“WILD CANNABIS”: A REVIEW OF THE TRADITIONAL USE AND PHYTOCHEMISTRY OF LEONOTIS LEONURUS.

“Leonotis leonurus, locally commonly known as “wilde dagga” (=wild cannabis), is traditionally used as a decoction, both topically and orally, in the treatment of a wide variety of conditions such as haemorrhoids, eczema, skin rashes, boils, itching, muscular cramps, headache, epilepsy, chest infections, constipation, spider and snake bites. The dried leaves and flowers are also smoked to relieve epilepsy. The leaves and flowers are reported to produce a mild euphoric effect when smoked and have been said to have a similar, although less potent, psychoactive effect to cannabis.

The phytochemistry of particularly the non-volatile constituents of Leonotis leonurus has been comprehensively investigated due to interest generated as a result of the wide variety of biological effects reported for this plant. More than 50 compounds have been isolated and characterised. Leonotis leonurus contains mainly terpenoids, particularly labdane diterpenes, the major diterpene reported is marrubiin. Various other compounds have been reported by some authors to have been isolated from the plant, including, in the popular literature only, the mildly psychoactive alkaloid, leonurine. Leonurine has however, never been reported by any scientific analysis of the extracts of L. leonurus.

Despite the publication of various papers on L. leonurus, there is still, however, the need for definitive research and clarification of other compounds, including alkaloids and essential oils from L. leonurus, as well as from other plant parts, such as the roots which are extensively used in traditional medicine. The traditional use by smoking also requires further investigation as to how the chemistry and activity are affected by this form of administration. Research has proven the psychoactive effects of the crude extract of L. leonurus, but confirmation of the presence of psychoactive compounds, as well as isolation and characterisation, is still required. Deliberate adulteration of L. leonurus with synthetic cannabinoids has been reported recently, in an attempt to facilitate the marketing of these illegal substances, highlighting the necessity for refinement of appropriate quality control processes to ensure safety and quality. Much work is therefore still required on the aspect of quality control to ensure safety, quality and efficacy of the product supplied to patients, as this plant is widely used in South Africa as a traditional medicine. Commercially available plant sources provide a viable option for phytochemical research, particularly with regard to the appropriate validation of the plant material (taxonomy) in order to identify and delimit closely related species such as L. leonurus and L. nepetifolia which are very similar in habit.”

http://www.ncbi.nlm.nih.gov/pubmed/26292023

Sativex® and clinical-neurophysiological measures of spasticity in progressive multiple sclerosis.

“Despite the proven efficacy of Sativex® (9-delta-tetrahydrocannabinol plus cannabidiol) oromucosal spray in reducing spasticity symptoms in multiple sclerosis (MS), little is known about the neurophysiological correlates of such effects.

The aim of the study was to investigate the effects of Sativex on neurophysiological measures of spasticity (H/M ratio) and corticospinal excitability in patients with progressive MS.

This was a randomized, double-blind, placebo-controlled, crossover study…

Our findings confirm the clinical benefit of Sativex on MS spasticity.”

http://www.ncbi.nlm.nih.gov/pubmed/26289497

[CANNABIS AND GLAUCOMA: AN ANCIENT LEGEND OR A NOVEL THERAPEUTIC HORIZON?].

“Glaucoma causes damage to the optic nerve and compromises the visual field. The main risk factor of the disease is the level of the intra-ocular pressure. Therapeutic options include medical and surgical treatment, aimed to lower the intra-ocular pressure.

Consumption of the cannabis plant (Cannabis Satival has been known since ancient times. It can be consumed orally, topically, intra-venous or by inhalation.

The main active ingredient of cannabis is THC (Tetra-Hydro-Cannabinol). One of THC’s reported effects is the reduction of intra-ocular pressure.

Several studies have demonstrated temporary intra-ocular pressure decrease in both healthy subjects and glaucoma patients following topical application or systemic consumption.

Cannabis may be considered as a therapeutic option in glaucoma.”

http://www.ncbi.nlm.nih.gov/pubmed/26281086

A 4-Week Pilot Study With the Cannabinoid Receptor Agonist Dronabinol and Its Effect on Metabolic Parameters in a Randomized Trial.

