article/pii/S0028390819301212?via%3Dihub

AM-1241 CB2 Receptor Agonist Attenuates Inflammation, Apoptosis and Stimulate Progenitor Cells in Bile Duct Ligated Rats.

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 “The cannabinoid receptor 2 (CB2) plays a pleiotropic role in the innate immunity and is considered a crucial mediator of liver disease.

Cannabinoid CB2 receptor activation has been reported to attenuate liver fibrosis in CCl4 exposed mice and also plays a potential role in liver regeneration in a mouse model of I/R and protection against alcohol-induced liver injury.

AIM:

In this study, we investigated the impact of CB2 receptors on the antifibrotic and regenerative process associated with cholestatic liver injury.

RESULTS:

Following bile duct ligation (BDL) for 3 weeks, there was increased aminotransferase levels, marked inflammatory infiltration and hepatocyte apoptosis with induced oxidative stress, as reflected by increased lipid peroxidation. Conversely, following treatment with the CB2 agonist, AM-1241, BDL rats displayed a reduction in liver injury and attenuation of fibrosis as reflected by expression of hydroxyproline and α-smooth muscle actin. AM1241 treatment also significantly attenuated lipid peroxidation end-products, p53-dependent apoptosis and also attenuated inflammatory process by stimulating IL-10 production. Moreover, AM1241 treated rats were associated with significant expression of hepatic progenitor/oval cell markers.

CONCLUSION:

In conclusion, this study points out that CB2 receptors reduce liver injury and promote liver regeneration via distinct mechanisms including IL-10 dependent inhibition of inflammation, reduction of p53-reliant apoptosis and through stimulation of oval/progenitor cells. These results suggest that CB2 agonists display potent hepatoregenrative properties, in addition to their antifibrogenic effects.”

https://www.ncbi.nlm.nih.gov/pubmed/30976335

https://www.id-press.eu/mjms/article/view/oamjms.2019.194

Psychopathological symptoms associated with synthetic cannabinoid use: a comparison with natural cannabis.

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“Synthetic cannabinoids (SCs) are a class of new psychoactive substances that have been rapidly evolving around the world throughout recent years. Many different synthetic cannabinoid analogues are on the consumer market and sold under misleading names, like “spice” or “incense.”

A limited number of studies have reported serious health effects associated with SC use. In this study, we compared clinical and subclinical psychopathological symptoms associated with SC use and natural cannabis (NC) use.

SC users scored higher than NC users on all used psychometric measures, indicating a higher likelihood of drug abuse, sleep problems, (hypo)manic symptoms, and the nine dimensions comprising the BSI, somatization, obsessive-compulsive behavior, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism.

This study shows that SC use is associated with increased mental health symptomatology compared to NC use.”

https://www.ncbi.nlm.nih.gov/pubmed/30968175

https://link.springer.com/article/10.1007%2Fs00213-019-05238-8

“While cannabis use usually induces psychotropic effects such as euphoria, relaxation, and a general pleasant feeling, the use of Synthetic Cannabinoid drugs is associated with more undesired effects including; agitation, irritability, confusion, hallucinations, delusions, psychosis, and death.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999798/
“These side effects (including psychosis, tachyarrhythmia, and seizures) are not typically seen with marijuana (Cannabis sativa) use.”  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726077/

Prescription of a THC/CBD-Based Medication to Patients with Dementia: A Pilot Study in Geneva

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“Dementia is increasing worldwide. No effective medication is currently available for the treatment of the underlying disease and accompanying behavioral symptoms. Cannabinoids might have a beneficial effect, but clinical studies with (low-dose) synthetic THC have not been conclusive.

Objective: To test the acceptability, practical aspects, and clinical outcomes of the introduction of a THC/CBD-based oral medication in severely demented patients in a specialized nursing home in Geneva.

Methods: This was a prospective observational study.

Results: Ten female demented patients with severe behavior problems received oral medication with on average 7.6 mg THC/13.2 mg CBD daily after 2 weeks, 8.8 mg THC/17.6 mg CBD after 1 month, and 9.0 mg THC/18.0 mg CBD after 2 months. The THC/CBD-based oil was preferred. Neuropsychiatric Inventory, Cohen-Mansfield Agitation Inventory score, and a behavior problem visual analog scale decreased by 40% after 2 months, rigidity score by 50%. Half of the patients decreased or stopped other psychotropic medications. The staff appreciated the decrease in rigidity, making daily care and transfers easier, the improved direct contact with the patients, the improvement in behavior, and the decrease in constipation with less opioids. There was no withholding of the medication for reasons of side effects, and the effects persisted after 2 months.

Conclusions: An oral cannabis extract with THC/CBD, in higher dosages than in other studies, was well tolerated and greatly improved behavior problems, rigidity, and daily care in severely demented patients.”

https://www.karger.com/Article/Abstract/498924