Cannabinoids as Medicine

Today I was caught by surprise from  a US Federal Government statement. They stated that in their opinion there is no medical value in marijuana. The claim is premature and in contradiction to a world wide research interest into cannabinoids for therapeutic purposes ranging from the management of atherosclerosis to cancer to neurodegeneration.

Just today Science Daily posted this news items indicating that blockade of the CB 1 receptor(CB=cannabinoid) accelerates neurodegeneration in the animal model. The abstract of the relevant study reads ....

Brain aging is associated with cognitive decline that is accompanied by progressive neuroinflammatory changes. The endocannabinoid system (ECS) is involved in the regulation of glial activity and influences the progression of age-related learning and memory deficits. Mice lacking the Cnr1 gene (Cnr1^−/−), which encodes the cannabinoid receptor 1 (CB1), showed an accelerated age-dependent deficit in spatial learning accompanied by a loss of principal neurons in the hippocampus. The age-dependent decrease in neuronal numbers in Cnr1^−/− mice was not related to decreased neurogenesis or to epileptic seizures. However, enhanced neuroinflammation characterized by an increased density of astrocytes and activated microglia as well as an enhanced expression of the inflammatory cytokine IL-6 during aging was present in the hippocampus of Cnr1^−/− mice. The ongoing process of pyramidal cell degeneration and neuroinflammation can exacerbate each other and both contribute to the cognitive deficits. Deletion of CB1 receptors from the forebrain GABAergic, but not from the glutamatergic neurons, led to a similar neuronal loss and increased neuroinflammation in the hippocampus as observed in animals lacking CB1 receptors in all cells. Our results suggest that CB1 receptor activity on hippocampal GABAergic neurons protects against age-dependent cognitive decline by reducing pyramidal cell degeneration and neuroinflammation.

PNAS, July 5, 2011, Vol 108, No. 27, 11256-11261 

I am cautious about gene knock out studies but in this study the findings are consistent with the known pharmacology of cannabinoids. Thus as stated in the abstract the increase in neuroinflammation is consistent with a welter of studies indicating cannabinoids can exert both anti-oxidant and anti-inflammatory activities. However given that CB 1 receptors are the most abundant G protein coupled receptors(x10) in the human brain we need to treat this result with some reserve. This is particularly true because the CB 1 receptor acts as a retrograde inhibitory neurotransmitter, hence the loss of these receptors may lead to excessive levels of neuronal activity and possibly inducing excito-toxicity.

These news releases prompted me to delve into my ever growing pile of the Great Unread.

REVIEW
Cannabinoids as therapeutic agents in cardiovascular disease: a tale of passions and illusions
VE Mendiza´bal and E Adler-Graschinsky
British Journal of Pharmacology (2007) 151, 427–440

Abstract:
In addition to their classical known effects, such as analgesia, impairment of cognition and learning and appetite enhancement, cannabinoids have also been related to the regulation of cardiovascular responses and implicated in cardiovascular pathology. Elevated levels of endocannabinoids have been related to the extreme hypotension associated with various forms of shock as well as to the cardiovascular abnormalities that accompany cirrhosis. In contrast, cannabinoids have also been associated with beneficial effects on the cardiovascular system, such as a protective role in atherosclerosis progression and in cerebral and myocardial ischaemia. In addition, it has also been suggested that the pharmacological manipulation of the endocannabinoid system may offer a novel approach to antihypertensive therapy. During the last decades, the tremendous increase in the understanding of the molecular basis of cannabinoid activity has encouraged many pharmaceutical companies to develop more potent synthetic cannabinoid analogues and antagonists, leading to an explosion of basic research and clinical trials. Consequently. not only the synthetic THC dronabinol (Marinol) and the synthetic THC analogue nabilone (Cesamet) have been approved in the United States, but also the standardized cannabis extract (Sativex) in Canada. At least three strategies can be foreseen in the future clinical use of cannabinoid-based drugs: (a) the use of CB1 receptor antagonists, such as the recently approved rimonabant (b) the use of CB2-selective agonists, and (c) the use of inhibitors of endocannabinoid degradation. In this context, the present review examines the effects of cannabinoids

Note the statement about the approval of synthetic cannabinoids for therapeutic purposes. Such drugs mimic the effects of natural cannabinoids but cost a lot more!

It is too early to answer the question of whether or not marijuana has therapeutic potential, at least from a strict scientific point of view. However, we peasants may be unpleasantly surprised by how much modern medical treatment is not justified from a "strict scientific point of view".

I do struggle with our culture's attitude towards psychoactive drugs. The psychiatric industry dishes out psychoactive drugs with sometimes reckless abandon but again here we do not see the hedonic aspect of drugs. Psychiatric drugs do not induce the pleasure typically associated with recreational drugs. Apparently any drug that makes you feel too happy is not a good thing. This is an almost pervasive attitude amongst governments.

That goverment attitude reminds me of a book I read some weeks ago. Ego and Soul, by the Australian sociologist John Carroll.  In that text the author at considerable length expounds on our "Calvinist Culture" and how we value work over everything else. His thoughts reminded me of a statement I read long ago by the European philosopher John Gray. In Straw Dogs he writes:

171
Humans are ill suited to the incessant labour and recurrent migration that go with farming. Cities were created from the yearning for a settled existence.
195
Nothing is more alien to the present age than idleness. If we think of resting from our labours, it is only in order to return to them.
In thinking so highly of work we are aberrant. Few other cultures have ever done so. For nealry all of history and all prehistory, work was an indignity.
196
For the ancients, unending labour was the mark of a slave. the labours of Sisyphus are a punishment. In working for progress we submit to a labour no less servile.

Marijuana makes people happy. It also stops us working. Marijuana is not a drug for the productive, though I have argued and still maintain that the weekly consumption of marijuana may be a useful strategy for helping to protect the brain and our cardiovascular system. Consistent smoking, day in an day out, is not for those who wish to get things done. The problem, as nearly always it seems, is one of balance.

The US Federal Government, and the many other governments, with respect to marijuana, has a very unbalanced attitude. Prohibition has been declared a failure so often, the data on that is depressing and strong, yet governments continue to enact punitive measures against recreational drug users many of whom are productive citizens who are made criminals by governments ensnared within a Calvinist mind set. So perhaps Max Weber was onto something after all!

That the US Federal Government should declare the "science is settled" with respect to the therapeutic value of marijuana, and has done so in spite of abundant evidence that marijuana can have medicinal value, and that the current body of research in the very least suggests a potentially very broad range of therapeutic applications, is yet again more evidence that governments live in fear of their citizens being too happy. As Andrew Schmookler noted in that great text, Parable of the Tribes,

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A fulfilled person at peace with the world is an instrument of limited utility, but frustrate him enough and you can bend him to society's ends.
p 174
"As long as power is a function of human productivity, civilization will tend to regard the free spirit as a wastrel and the dedicated drudge as a virtuous man. The selection for power places man under the yoke."