While examining the pro-pot and cannabis-cons from the World Congress on Pain, a certain expert physician quipped that one of the biggest drawbacks to recommending cannabis was that it causes neurodegeneration with chronic use.
Well, where’s the evidence?
I’m not convinced that he’s right. I have seen plenty of research showing that the cannabinoids actually protect the brain from neurodegeneration.
Technically, you can’t have both so which is it? Do the noble nuggets cause your brain to atrophy or do they protect you?
Not only is this appropriate to understand when concerned with neurodegenerative diseases, but also the average cannabis smoker needs to know if a marijuana habit will cause problems later in life.
Let’s start off on page one with a definition of neurodegeneration.
….in the strict sense of the word, neurodegeneration corresponds to any pathological condition primarily affecting neurons. In practice, neurodegenerative diseases represent a large group of neurological disorders…; they arise for unknown reasons and progress in a relentless manner. Conversely, neoplasm, edema, hemorrhage, and trauma of the nervous system, which are not primary neuronal diseases, are not considered to be neurodegenerative disorders. Diseases of the nervous system that implicate not neurons per se but rather their attributes, such as the myelin sheath as seen in multiple sclerosis, are not neurodegenerative disorders either, nor are pathologies in which neurons die as the result of a known cause such as hypoxia, poison, metabolic defects, or infections.
Among the hundreds of different neurodegenerative disorders, so far the lion’s share of attention has been given only to a handful, including Alzheimer disease (AD), Parkinson disease (PD), Huntington disease (HD), and amyotrophic lateral sclerosis (ALS). Many of the less common or publicized neurodegenerative disorders, though no less devastating, have remained essentially ignored.[ref]J Clin Invest. 2003 Jan 1; 111(1): 3–10.[/ref]
Our growing understanding of the roles of the endogenous cannabinoids has suggested two main pathways by which cannabinoids may impact upon neurodegenerative processes; neuromodulation and immunomodulation.
Aside from this crucial regulatory role in the activity of neurons, endocannabinoids also play a key role in peripheral and brain immune function. As mentioned, CB2 is expressed on various circulating and resident immune cells, particularly when these cells are activated, and its agonism [stimulation] is typically associated with a dampening of their pro-inflammatory activities.[ref]Br J Pharmacol. 2010 Jun; 160(3): 480–498.[/ref]
DYSREGULATION OR ENDOCANNABINOIDS
Preliminary evidence suggests that regions of endocannabinoid hypofunction or dysregulation within the brain may be responsible for some of the symptomatology of a diverse group of neurodegenerative diseases including multiple sclerosis (yes, some authors list MS in the neurodegenerative category), Huntington’s (HD), Parkinson’s (PD) and Alzheimer’s (AD) diseases, and amyotrophic lateral sclerosis (ALS).
It’s also more than inquisitive that the abundance of CB1 receptors are bundled within singular areas of the brain responsible for executive thought and movement. Both of these regions are ground zero for degenerative movement disorders such as Huntington’s and Parkinson’s diseases.
This also provides a model for how cannabinoids may play a role in psychotic behavior. Psychosis is reputed to be due to overstimulation of dopamine pathways which are shared with CB receptors.
In HD, AD, and ALS we see upregulation (increase in the number) of CB2 receptors within the brain. This is a protective response which helps to mitigate the immune/inflammatory response that characterizes these diseases. Sadly, it is insufficient to prevent neuronal damage which may also be potentiated by the downregulation of CB1 receptors seen in HD and AD.
In MS, cannabinoids have shown great promise in animal models. Sativex®, an oromucosal spray composed of THC and CBD, has demonstrated efficacy in the treatment of spasm, neuropathic pain, and sleep disturbances seen in MS patients. It is approved by the FDA for this condition.
If the exciting findings of cannabinoid-mediated attenuation of inflammation, stimulation of remyelination [repair of certain neurons], and behavioural and symptomatic recovery translate from model systems to humans, cannabinoids may be promising therapeutics in MS.[ref]IBID[/ref]
In all of the disorders: ALS, MS, PD, and AD, it is uncertain if the alterations in endocannabinoids in these diverse diseases is a result of the cell destruction from the disease process itself. Or do the endocannabinoid changes cause the eventual development of these diseases?
In other words is the dysfunction of the endocannabinoid system in these ailments creating a condition ripe for neurodegeneration, or are these changes simply an artifact of extensive neuronal damage?
Whether integral to the disease, or a symptom of it, the studies described in this review highlight the potential role that endocannabinoids may play in either protecting cells from the disease process, or treating the symptoms of the disease.[ref]Br J Pharmacol. 2010 Jun; 160(3): 480–498.[/ref]
Parkinson’s disease: A slowly progressive neurologic disease that is characterized by a fixed inexpressive face, tremor at rest, slowing of voluntary movements, gait with short accelerating steps, peculiar posture and muscle weakness (caused by degeneration of an area of the brain called the basal ganglia), and low production of the neurotransmitter dopamine. Most patients are over 50, but at least 10 percent are under 40. Treatment involves use of medication, such as levodopa and carbidopa.
This disease occurs from the cumulative destruction of dopaminergic neurons in an area of the brain called the nigro-striatal pathway.
Here the neuromodulatory effects of the endocannabinoids exist in tandem with dopamine pathways where there exists reciprocal regulation between dopamine and endocannabinoids.
For example D1 and D2 receptors (dopamine receptors within the brain) exist with CB1 receptors, called co-localization, on these neurons.
This arrangement leads to very complex signaling within this special area of the brain. So we know that endocannabinoids play a vital role, which type of role is not presently known in any detail.
