Overview
Cannabis: Old medicine with new promise for neurological disorders

Marijuana is a complex substance containing over 60
different forms of cannabinoids, the active ingredients.
Cannabinoids are now known to have the capacity for
neuromodulation, via direct, receptor-based mechanisms at
numerous levels within the nervous system. These have
therapeutic properties that may be applicable to the
treatment of neurological disorders; including antioxidative,
neuroprotective, analgesic and anti-inflammatory
actions; immunomodulation, modulation of glial cells and
tumor growth regulation. This article reviews the emerging
research on the physiological mechanisms of endogenous
and exogenous cannabinoids in the context of neurological
disease.

Over the past few decades there has been widening interest in
the viable medicinal uses of cannabis [1]. The National
Institutes of Health, the Institute of Medicine and the Food
and Drug Administration have all issued statements calling
for further investigation [1-3]. The discovery of an
endogenous cannabinoid system with specific receptors and
ligands has led the progression of our understanding of the
actions of cannabis from folklore to valid science. It now
appears that the cannabinoid system evolved with our species
and is intricately involved in normal human physiology,
specifically in the control of movement, pain, memory and
appetite, among others. The detection of widespread
cannabinoid receptors in the brain and peripheral tissues
suggests that the cannabinoid system represents a previously
unrecognized ubiquitous network in the nervous system.
Dense receptor concentrations have been found in the
cerebellum, basal ganglia and hippocampus, accounting for
the effects on motor tone, coordination and mood state [4,5].
Low concentrations are found in the brainstem, accounting
for the remarkably low toxicity. Lethal doses in humans have
not been described [5-7].

Marijuana is a complex plant, with several subtypes of
cannabis, each containing over 400 chemicals [8,9].
Approximately 60 are chemically classified as cannabinoids
[5,9]. The cannabinoids are 21 carbon terpenes, biosynthesized
predominantly via a recently discovered deoxyxylulose
phosphate pathway [10]. The cannabinoids are lipophilic and
not soluble in water. Among the most psychoactive is '9-
tetrahydrocannabinol (THC), the active ingredient in
dronabinol (Unimed Pharmaceuticals Inc) [9]. Other major
cannabinoids include cannabidiol (CBD) and cannabinol
(CBN), both of which may modify the pharmacology of THC
or have distinct effects of their own. CBD is not psychoactive
but has significant anticonvulsant, sedative and other
pharmacological activity likely to interact with THC [8]. In
mice, pretreatment with CBD increased brain levels of THC
nearly 3-fold and there is strong evidence that cannabinoids
can increase the brain concentrations and pharmacological
actions of other drugs [11].
Two endogenous lipids, anandamide (AEA) and 2-
arachidonylglycerol (2-AG), have been identified as
cannabinoids, although there are likely to be more [12]. The
physiological roles of these endocannabinoids have been only
partially clarified but available evidence suggests they
function as diffusible and short-lived intercellular messengers
that modulate synaptic transmission. Recent studies have
provided strong experimental evidence that endogenous
cannabinoids mediate signals retrogradely from depolarized
postsynaptic neurons to presynaptic terminals to suppress
subsequent neurotransmitter release, driving the synapse into
an altered state [12]. In hippocampal neurons, depolarization
of postsynaptic neurons and the resultant elevation of calcium
lead to transient suppression of inhibitory transmitter release.
Depolarized hippocampal neurons rapidly release both AEA
and 2-AG in a calcium-dependent manner. In the
hippocampus, cannabinoid receptors are expressed mainly by
GABA-mediated inhibitory interneurons. Synthetic
cannabinoid agonists depress GABA release from
hippocampal slices [12]. However, in cerebellar Purkinje cells,
depolarization-induced elevation of calcium causes transient
suppression of excitatory transmitter release [13]. Thus
endogenous cannabinoids released by depolarized
hippocampal neurons may function to downregulate GABA
release [12,13]. Further, signaling by the endocannabinoid
system appears to represent a mechanism enabling neurons to
communicate backwards across synapses in order to
modulate their inputs.
There are two known cannabinoid receptor subtypes;
subtype 1 (CB1) is expressed primarily in the brain, whereas
subtype 2 (CB2) is expressed primarily in the periphery
[4,14]. Cannabinoid receptors constitute a major family of G
protein-coupled, 7-helix transmembrane nucleotides, similar
to the receptors of other neurotransmitters such as
dopamine, serotonin and norepinephrine [4,5]. Activation of
protein kinases may be responsible for some of the cellular
responses elicited by the CB1 receptor [15].