“Dronabinol (synthetic Δ9- tetrahydrocannabinol) is used in patients with nausea and vomiting from chemotherapy and in AIDS patients for appetite stimulation.

Recently, dronabinol was used to successfully treat visceral hypersensitivity causing noncardiac chest pain. With widening uses of this medication, we aim to explore its effects on metabolic parameters in long-term dosing and hypothesize that it will not affect major metabolic parameters.

A double-blind, placebo-controlled, 28-day trial was performed with patients 18 to 75 years old without cardiac disease…

Dronabinol administration does not significantly affect basic metabolic components after a period of 28 days.

The implications of these findings are important because dronabinol may be able to be used in patients with metabolic disorders. The favorable trends observed here warrant further exploration into its long-term effects.”

http://www.ncbi.nlm.nih.gov/pubmed/26283236

The Endocannabinoid System and its Modulation by Phytocannabinoids

“The endocannabinoid system is currently defined as the ensemble of the two 7-transmembrane-domain and G protein-coupled receptors for Δ9-tetrahydrocannabinol (but not for most other plant cannabinoids or phytocannabinoids)—cannabinoid receptor type-1 (CB1R) and cannabinoid receptor type-2 (CB2R); their two most studied endogenous ligands, the “endocannabinoids” N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG); and the enzymes responsible for endocannabinoid metabolism.

However, anandamide and 2-AG, and also the phytocannabinoids, have more molecular targets than just CB1R and CB2R.

Furthermore, the endocannabinoids, like most other lipid mediators, have more than just one set of biosynthetic and degrading pathways and enzymes, which they often share with “endocannabinoid-like” mediators that may or may not interact with the same proteins as Δ9-tetrahydrocannabinol and other phytocannabinoids.

In some cases, these degrading pathways and enzymes lead to molecules that are not inactive and instead interact with other receptors.

Finally, some of the metabolic enzymes may also participate in the chemical modification of molecules that have very little to do with endocannabinoid and cannabinoid targets.

Here, we review the whole world of ligands, receptors, and enzymes, a true “endocannabinoidome”, discovered after the cloning of CB1R and CB2R and the identification of anandamide and 2-AG, and its interactions with phytocannabinoids.”

http://www.ncbi.nlm.nih.gov/pubmed/26271952

http://link.springer.com/article/10.1007%2Fs13311-015-0374-6

Early Phase in the Development of Cannabidiol as a Treatment for Addiction: Opioid Relapse Takes Initial Center Stage.

“Multiple cannabinoids derived from the marijuana plant have potential therapeutic benefits but most have not been well investigated, despite the widespread legalization of medical marijuana in the USA and other countries.

Therapeutic indications will depend on determinations as to which of the multiple cannabinoids, and other biologically active chemicals that are present in the marijuana plant, can be developed to treat specific symptoms and/or diseases.

Such insights are particularly critical for addiction disorders, where different phytocannabinoids appear to induce opposing actions that can confound the development of treatment interventions. Whereas Δ9-tetracannabinol has been well documented to be rewarding and to enhance sensitivity to other drugs, cannabidiol (CBD), in contrast, appears to have low reinforcing properties with limited abuse potential and to inhibit drug-seeking behavior.

Other considerations such as CBD’s anxiolytic properties and minimal adverse side effects also support its potential viability as a treatment option for a variety of symptoms associated with drug addiction.

However, significant research is still needed as CBD investigations published to date primarily relate to its effects on opioid drugs, and CBD’s efficacy at different phases of the abuse cycle for different classes of addictive substances remain largely understudied.

Our paper provides an overview of preclinical animal and human clinical investigations, and presents preliminary clinical data that collectively sets a strong foundation in support of the further exploration of CBD as a therapeutic intervention against opioid relapse.

As the legal landscape for medical marijuana unfolds, it is important to distinguish it from “medical CBD” and other specific cannabinoids, that can more appropriately be used to maximize the medicinal potential of the marijuana plant.”

http://www.ncbi.nlm.nih.gov/pubmed/26269227

Dissecting the cannabinergic control of behavior: The where matters.

“The endocannabinoid system is the target of the main psychoactive component of the plant Cannabis sativa, the Δ9 -tetrahydrocannabinol (THC).

