“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

METABOLIC EFFECTS OF MARIJUANA USE AMONG BLACKS

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“Given the paucity of data on metabolic significance of marijuana use, particularly among the black population, the objective of the study was to investigate the potential effects of marijuana on metabolic risk factors and body weight among black patients…

Current marijuana use is associated with significantly lower waist circumference, compared to former users and never users.

Except for diastolic BP that was significantly lower among current users, other metabolic parameters showed tendency towards favorable profile…

Our study on the cardio-metabolic effects on marijuana use among black population from an inner city institution showed consistent results on the association of marijuana use with lower waist circumference that has been demonstrated previously among populations that are largely white.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523241/

 

Cannabinoids and Glucocorticoids in the Basolateral Amygdala Modulate Hippocampal-Accumbens Plasticity after Stress.

“Acute stress results in release of glucocorticoids which are potent modulators of learning and plasticity. This process is presumably mediated by the basolateral amygdala (BLA) where cannabinoids CB1 receptors play a key role in regulating the hypothalamic-pituitary-adrenal (HPA) axis.

Growing attention has been focused on nucleus accumbens (NAc) plasticity which regulates mood and motivation. The NAc integrates affective and context dependent input from the BLA and ventral subiculum (vSub), respectively.

Since our previous data suggest that the CB1/2 receptor agonist WIN55,212-2 (WIN) and glucocorticoid receptor (GR) antagonist RU-38486 (RU) can prevent the effects of stress on emotional memory, we examined whether intra-BLA WIN and RU can reverse the effects of acute stress on NAc plasticity…

The results suggest that glucocorticoid and cannabinoid systems in the BLA can restore normal function of the NAc and hence may play a central role in the treatment of a variety of stress-related disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/26289146

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

Molecular Targets of Cannabidiol in Neurological Disorders.

“Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plantcannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD’s beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD’s relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug’s action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excluding unlikely and implausible targets, the remaining molecular targets of CBD with plausible evidence for involvement in therapeutic effects in neurological disorders (e.g., voltage-dependent anion channel 1, G protein-coupled receptor 55, CaV3.x, etc.) are associated with either the regulation of, or responses to changes in, intracellular calcium levels. While no causal proof yet exists for CBD’s effects at these targets, they represent the most probable for such investigations and should be prioritized in further studies of CBD’s therapeutic mechanism of action.”

http://www.ncbi.nlm.nih.gov/pubmed/26264914

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

The role of the peripheral cannabinoid system in the pathogenesis of detrusor overactivity evoked by increased intravesical osmolarity in rats.

“The cannabinoid receptors CB1 and CB2 are localized in the urinary bladder and play a role in the regulation of its function. We investigated the pathomechanisms through which hyperosmolarity induces detrusor overactivity (DO)…

These results demonstrate that hyperosmolar-induced DO is mediated by CB1 and CB2 receptors. Therefore, the cannabinoid pathway could potentially be a target for the treatment of urinary bladder dysfunction.”

http://www.ncbi.nlm.nih.gov/pubmed/26243021

Therapeutic potential of cannabis-related drugs.

“In this review, I will consider the dual nature of Cannabis and cannabinoids.

The duality arises from the potential and actuality of cannabinoids in the laboratory and clinic and the ‘abuse’ of Cannabis outside the clinic.

The therapeutic areas currently best associated with exploitation of Cannabis-related medicines include pain, epilepsy, feeding disorders, multiple sclerosis and glaucoma.

As with every other medicinal drug of course, the ‘trick’ will be to maximise the benefit and minimise the cost.

After millennia of proximity and exploitation of the Cannabis plant, we are still playing catch up with an understanding of its potential influence for medicinal benefit.”

http://www.ncbi.nlm.nih.gov/pubmed/26216862

Mitochondrial CB1 receptor is involved in ACEA-induced protective effects on neurons and mitochondrial functions.

“Mitochondrial dysfunction contributes to cell death after cerebral ischemia/reperfusion (I/R) injury.

Cannabinoid CB1 receptor is expressed in neuronal mitochondrial membranes (mtCB1R) and involved in regulating mitochondrial functions under physiological conditions…

In purified neuronal mitochondria, mtCB1R activation attenuated Ca(2+)-induced mitochondrial injury.

In conclusion, mtCB1R is involved in ACEA-induced protective effects on neurons and mitochondrial functions, suggesting mtCB1R may be a potential novel target for the treatment of brain ischemic injury.”

http://www.ncbi.nlm.nih.gov/pubmed/26215450

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