As we are developing an increased cognizance of the
physiological function of endogenous and exogenous
cannabinoids it is becoming evident that they may be
involved in the pathology of certain diseases, particularly
neurological disorders. Cannabinoids may induce
proliferation, growth arrest or apoptosis in a number of
cells, including neurons, lymphocytes and various
transformed neural and non-neural cells [16-21]. In the CNS,
most of the experimental evidence indicates that
cannabinoids may protect neurons from toxic insults such as
glutamatergic overstimulation, ischemia and oxidative
damage [22-26]. The neuroprotective effect of cannabinoids
may have potential clinical relevance for the treatment of
neurodegenerative disorders such as amyotrophic lateral
sclerosis (ALS), multiple sclerosis (MS), Parkinson's disease,
cerebrovascular ischemia and stroke. Both endogenous and
exogenous cannabinoids appear to have neuroprotective
and antioxidant effects. Recent studies have demonstrated
the neuroprotective effects of synthetic, non-psychotropic
cannabinoids, which appear to protect neurons from
chemically induced excitotoxicity [23-25]. Direct
measurement of oxidative stress reveals that cannabinoids
prevent cell death by antioxidation. The antioxidative
property of cannabinoids is confirmed by their ability to
antagonize oxidative stress and consequent cell death
induced by the powerful oxidant, retinoid anhydroretinol.
Cannabinoids also modulate cell survival and the growth of
B-lymphocytes and fibroblasts [23-25,27].
The neuroprotective actions of cannabidiol and other
cannabinoids have been examined in rat cortical neuron
cultures exposed to toxic levels of the excitatory
neurotransmitter glutamate. Glutamate toxicity was reduced
by both CBD (non-psychoactive) and THC [26]. The
neuroprotection observed with CBD and THC was unaffected
by a cannabinoid receptor antagonist, indicating it to be
cannabinoid receptor-independent. CBD was more protective
against glutamate neurotoxicity than either ascorbate (vitamin
C) or D-tocopherol (vitamin E) [26].
Cannabinoids have demonstrated efficacy as immune
modulators in animal models of neurological conditions
such as MS and neuritis [19]. Current data suggests that the
naturally occurring, non-psychotropic cannabinoid, CBD,
may have a potential role as a therapeutic agent for
neurodegenerative disorders produced by excessive cellular
oxidation, such as ALS, a disease characterized by excess
glutamate activity in the spinal cord [28].
It is not yet known how glutamatergic insults affect in vivo
endocannabinoid homeostasis, including AEA, 2-AG, as
well as other constituents of their lipid families, Nacylethanolamines
(NAEs) and 2-monoacylglycerols (2-
MAGs). Hansen et al used three in vivo neonatal rat models
characterized by widespread neurodegeneration as a
consequence of altered glutamatergic neurotransmission
and assessed changes in endocannabinoid homeostasis
[29]. A 46-fold increase of cortical NAE concentrations and
a 13-fold increase in AEA was noted 24 h after
intracerebral NMDA injection, while less severe insults
triggered by mild concussive head trauma or NMDA
receptor blockade produced a less pronounced NAE
accumulation. In contrast, levels of 2-AG and other 2-
MAGs were unaffected by the insults employed, rendering
it likely that key enzymes in biosynthetic pathways of the
two different endocannabinoid structures are not equally
associated to intracellular events that cause neuronal
damage in vivo. Analysis of cannabinoid CB1 receptor
mRNA expression and binding capacity revealed that
cortical subfields exhibited an upregulation of these
parameters following mild concussive head trauma and
exposure to NMDA receptor blockade. This suggests that
mild-to-moderate brain injury may trigger elevated
endocannabinoid activity via concomitant increase of
anandamide levels, but not 2-AG, and CB1 receptor
density [29].
Panikashvili et al demonstrated that 2-AG has an important
neuroprotective role [30]. After closed head injury (CHI) in
mice, the level of endogenous 2-AG was significantly
elevated. After administering synthetic 2-AG to mice
following CHI they found a significant reduction of brain
edema, better clinical recovery, reduced infarct volume and
reduced hippocampal cell death compared with controls.
When 2-AG was administered together with additional
inactive 2-acyl-glycerols that are normally present in the
brain, functional recovery was significantly enhanced. The
beneficial effect of 2-AG was dose-dependently attenuated
by SR-141716A (Sanofi-Synthélabo), an antagonist of the
CB1 receptor [30]. Ferraro et al looked at the effects of the
cannabinoid receptor agonist Win-55212-2 (Sanofi Winthrop
Inc) on endogenous extracellular GABA levels in the
cerebral cortex of the awake rat using microdialysis [31].
Win-55212-2 was associated with a concentration-dependent
decrease in dialysate GABA levels. Win-55212-2-induced
inhibition was counteracted by the CB1 receptor antagonist
SR-141716A, which by itself was without effect on cortical
GABA levels. These findings suggest that cannabinoids
decrease cortical GABA levels in vivo [31].
Sinor has shown that AEA and 2-AG increase cell viability
in cerebral cortical neuron cultures subjected to 8 h of
hypoxia and glucose deprivation. This effect was observed
at nanomolar concentrations, was reproduced by a
non-hydrolyzable analog of anandamide, and was unaltered
by CB1 or CB2 receptor antagonists [32]. In the immune
system, low doses of cannabinoids may enhance cell
proliferation, whereas high doses of cannabinoids usually
induce growth arrest or apoptosis [27,33,34].
In addition, cannabinoids produce analgesia by modulating
rostral ventromedial medulla neuronal activity in a manner
similar to, but pharmacologically distinct from, that of
morphine. Cannabinoids have been shown to produce an
anti-inflammatory effect by inhibiting the production and
action of tumor necrosis factor (TNF) and other acute phase
cytokines. These areas are discussed in great detail in a
recent paper by Rice [35].

