How Cannabis (really) Works – the ‘Entourage Effect’

yes, there’s more to it than meets the eye;
way more than HomoSociopathis can comprehend,
and our High Society wants to admit.
Here, numb-nuts-science is just getting a glimpse of the bigger picture,
a sweet taste of the real world out there.

Welcome to a reality where economy begins with ecology,
where life & death belong together
and the world runs on synergy and not on power.

This is real Life, were you & me are connected, and completely entangled with the rest of creation,
but also utterly clueless how to respond to it and/or correspond with all of this.

The Entourage Effect from Insights on Vimeo.

Maybe we should have called it Life Beyond THC.com….

How Cannabis Works

By Fred Gardner fred@plebesite.com.
who has been an editor of Scientific American and public information officer for the District Attorney of San Francisco.

The chemical structure of tetrahyrdocannabinol (THC) was determined in 1964 by R. Mechoulam & Y. Gaoni.
For more than three decades thereafter, its blatant psychoactivity induced scientists
to define THC as the active ingredient in the plant.

Experienced marijuana smokers who tried the drug Marinol (pure, synthetic THC) when it became
prescribable in the mid-1980s, reported that the effects were noticeably dissimilar.
But it wasn’t until the late 1990s that the research establishment acknowledged that another compound,
cannabidiol (CBD), was exerting significant effects, too.

In 1999 a British start-up, G.W. Pharmaceuticals, began clinical trials of a plant extract
containing equal amounts of THC and CBD. Multiple Sclerosis patients found the combination
more effective in reducing pain & spasticity than a THC extract, and less psychoactive.
The THC-CBD combo, ‘Sativex‘, has now been approved for use by MS patients in England,
Canada, New Zealand, and a growing list of European countries.

Several of the so-called ‘minor cannabinoids’ —notably tetrahydrocannabavarin (THCV),
cannabigerol (CBG) & cannabichromene (CBC) — also show therapeutic promise,
and plants with high levels of each have been grown out in G.W.’s glasshouses for research purposes.

Now scientists are formally acknowledging something else that Cannabis consumers
have long taken for granted:aroma is associated with effect.

Plant cannabinoids, —21-carbon molecules found only in Cannabis, are odorless.
It’s the terpenoids —components of the plant’s “essential oils”— that create the fragrance.
Terpenoids contain repeating units of a 5-carbon molecule called isoprene, and are prevalent
in smelly herbs such as mints & sage, citrus peel, some flowers, aromatic barks and woods.
The aroma of a given plant depends on which terpenoids predominate.
They tend to be volatile molecules that readily evaporate, and they’re very potent
—all it takes is a few reaching the nose to announce their presence.
The cannabinoid content of a trichome might be 10 times heavier than the terpenoid content.

Evidence that phytocannabinoid-terpenoid interactions’ enhance the therapeutic effects of cannabis
was presented by Ethan Russo, MD, at a conference in Israel last fall and is about to be published
in the British Journal of Pharmacology. Russo, a neurologist and ethnobotanist,
is senior medical adviser at G.W. Pharmaceuticals.

Terpenoids and cannabinoids are both secreted inside the Cannabis plant’s glandular trichomes
and they have a parent compound in common (geranyl pyrophosphate).
More than 100 terpenoids have been identified in Cannabis.
The most common and most studied include limonene, myrcene, alpha-pinene,
linalool, beta-caryophyllene, caryophyllene oxide, nerolidol and phytol.
Anecdotal evidence suggests that alpha-pinene is alerting,
limonene is ‘sunshine-y‘, and beta-myrcene is sedating.

As the names suggest, pinene is abundant in pine needles and limonene in lemons.
Myrcene is found in hops (Humulus), the only other member of the Cannabicae plant family.

The fact that most terpenoid compounds are common components of the human diet and ‘generally recognized
as safe‘ by the Food and Drug Administration has made research possible, and scientists
employed by flavors & fragrances manufacturers have investigated their properties over the years.
But the terpenoids ‘remain understudied’ in terms of therapeutic potential, according to Russo.

His paper mustered all the evidence, —proof in some cases, mere hints in others— that a
cannabinoid-terpenoid synergy is involved when Cannabis abates the symptoms of various conditions.
He listed “pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal & bacterial
infections (including methicillin-resistant Staphylococcus aureus).”

For example, as an indication that some terpenoids may, like CBD, be ‘antidotes to the
intoxicating effects of THC‘, Russo noted that traditional responses to Cannabis overdose
include limonene-rich citrus and pinene-rich black pepper.

Jeffrey Hergenrather, MD, president of the Society of Cannabis Clinicians, who attended
Russo’s talk in Israel, expects its publication to “generate great interest in terpenes among
medical cannabis users as well as physicians.” The SCC recently began collecting data on patients’ responses
to CBD-rich Cannabis. Future surveys will seek to document which terpenoids are having which effects.

bph0163-1344-f2

Phytocannabinoid & cannabis terpenoid biosynthesis →

Synergy research: approaching a new generation of phytopharmaceuticals 

The ‘Entourage Effect’

The conference at which Russo presented his paper was held at Hebrew University, Jerusalem,
where Raphael Mechoulam directs a lab, in honor of Mechoulam’s 80th birthday.

