Monday, July 15, 2013

Everybody Must Get Stoned?

This is a startling result and I have to wonder why it isn't being more widely publicised:

In the present study, we observed smaller brain weights and volumes in male macaque monkeys after 1.5–2.3 years of exposure to marijuana at plasma drug levels comparable to those in treated humans. Exposure to marijuana was associated with a similar reduction in mean fresh brain weight, as well as mean fresh weight and volume of the left cerebrum, compared to matched, placebo-exposed animals. For both drugs, the magnitude of these effects was in the range of 8–11%. The reduction seemed to be global (ie including all brain regions), but was most robust in the frontal and parietal lobes. In addition, both gray and white matter volumes appeared to be reduced to a similar degree.

I've read the above study, they used multiple analyses to derive their conclusions and carefully controlled for many factors except one: they did not blind the raters of those taking the cerebral volume measurements. After so much good work they did not do that. What a shame.

But the above study nothing to do with marijuana, it concerns a study of haloperidol and olanzapine, the first being a typical antipsychotic and the latter being an atypical antipsychotic. I simply replaced those drug names with the word marijuana.
The Influence of Chronic Exposure to Antipsychotic Medications on Brain Size before and after Tissue Fixation: A Comparison of Haloperidol and Olanzapine in Macaque Monkeys
Neuropsychopharmacology (2005) 30, 1649–1661. doi:10.1038/sj.npp.1300710; published online 9 March 2005
If it was a study that found results like that for marijuana we'd never hear the end of it. We won't even hear about this study because:

1. The last thing the psychiatric community wants to broadcast is that they drugs they provide may be inducing brain shrinkage. The lack of blinding is a serious problem and there are other quibbles I have with this study but the results as revealed, together with a range of other studies on antipsychotics, especially the first generation antipsychotics, raise some troubling questions about the ever increasing off label use of anti-psychotics. Anti-psychotic drugs have redeemed many lives but how about some honesty?

2. Media outlets will be loathe to report these results lest Big Pharma comes hunting after them with a huge pack of barristers and a fat wallet.

3. No-one will take you to court for making unwarranted claims about the dangers of marijuana.


A News Release on Cannabinoids and Neuroprotection

There are now hundreds of studies pointing out that both exogenous and endogenous cannabinoids are neuroprotective across a range of insults and may provide considerable protection against age associated cognitive decline; especially in relation to dementias.

In a previous post I demonstrated how a news report on a recent cannabis study completed mis-interpreted the results and went for an alarmist position. Today I read a news reports which uses a published article in a highly respected journal to claim this proves marijuana is neuroprotective but wait there's more ...
 Cannabinoids may very well be the best cancer fighting substance out there!
The paper they rely on is:

The endocannabinoid system in normal and pathological brain ageing
  1. Andras Bilkei-Gorzo*
The role of endocannabinoids as inhibitory retrograde transmitters is now widely known and intensively studied. However, endocannabinoids also influence neuronal activity by exerting neuroprotective effects and regulating glial responses. This review centres around this less-studied area, focusing on the cellular and molecular mechanisms underlying the protective effect of the cannabinoid system in brain ageing. The progression of ageing is largely determined by the balance between detrimental, pro-ageing, largely stochastic processes, and the activity of the homeostatic defence system. Experimental evidence suggests that the cannabinoid system is part of the latter system. Cannabinoids as regulators of mitochondrial activity, as anti-oxidants and as modulators of clearance processes protect neurons on the molecular level. On the cellular level, the cannabinoid system regulates the expression of brain-derived neurotrophic factor and neurogenesis. Neuroinflammatory processes contributing to the progression of normal brain ageing and to the pathogenesis of neurodegenerative diseases are suppressed by cannabinoids, suggesting that they may also influence the ageing process on the system level. In good agreement with the hypothesized beneficial role of cannabinoid system activity against brain ageing, it was shown that animals lacking CB1 receptors show early onset of learning deficits associated with age-related histological and molecular changes. In preclinical models of neurodegenerative disorders, cannabinoids show beneficial effects, but the clinical evidence regarding their efficacy as therapeutic tools is either inconclusive or still missing.
Phil. Trans. R. Soc. Bvol. 367no. 1607 3326-3341

The news report has the title: New Study Shows Cannabinoids Improve Efficiency Of Mitochondria And Remove Damaged Brain Cells. Whoever wrote this article must have been on long term antipsychotic treatment because the news report is littered with so many errors it certainly can't be because of marijuana use. So to engage in some exegesis:

These discoveries shed new insight on how natural marijuana cannabinoids hold the capacity to literally kill the brain inflammation responsible for causing cognitive decline, neural failure, and brain degeneration.
The study concerns the endogenous cannabinoids, those chemicals our bodies make, especially anandamide and 2-AG. That these are neuroprotective does not mean the exogenous cannabinoids are also neuroprotective, though other studies do point to those effects being possible. Note the insertion of the word "natural" in the quoted text. It's a plant, it's natural. Der ... . Rhetorical trickery because some people reflexly assume natural=good. The problem is that because chronic marijuana consumption has widespread effects on the CNS any protective possible protective benefit may be lost due to the general disruption of the CNS and the decline in intellectual and physical activity that so often happens with chronic marijuana consumption.

