Towards a better Cannabis drug.

“Opium smoking has been mostly replaced by i.v. injection of morphine and heroin and we see cocaine sniffing rather than chewing of coca leaves. Cannabis use – be it of marijuana, hashish or bhang – differs.

Any cannabis cognoscente will insist that the crude material is ‘much better’ than pure Δ9 – tetrahydrocannabinol (THC), the only major psychoactive constituent of cannabis (Mechoulam et al., 1970).

Indeed, although pure THC is available as a drug (named Dronabinol) it is apparently not used illicitly.

The pharmacological/biochemical basis for this difference is not clear and is presumably due to several factors. A major reason seems to be the pharmacokinetic difference between cannabis smoking and the oral administration of THC.

 On smoking, the cannabis effects are noted almost immediately, while a 1.5 – 2 hour delay is observed on oral administration.

A further factor may be conditioning to the smell, although there are no published data along these lines. A further factor may be the presence of the terpenoid CB2 agonist beta-caryophyllene in cannabis (Gertsch et al., 2008).

CB2 agonists are well known to cause numerous effects (mostly of a protective nature) which may counteract some of the effects of THC (Pacher & Mechoulam, 2011).”

http://www.ncbi.nlm.nih.gov/pubmed/24024867

Therapeutic potential of cannabinoid medicines.

Drug Testing and Analysis

“Cannabis was extensively used as a medicine throughout the developed world in the nineteenth century but went into decline early in the twentieth century ahead of its emergence as the most widely used illicit recreational drug later that century. Recent advances in cannabinoid pharmacology alongside the discovery of the endocannabinoid system (ECS) have re-ignited interest in cannabis-based medicines.

The ECS has emerged as an important physiological system and plausible target for new medicines. Its receptors and endogenous ligands play a vital modulatory role in diverse functions including immune response, food intake, cognition, emotion, perception, behavioural reinforcement, motor co-ordination, body temperature, wake/sleep cycle, bone formation and resorption, and various aspects of hormonal control. In disease it may act as part of the physiological response or as a component of the underlying pathology.

In the forefront of clinical research are the cannabinoids delta-9-tetrahydrocannabinol and cannabidiol, and their contrasting pharmacology will be briefly outlined. The therapeutic potential and possible risks of drugs that inhibit the ECS will also be considered. This paper will then go on to review clinical research exploring the potential of cannabinoid medicines in the following indications: symptomatic relief in multiple sclerosis, chronic neuropathic pain, intractable nausea and vomiting, loss of appetite and weight in the context of cancer or AIDS, psychosis, epilepsy, addiction, and metabolic disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/24006213

http://onlinelibrary.wiley.com/doi/10.1002/dta.1529/abstract

Cannabis, a complex plant: different compounds and different effects on individuals.

“Cannabis is a complex plant, with major compounds such as delta-9-tetrahydrocannabinol and cannabidiol, which have opposing effects. The discovery of its compounds has led to the further discovery of an important neurotransmitter system called the endocannabinoid system.

This system is widely distributed in the brain and in the body, and is considered to be responsible for numerous significant functions.

There has been a recent and consistent worldwide increase in cannabis potency, with increasing associated health concerns. A number of epidemiological research projects have shown links between dose-related cannabis use and an increased risk of development of an enduring psychotic illness. However, it is also known that not everyone who uses cannabis is affected adversely in the same way.

What makes someone more susceptible to its negative effects is not yet known, however there are some emerging vulnerability factors, ranging from certain genes to personality characteristics.

 In this article we first provide an overview of the biochemical basis of cannabis research by examining the different effects of the two main compounds of the plant and the endocannabinoid system, and then go on to review available information on the possible factors explaining variation of its effects upon different individuals.”

http://www.ncbi.nlm.nih.gov/pubmed/23983983

Around-the-clock oral THC effects on sleep in male chronic daily cannabis smokers.

“Δ9-tetrahydrocannabinol (THC) promotes sleep in animals; clinical use of THC is associated with somnolence (sleepiness)…

These findings suggest that tolerance to the somnolent effects of THC may have occurred…

Somnolence from oral THC may dissipate with chronic, high-dose use.

This has implications for patients who may take chronic oral THC for medicinal purposes, including cannabis dependence treatment.”

http://www.ncbi.nlm.nih.gov/pubmed/23952899

Cannabidiol potentiates pharmacological effects of Delta(9)-tetrahydrocannabinol via CB(1) receptor-dependent mechanism.

“Cannabidiol, a non-psychoactive component of cannabis, has been reported to have interactions with Delta(9)-tetrahydrocannabinol (Delta(9)-THC)…

In the present study, we investigated whether cannabidiol modulates the pharmacological effects of Delta(9)-THC…

Cannabidiol potentiated pharmacological effects of Delta(9)-THC via CB(1) receptor-dependent mechanism.

These findings may contribute in setting the basis for interaction of cannabinoids and to find a cannabinoid mechanism in central nervous system.”

http://www.ncbi.nlm.nih.gov/pubmed/18021759

Cannabidiol enhances the inhibitory effects of Δ9-tetrahydrocannabinol on human glioblastoma cell proliferation and survival

Molecular Cancer Therapeutics

Δ9-THC and other cannabinoids can act as direct anticancer agents in multiple types of cancer in culture and in vivo. 