This system is composed by the cannabinoid receptors, the endogenous ligands, and the enzymes involved in their metabolic processes, which works both centrally and peripherally to regulate a plethora of physiological functions.

This review aims at explaining how the site-specific actions of the endocannabinoid system impact on memory and feeding behavior through the cannabinoid receptors 1 (CB1 R).

Centrally, CB1 R is widely distributed in many brain regions, different cell types (e.g. neuronal or glial cells) and intracellular compartments (e.g. mitochondria).

Interestingly, cellular and molecular effects are differentially mediated by CB1 R according to their cell-type localization (e.g. glutamatergic or GABAergic neurons).

Thus, understanding the cellular and subcellular function of CB1 R will provide new insights and aid the design of new compounds in cannabinoid-based medicine.”

http://www.ncbi.nlm.nih.gov/pubmed/26260530

An Overview of Products and Bias in Research.

“Cannabis is a genus of annual flowering plant.

Cannabis is often divided into 3 species-Cannabis sativa, Cannabis indica, and Cannabis ruderalis-but there is significant disagreement about this, and some consider them subspecies of the same parent species.

Cannabis sativa can grow to 5-18 feet or more, and often has a few branches.

Cannabis indica typically grows 2-4 feet tall and is compactly branched.

Cannabis ruderalis contains very low levels of Δ-9-tetrahyocannabinol so is rarely grown by itself. Cannabis ruderalis flowers as a result of age, not light conditions, which is called autoflowering. It is principally used in hybrids, to enable the hybrid to have the autoflowering property.

There are > 700 strains of cannabis, often with colorful names.

Some are strains of 1 of the 3 subspecies. Many are crossbred hybrids.

The strains can be named in a variety of ways: smell or lineage are common ways of naming. There are only a few rules about how the strains are named, and most strains’ names do not follow the rules.

There are 4 basic preparations of marijuana: bhang, hasish, oil (or hash oil), and leaves and/or buds.

In medical marijuana trials, subjective outcomes are frequently used but blind breaking can introduce significant bias. Blind breaking occurs when patients figure out if they are in the control or the treatment group. When this occurs, there is significant overestimation of treatment effect.”

http://www.ncbi.nlm.nih.gov/pubmed/26202343

Ultra Low Dose Delta 9-Tetrahydrocannabinol Protects Mouse Liver from Ischemia Reperfusion Injury.

“Ischemia/reperfusion (I/R) injury is the main cause of both primary graft dysfunction and primary non-function of liver allografts.

Cannabinoids has been reported to attenuate myocardial, cerebral and hepatic I/R oxidative injury.

Delta-9-tetrahydrocannabinol (THC), a cannabinoid agonist, is the active components of marijuana.

In this study we examined the role of ultralow dose THC (0.002mg/kg) in the protection of livers from I/R injury. This extremely low dose of THC was previously found by us to protect the mice brain and heart from a variety of insults.

CONCLUSION:

A single ultralow dose THC can reduce the apoptotic, oxidative and inflammatory injury induced by hepatic I/R injury.

THC may serve as a potential target for therapeutic intervention in hepatic I/R injury during liver transplantation, liver resection and trauma.”

http://www.ncbi.nlm.nih.gov/pubmed/26202357

Δ9-Tetrahydrocannabinolicacid synthase production in Pichia pastoris enables chemical synthesis of cannabinoids.

“Δ9-tetrahydrocannabinol (THC) is of increasing interest as a pharmaceutical and bioactive compound.

Chemical synthesis of THC uses a laborious procedure and does not satisfy the market demand.

The implementation of biocatalysts for specific synthesis steps might be beneficial for making natural product availability independent from the plant.

Δ9-Tetrahydrocannabinolicacid synthase (THCAS) from C. sativa L. catalyzes the cyclization of cannabigerolic acid (CBGA) to Δ9-tetrahydrocannabinolic acid (THCA), which is non-enzymatically decarboxylated to THC.

In conclusion, production of THCAS in Pichia pastoris MutS KM71 KE1, subsequent isolation, and its application in a two-liquid phase setup enables the synthesis of THCA on a mg scale.”

http://www.ncbi.nlm.nih.gov/pubmed/26197418