In 1998 Mechoulam co-authored a paper with Shimon Ben-Shabat suggesting that cannabinoids,
made in the body, work by means of an entourage effect’. →
They had found that the endocannabinoid 2-AG (2-arachidonoylglycerol), tested by itself, did not bind
very strongly to the cannabinoid receptors or exert pronounced behavioral effect on mice.
But when administered with two related compounds, it did both.

To pharmacologists who customarily designed experiments aimed at finding the active ingredient,
this had heavy implications. Mechoulam spelled them out: “Biochemically active natural products,
from either plant or animal origin, are in many instances accompanied by chemically related
though biologically inactive constituents. Very seldom is the biological activity of
the active constituent assayed together with inactive ‘entourage’ compounds.
Investigations of the effect of the active component in the presence of its ‘entourage’ compounds
may lead to results that differ from those observed with the active component only.

In 2001 John McPartland and Russo published a paper in the Journal of Cannabis Therapeutics applying
the ‘entourage concept to the plant itself. “Good evidence shows that secondary compounds in cannabis
may enhance the beneficial effects of THC… and reduce THC-induced anxiety, cholinergic deficits,
and immunosuppresion,” they wrote. “Cannabis terpenoids and flavonoids may also increase cerebral blood flow,
enhance cortical activity, kill respiratory pathogens, and provide anti-inflammatory activity.”

Talking Terpenoids

A decade later, Russo is substantiating the molecular-teamwork hypothesis and expanding on it.
His forthcoming BJP paper, Taming THC – potential cannabis synergy and the
phytocannabinoid-terpenoid entourage effects
. contains 304 citations.

A really good scientific review paper is built like a stone wall by an artistic mason.
Documented fact upon documented fact upon documented fact, with insights positioned fittingly.
Russo, citing Robert Clarke (2010), suggests that “distinctions between available cannabis ‘strains’
are most likely related to relative terpenoid contents and ratios.”
Citing David Potter (2009), he notes that “the mechanical stickiness of the trichomes is capable
of trapping insects with all six leg.”
Citing Jirovetz et al, “Linalool is the likely suspect in the remarkable therapeutic capabilities
of lavender essential oil to alleviate skin burns without scarring.

Citing investigators too numerous to list here, Russo reports the effects attributed to various terpenoids:

Limonene (also found in lemon): Potent immunostimulant via inhalation. Anxiolytic.
Apoptosis of breast cancer cells. Active agent against acne bacteria. Dermatophytes. Gastro-esophaeal reflux.

Alpha-pinene (found in pine needles): Bronchodilatory in humans. Acetylcholinesterase inhibitor, aiding memory.

Beta-myrcene (found in hops): Blocks inflammation via PGE-2. Analgesic, antagonized by naloxone.
Sedating, muscle relaxant, hypnotic. Blocks hepatic carcinogenesis by aflatoxin.

Linalool (found in lavender): Anti-anxiety. Sedative on inhalation in mice. Local anesthetic.
Anagesic via adenosine A2A. Anticonvulsant/anti-glutamate.

Beta-Caryophyllene (found in pepper, Echinacea): Potent anti-leishmanial. Gastric cytoprotective.
Anti-malarial. Selective CB2 antagonist. Treatment of pruritis? Treatment of addiction? Decreases platelet aggregation.

Caryophyllene Oxide (found in lemon balm): Anti-fungal. Insecticidal.

Nerolidol (found in orange): Sedative. Skin penetrant. Potent antimalarial.
Anti-leishmanial activity. Breakdown product of chlorophyll.

Phytol (found in green tea): Prevents Vitamin-A teratogenesis. Increases GABA.

Phytocannabinoid activity table → bph0163-1344-mu1

Cannabis Terpenoid activity table

bph0163-1344-mu2

 

 

 

 

Cannabinoids Formerly Known as Minor

Although this article has focused on the terpenoids, Russo’s talk in Israel gave equal time to CBD, THC-V,
CBC, and CBG (the parent compound of the others). Evidently the extensive breeding program directed by
G.W.’s Etienne de Meijer has yielded plants rich in each of these cannabinoids, and probably others.
At the 2011 meeting of the International Cannabinoid Research Society, held in Chicago in July,
several talks & posters described promising results with G.W. extracts whose exact contents
were not revealed by the investigators.

Intrepid California cultivators are trying to follow G.W.’s lead. Labs have already begun testing
for the cannabinoids that may not be “minor” after all, and for terpenoids.

Project CBD and the Society of Cannabis Clinicians are helping to collect & report on patients’ responses to the newly identified active ingredients.

It seems that this Herb can provide another perspective of things, a new opportunity to change our ways, a mental guidance for the desperately needed paradigm shift.

The ‘entourage effect applies to all aspects of life,
from our social psychological behavior and economic policies towards the environment,
to all scientific research and teachings.

The drug policy reform movement, like all single-issue movements & solutions, are the political equivalent of Marinol

More on all this at MedicalJane’s Cannabis Classroom and in
O’Shaughnessy’s, the journal of Cannabis in Clinical Practice.

My advise: Go, forget what they taught you so far and educate your self !

Understanding-Medical-Cannabis-2

International Cannagraphic

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