Individually, Δ9-THC and CBD can activate distinct pathways in glioblastoma cells that ultimately culminate in inhibition of cancer cell growth and invasion as well as induction of cell death.

We hypothesized that, if the individual agents were combined, a convergence on shared pathways may ensue leading to an enhanced ability of the combination treatment to inhibit certain cancer cell phenotypes.

We found this to be true in this investigation.

CBD enhances the inhibitory effects of Δ9-THC on glioblastoma cell growth.

Cannabidiol significantly improved the inhibitory effects of Δ9-tetrahydrocannabinol on glioblastoma cell proliferation and survival.

The Combination Treatment of Δ9-THC and Cannabidiol Inhibits Cell Cycle and Induces Apoptosis.

Our results suggest that the addition of CBD to Δ9-THC may improve the overall effectiveness of Δ9-THC in the treatment of glioblastoma in cancer patients.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806496/

http://mct.aacrjournals.org/content/9/1/180.full

“CBD Enhances the Anticancer Effects of THC”  https://www.scribd.com/document/50154001/CBD-Enhances-the-Anticancer-Effects-of-THC-Journal-MCT-Marcu

Active Chemicals in Cannabis Inhibits Prostate Cancer Cell Growth

“According to researchers, active chemicals in cannabis inhibits prostate cancer cell growth…

cannabis

Professor Ines Diaz-Laviada, study author said: “Our research shows that there are areas on prostate cancer cells which can recognize and talk to chemicals found in cannabis called cannabinoids. These chemicals can stop the division and growth of prostate cancer cells and could become a target for new research into potential drugs to treat prostate cancer.””  http://www.elements4health.com/active-chemicals-in-cannabis-inhibits-prostate-cancer-cell-growth.html

“Inhibition of human tumour prostate PC-3 cell growth by cannabinoids R(+)-Methanandamide and JWH-015: Involvement of CB2″ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743360/

“Delta9-tetrahydrocannabinol induces apoptosis in human prostate PC-3 cells via a receptor-independent mechanism.” http://www.ncbi.nlm.nih.gov/pubmed/10570948

Cannabinoids Decrease the Th17 Inflammatory Autoimmune Phenotype.

“Cannabinoids, the Cannabis constituents, are known to possess anti-inflammatory properties but the mechanisms involved are not understood. Here we show that the main psychoactive cannabinoid, Δ-9-tetrahydrocannabinol (THC), and the main nonpsychoactive cannabinoid, cannabidiol (CBD), markedly reduce the Th17 phenotype which is known to be increased in inflammatory autoimmune pathologies such as Multiple Sclerosis…

Pretreatment with CBD also resulted in increased levels of the anti-inflammatory cytokine IL-10. Interestingly, CBD and THC did not affect the levels of TNFα and IFNγ. The downregulation of IL-17 secretion by these cannabinoids does not seem to involve the CB1, CB2, PPARγ, 5-HT1A or TRPV1 receptors…

In conclusion, the results show a unique cannabinoid modulation of the autoimmune cytokine milieu combining suppression of the pathogenic IL-17 and IL-6 cytokines along with boosting the expression of the anti-inflammatory cytokine IL-10.”

http://www.ncbi.nlm.nih.gov/pubmed/23892791

The Hypocretin/Orexin Receptor-1 as a Novel Target to Modulate Cannabinoid Reward.

“Although there is a high prevalence of users who seek treatment for cannabis dependence, no accepted pharmacologic treatment is available to facilitate and maintain abstinence.

 The hypocretin/orexin system plays a critical role in drug addiction, but the potential participation of this system in the addictive properties of cannabinoids is unknown.

 We investigated…  studies were performed to evaluate dopamine extracellular levels in the nucleus accumbens after acute Δ9-tetrahydrocannabinol administration..

… role of Hcrtr-1 in the reinforcing and motivational properties of WIN55,212-2 (THC) was confirmed…

CONCLUSIONS:

These findings demonstrate that Hcrtr-1 modulates the reinforcing properties of cannabinoids, which could have a clear therapeutic interest.”

http://www.ncbi.nlm.nih.gov/pubmed/23896204

Palmitoylethanolamide: From endogenous cannabimimetic substance to innovative medicine for the treatment of cannabis dependence.

“Palmitoylethanolamide (PEA) is a fatty acid amide showing some pharmacodynamic similarities with Δ9-tetrahydrocannabinol, the principal psychoactive compound present in the cannabis plant.

Like Δ9-tetrahydrocannabinol, PEA can produce a direct or indirect activation of cannabinoid receptors.

 Furthermore, it acts as an agonist at TRPV1 receptor.

The hypothesis is that PEA has anti-craving effects in cannabis dependent patients, is efficacious in the treatment of withdrawal symptoms, produces a reduction of cannabis consumption and is effective in the prevention of cannabis induced neurotoxicity and neuro-psychiatric disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/23896215