There is now accumulating in vitro evidence that glia
(astrocytes and microglia in particular) have cannabinoid
signaling systems. This provides further insight into the
understanding of the therapeutic effects of cannabinoid
compounds. Glial cells are the non-neuronal cells of the
CNS. In humans they outnumber neurons by a factor of
about 10:1. Because of their smaller average size they make
up about 50% of the cellular volume of the brain. Glial cells
of the CNS fall into three general categories: astrocytes,
oligodendrocytes and microglia. Schwann cells and the less
well-recognized enteric glia are their counterparts in the
peripheral nervous system. Glia are ubiquitous in the
nervous system and are critical in maintaining the
extracellular environment, supporting neurons, myelinating
axons and immune surveillance of the brain. Glia are
involved, actively or passively, in virtually all disorders or
insults involving the brain. This makes them logical targets
for therapeutic pharmacological interventions in the CNS.
Astrocytes are the most abundant cell type of the CNS. They
express CB1 receptors, and take up and degrade the
endogenous cannabinoid anandamide [36,37]. The
expression of CB2 receptors in this population appears to be
limited to gliomas and may be an indicator of tumor
malignancy [38]. Two recent studies suggest that some of the
anti-inflammatory effects of cannabinoids, such as the
inhibition of nitric oxide (NO) and TNF release are mediated
by CB1 receptors on astrocytes [39,40].
The most recent therapeutic role for cannabinoids in the
CNS evolved from the discovery that cannabinoids
selectively induce apoptosis in glioma cells in vitro and that
THC and other cannabinoids lead to a spectacular
regression of malignant gliomas in immune-compromised
rats in vivo [41,42]. The mechanism underlying this is not yet
clear but it appears to involve both CB1 and CB2 receptor
activation [42,43]. A recent study comparing the
antiproliferative effects of cannabinoids on C6 glioma cells
suggests the involvement of vanilloid receptors [44].
Microglia are the tissue macrophages of the brain. In
variance from other immune tissue but in accordance with
their place in the CNS microglia appear to lack CB2
receptors and have been shown to express CB1 receptors
on protein and RNA levels [45]. Similar to their effect on
peripheral macrophages, cannabinoids inhibit the release
of NO and the production of various inflammatory
cytokines in microglia [46-48]. Interestingly, the inhibition
of NO release seems to be CB1 receptor-mediated, whereas
the differential inhibition of cytokines is not mediated by
either CB1 or CB2 receptors, suggesting as yet unidentified
receptors or a receptor-independent mechanism.
Irrespective, the potential of cannabinoids to modulate the
immune response of microglia must be considered when
interpreting the effects of cannabinoids on inflammatory
processes such as a mouse model of MS or future
experiments on brain tumors in immunocompetent
animals [49].
Nothing is known of the effects of cannabinoids on
oligodendroglia. In the light of the clinical and
experimental evidence suggesting the beneficial effects of
cannabinoids in MS, investigations in this direction appear
promising [49,50].