THE WAY IS UNCLEAR
It’s too early to tell whether marijuana will be helpful in treating Parkinson’s disease. In PD patients, the endocannabinoid changes are difficult to assess. Due to the numerous pharmaceuticals PD patients need to take, researchers are hamstrung in teasing out what brain effects are due to the drugs and which are due to the disease.
Furthermore, it’s uncertain what the effect of powerful centrally acting medications, the so-called antipsychotics, have on the brain’s endocannabinoids. Only one study (Pisani et al., 2005) has assessed cannabinoid levels (AEA) within the brain. They found them to be double that of controls.
Studies on the potential therapeutic utility of cannabinoid agonists and antagonists in PD have also produced conflicting results. Some animal studies have shown promise while others have not.
The same is true for human studies where nabilone, a cannabinoid agonist, significantly reduced movement disorders in a special class of PD patients (Sieradzan et al., 2001) while cannabis had no effect on a group of PD patients in another study (Carroll et al., 2004).
ALZHEIMER’S DISEASE (AD)
Scientists have pondered a role for the cannabinoids in the development of AD since one of the first changes to occur is the loss of memory in early stage AD. Likewise, the loss of short term memory is legion among cannabis smokers.
From Alzheimer’s Foundation of America:
– Alzheimer’s disease is a progressive, degenerative disorder that attacks the brain’s nerve cells, or neurons, resulting in loss of memory, thinking and language skills, and behavioral changes.
– These neurons, which produce the brain chemical, or neurotransmitter, acetylcholine, break connections with other nerve cells and ultimately die. For example, short-term memory fails when Alzheimer’s disease first destroys nerve cells in the hippocampus, and language skills and judgment decline when neurons die in the cerebral cortex.
– Two types of abnormal lesions clog the brains of individuals with Alzheimer’s disease: Beta-amyloid plaques—sticky clumps of protein fragments and cellular material that form outside and around neurons; and neurofibrillary tangles—insoluble twisted fibers composed largely of the protein tau that build up inside nerve cells. Although these structures are hallmarks of the disease, scientists are unclear whether they cause it or a byproduct of it.
– Alzheimer’s disease is the most common cause of dementia, or loss of intellectual function, among people aged 65 and older.
– Alzheimer’s disease is not a normal part of aging.
THE WELL-KNOWN EFFECTS OF ALZHEIMERS ON MEMORY MAY BE RELATED TO ENDOCANNABINOIDS
The disruptive effects of Δ9-THC on memory are well documented and have recently been more fully characterized at the molecular level (Puighermanal et al., 2009). Alzheimer’s disease (AD), a disease with major impact on memory systems, has therefore been investigated for evidence of dysfunction of the endocannabinoid system resulting from, or contributing to, disease pathophysiology. AD is the most common neurodegenerative disorder, with a prevalence of approximately 10% in humans over 80 years old (Ferri et al., 2005).[ref]Br J Pharmacol. 2010 Jun; 160(3): 480–498.[/ref]
The rate of AD in an 85-year-old American is 50%, and it’s increasing. It eclipses all other forms of dementia by a long shot.
The brain’s microglia are special immune cells. In AD patients, researchers have discovered that CB2 receptors are expressed on the microglia clustered around beta-amyloid plaques. These plaques are pathognomonic for the lesions that develop in AD. It therefore suggests that endocannabinoids may have the ability to modulate the effector cells of AD (Benito et al., 2003)
While CB2 receptors are upregulated on microglia, scientists have unexpectedly discovered that CB1 receptors are decreased or downregulated. This is an unusual and unexpected finding. Note also that CB2 receptors are infrequently found centrally (in the brain). They are clustered more in the immune system and peripheral nervous tissues.
CANNABINOIDS AS THERAPEUTIC AGENTS IN ALZHEIMERS
Groundbreaking work over the last two decades suggests that cannabinoid agonists may play a therapeutic role in the treatment of AD.
Synthetic Δ9-THC (dronabinol) has been shown to alleviate behavioural disturbances and weight loss, and night-time agitation symptoms in human studies of Alzheimer’s and severe dementia respectively (Volicer et al., 1997; Walther et al., 2006).[ref]IBID[/ref]
Scientists have speculated on a unifying hypothesis for AD. In its broadest application it applies to other forms of neurodegeneration too. It states that pathologic changes in endocannabinoid levels within the affected regions of brain tissue, and CB2 expression, are induced by the inflammatory effects of the disease. In this case we are referring to AD. Therefore AD comes first, the endocannabinoid changes occur in response to the disease.
It’s a gallant attempt to heal dysfunctional brain cells. By increasing the quantity of CB2 receptors on the affected neurons the brain is partially able to decrease microglial activation. This activation, although well intended, is a powerful immune/inflammatory response which is responsible for much of the cellular damage seen in AD. It can be very destructive. AIDS related dementia is due to the same mechanism.
However, it’s too little too late. The upregulation of CB2 is insufficient to arrest the inflammatory damage to the neurons. The unexplained downregulation of CB1 receptors may potentiate this effect.
It appears then that the system suffers from a relative deficiency of endocannabinoids. The proof is that cannabinoid agonists help this situation by providing much needed stimulation of CB2 (and CB1) receptors.
On the basis of the pre-clinical efficacy already demonstrated, cannabinoid stimulators may have therapeutic benefit by augmenting the brain’s innate response.
Cannabinoid agonists in human trials to date have been well tolerated and safe, but clearly psychoactivity following CB1 activation is often an unacceptable consequence, particularly for long-term drug treatment; it is hoped that modulation of endocannabinoid levels may provide a more suitable alternative.[ref]IBID[/ref]
Although I agree in principle with the author’s last statement it should be noted that with chronic use the psychoactive effects of THC diminish over time. I don’t think the central effects of THC are as detrimental as many authors seem to suggest.
Let’s face it, some patients might even enjoy it.