A growing number of strategies for separating the
sought-after therapeutic effects of cannabinoid receptor
agonists from the unwanted consequences of CB1 receptor
activation are now emerging. However, further
improvements in the development of selective agonists and
antagonists for CB1 and CB2 receptors are needed. This
would allow for the refinement of cannabinoids with good
therapeutic potential and would facilitate the design of
effective therapeutic drugs from the cannabinoid family.
Customized delivery systems are also needed; as the
cannabinoids are volatile, they will vaporize at a
temperature much lower than actual combustion. Thus
heated air can be drawn through marijuana and the active
compounds will vaporize and can easily be inhaled.
Theoretically this removes most of the health hazards of
smoking, although this has not been well studied. Recently,
pharmacologically active, aerosolized forms of THC have
been developed [51]. This form of administration is achieved
via a small particle nebulizer that generates an aerosol
which penetrates deeply into the lungs.
From a regulatory perspective, the scientific process should
be allowed to evaluate the potential therapeutic effects of
cannabis, dissociated from the societal debate over the
potentially harmful effects of nonmedical marijuana use.
This class of compounds not only holds tremendous
therapeutic potential for neurological disease but is also
confirmed as having remarkably low toxicity [52-54].

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http://thefranklinscandal.blogspot.com/2010/08/august-13-15-2010-special-report-story.html

A LITTLE OVER A YEAR AGO, Ralph Nader, whose name when indiscreetly uttered aloud tends to induce apoplexy in the captains of commerce and industry, published a book with the astonishing title Only the Super-Rich Can Save Us!

A formidable tome of over 700 pages (we weep when we think of how many trees it took to supply the paper), it's a utopian fantasy, a 21st Century refrain of sorts of Edward Bellamy's Looking Backward. Just as the latter served to propagate Bellamy's societal take, Only the Super-Rich Can Save Us! provides a handy platform for Ralph's political notions.

The plot is a model of simplicity. Under the inspired direction of—who else?—Warren Buffett, 17 billionaires and mere millionaires (the latter, a lesser group consisting mostly of celebrities, were included, we guess, in the interests of economic and gender diversity), set out to right what's wrong with the U.S.A. and, like most fairy tales, this one ends on a happy note.

What made us think of Ralph's foray into fiction (his critics sneer that a lot of the things he writes fall into that category, but let's not be rude, please) was Warren Buffett's disclosure last week that 40 of what The Wall Street Journal nicely described as "mega-wealthy people" agreed to join Warren and Bill Gates Jr. in pledging to give away a healthy chunk of their wealth over the course of their lifetimes or as a bequest when they throw off this mortal coil. (Yes, Virginia, even mega-wealthy people pass on.)

A clear case of life imitating art. Hard times, in any case, do beget strange behavior, like Ralph Nader, the ultimate gadfly of the Establishment, proposing the mantle of the nation's savior be conferred on the super-rich. Or, the affluent beyond dreams of avarice seeking to burnish their tarred image by filling the coffers of charity (we gladly grant exemption from crass motives to Gates and Buffett, whose desire to share their wealth is not of recent vintage).

We strongly suspect that much of this idiosyncratic behavior is a response to what might be called the "riches rage" that suffuses the rising tide of populism throughout the country. Bankers and hedge-fund managers now rank somewhere below child molesters in the public's esteem. The only people in greater disfavor are incumbent politicians, and it doesn't much matter what their party label.

That being so prompts another example of a profoundly peculiar impulse: Why in the world are the Republicans drooling with excitement at the prospect of their taking control of the House and scoring big in the Senate come November? Don't they realize that, if indeed they do achieve anticipated gains and grab seats in significant numbers away from the bumbling Democrats, in its current dark mood the populace sure as shooting will turn its wrath on them in a blink?

Unless, of course, this sorry excuse for a recovery suddenly comes to life. Which simply isn't in the cards, as Friday's sorrowful report on what happened to jobs in July made crystal clear. For the second month in a row, employment remained essentially dead in the water.

As expected, with the exodus of the 143,000 temporary census employees, the Bureau of Labor Statistics reported a loss in jobs over all of 131,000. The private sector added 71,000 slots, quite a bit fewer than the 90,000-100,000 expected by the always-hopeful Street sages. The unemployment rate held at 9.5%, again mostly by virtue of a shrinkage in the workforce. But those bland figures fail to tell the whole sad story.

For openers, the June total was revised down by nearly 100,000. What that means is that, in fact, July saw a grand total of 4,000 non-census jobs added. Moreover, as the knowledgeable Dean Baker of the Center for Economic Policy and Research points out, a goodly portion of the 71,000 private-sector additions are less encouraging than a cursory glance would suggest.

Specifically, he cites the 36,000 hires in manufacturing. Most of this increase springs from a 20,500 gain in auto industry employment and a 9,100 rise of jobs in fabricated metals. The great bulk of these, he says, basically reflect the fact that the auto makers didn't shut down as they usually do in July to change models.

"The underlying rate of job growth in manufacturing," Dean asserts, " is very weak, even if at all positive."

As to the small uptick last month in average hours worked (all in the goods-producing sector), that merely nudged the number back to where it stood in May. And Dean insists there is "zero evidence to support the claim that firms were reluctant to hire because of uncertainty, since this would imply they were increasing hours," which they're decidedly not doing. He adds that nominal wages edged up at a paltry 1.4% annual rate, "also not a good sign."

And he concludes rather gloomily, "with the end of the inventory cycle, a huge wave of state and local cutbacks and further declines in house prices on the way, the situation looks bleak for the second half of 2010." You can say that again, Dean.

OUR FRIENDS PHILIPPA DUNNE and Doug Henwood at the Liscio Report are more forgiving (certainly than we are). So they view the July employment picture as indicating that "the job market isn't falling apart, but it is suffering from what the docs call a failure to thrive." We're sure that makes you feel a whole lot better.

Despite their innate generosity, though, they do point out a few less than salutary items as they comb their way through the report. One is that by the so-called household measure, employment fell by 159,000—or, when adjusted to match the payroll concept, by a not inconsiderable 315,000.

The dynamic duo also note that over the past year, the labor force has contracted by 791,000. And they ruefully comment, "In percentage terms, we haven't seen anything like this sort of contraction in the labor force since the early 1950s—but that was during the mobilization for the Korean War, when the total civilian population also shrank."

Now, of course, the civilian population is growing, not shrinking. And Philippa and Doug remind us that the labor force did not decline during the deep recessions of the mid-1970s and early 1980s. Obviously, we're dealing with a much different and more obdurate animal this time around.

The probability of someone on the dole finding a job last month fell to 21.5% (from 22.7% in June)—"not quite an all-time low, but not far from it."

The number of people unemployed 27 weeks or longer declined in July by 179,000, which, say the Liscio pair, "might be good news," but they caution it's quite possible those unfortunates just up and quit the labor force entirely.

They wind up their review of the July data with the not completely reassuring observation that "the job market is following the post-financial-crisis recession script all too well." And they warn, "If this continues, we can expect only very modest gains in employment in the coming months."

A possibility—we'd say probability—that leads them, good souls both, to fervently hope "that something gives soon, because at this rate, it will take nine years to make up the loss in private sector jobs." A dire prospect that they reasonably expect to cause mounting "pressures for more stimulative measures."

As it happens, we may not have long to wait to see if that stimulator par excellence, Ben Bernanke, is moved to add still further to the Fed's bloated holdings of mortgage-backed securities and kindred dubious assets, or perhaps old Ben will try some tricky new monetary maneuver. We may find out as soon as this Tuesday, when he and his jolly cohorts are slated to gather in solemn conclave. Keep tuned.

THE CONVICTION THAT THE TRULY depressing jobs report would light a fire under the Fed or Congress, or both, to do something to crank up the economy is what kept the stock market's reaction relatively muted after an initial gasp. Of course, Wall Street is so soaked in perennial optimism that it would take nothing short of the Apocalypse to douse its current euphoria, and maybe even that wouldn't do it.

And we have to concede, for well over a year now, the market has shrugged off the caveats thrown at it by worrywarts like us and gone its merry way, with only the most occasional pit stop. And even when the torrent of liquidity Uncle Sam has so vigorously been pouring into the financial system showed signs of running dry, investors have taken heart by assuring themselves there's always plenty more where that came from.

Besides, at 18 times trailing earnings, the conventional wisdom in the Street insists that valuations are not stretched, but quite the contrary, stocks are supposedly cheap.

And yes, no argument that the market has thumbed its nose at seemingly bad news. Yes, too, the powers that be are likely to bend yet again to the siren call of more stimulus. But this time, if we dare say, is different.

For one thing, stocks aren't down in the basement as they were back in March of 2009; the Dow is some 4,000 points higher. Nor, unless you've been lost in space the past year, can you expect anything resembling a rousing economic rebound. So far as stimulus goes, there are lots of reasons, political and geopolitical as well as financial, that suggest we may have already gone to that well once too often.

And as a wise man asked in this space a few weeks ago, where is it written that a market that in a not-too-distant past valued stocks at 60 times earnings can't value them, if the outlook sours, at six to eight times earnings?