The research clearly does point in the direction of cannabinoids offering neuroprotective potential but that is not sufficient. If cannabis is neuroprotective we should see some studies indicating that it is preserving cognition with age or increasing iq in younger users. As it turns out there is a study which can be interpreted in such way:
Results: Current marijuana use was significantly correlated (p < 0.05) in a dose- related fashion with a decline in IQ over the ages studied. The comparison of the IQ difference scores showed an average decrease of 4.1 points in current heavy users (p< 0.05) compared to gains in IQ points for light current users (5.8), former users (3.5) and non-users (2.6).
Even the non-users had a slight bump in IQ so eliminate that from the gains in light current users and former users and the iq differences are slight. The loss of iq in heavy users(5 joints a week) is entirely consistent with a wide range of studies showing various cognitive deficits from heavy marijuana use. These studies also demonstrate that sustained abstinence(at least 3 months) results in significant and often total reversal of these deficits.

The loss of iq in heavy smokers also suffers from a big problem in that the ages studied is from 17-20 years and hence is they lost 5.8 pts on iq in that small time frame by the the time they are 30 they should be raving idiots. So the decline in iq is not about neurologic damage but changes to the cerebral dynamics and these changes are basically a one off because if ongoing we should witness that iq decline in larger studies.

I cannot find any data to support the idea that regular cannabis consumption will protect the aging brain. In recent years a number of studies have at least pointed in that direction. But the problem is that chronic cannabis consumption induces some wide scale changes in brain function that can persist even when not stoned. Thus ....
No differences in behavioral performance or magnitude of task-related brain activations were evident between the groups. However, greater connectivity between the prefrontal cortex and the occipitoparietal cortex was evident in cannabis users, as compared with controls, as cognitive control demands increased. The magnitude of this connectivity was positively associated with age of onset and lifetime exposure to cannabis. These findings suggest that brain regions responsible for coordinating behavioral control have an increased influence on the direction and switching of attention in cannabis users, and that these changes may have a compensatory role in mitigating cannabis-related impairments in cognitive control or perceptual processes.
Full article available here. 

The above study was over 10 years and may reflect the fact that many chronic marijuana users are highly functional individuals with preserved cognition(within limits) who are indistinguishable from their non-smoking peers. So take it as a given that at various points in your working and social life you have been associating with heavy marijuana smokers who were stoned at the time and there was never any evidence to arouse your suspicion to the same, with the possible exception they liked to listen to music and laughed a lot. Again though we do not see any evidence that chronic marijuana consumption was preserving cognition let alone improving it, at least in your average individual ... .

The body regenerates best when it’s saturated with Phyto-Cannabinoids.
So when sick everyone must get stoned? The above sentence is outright propaganda. It is a ridiculous, dangerous, and stupid assertion. 

Cannabinoid system activity is neuroprotective, and increasing it could be a promising strategy for slowing down the progression of brain aging and for alleviating the systems of neurodegenerative disorders -Andras Biokei
The quote offers no support for increasing cannabinoid activity by using marijuana. The author of the study knows better than that. For example, it is well established that chronic marijuana use reduces the number of CB1 receptors. I suspect the same happens with CB2 receptors because receptor number dynamics can be highly fluid. That is another example of the multitude of mysteries that pervade cellular neuroscience. It's difficult!

We do not have any substantive evidence that chronic marijuana use damages brains nor do we have any evidence to suggest it preserves brains. If I was forced to make a decision on the basis on the available evidence I would argue that chronic marijuana use will confer no benefit but occasional marijuana use, once or twice a week, may provide some benefit. Here's why:

  • Chronic marijuana use down-regulates receptors thereby limiting if not eliminating any cognitive preservation value in chronic marijuana use.
  • The two principal cannabinoids, THC and CBD, have demonstrated antioxidant potential in excess of vitamins C and E.
  • The cannabinoids are fat soluble and our brains are 60% fat dry weight, so the cannabinoids will remain present in our CNS and other tissues for an extended period. As fat cells often express an inflammatory mediator, TNFa, there is the suggestion that cannabinoids, via the CB2 receptor, may be modulating systemic inflammation. 
  • Because CB1 activity helps prevent calcium influx into neurons it may provide some protection as excessive calcium influx in damaging to neurons.
  • Occasional use will not induce a reduction in CB1 receptors. 

The problem with occasional use is the adjustment period after cessation. Additionally, as indicated in my previous post, it was not the consumption of marijauna that induced inflammatory markers but rather the cessation of marijuana use which, 5 days later, led to the increase in those markers. Note however that the induction of inflammatory mediators does not equal inflammation and as noted in that study there was no evidence of cytotoxicity.

To use it once or twice a week is to leave your CNS in an "unsettled" state, hence there is a loss of stability which while perhaps not reflecting on cognition it probably does help maintain emotional stability. It may also confuse your neighbours and friends because you have days playing lots of music and frequently laughing to be followed the next day by your seeming somewhat slowed down and emotionally flat.


Again invoking the Authority Fallacy to drive home the argument the author of the news article then quotes
I’ve been trying to find a drug that will reduce brain inflammation and restore cognitive function in rats for over 25 years; cannabinoids are the first and only class of drugs that have ever been effective. I think that the perception about this drug is changing and in the future people will be less fearful. – Gerry Wenk, Professor of neuroscience, immunology and medical genetics at Ohio State University
With due respect to the good professor I regard that as a sweeping statement because there are many studies on many compounds which demonstrate neuroprotective effects. If the poor lab rats improved with marijuana it might be because for the first time in their miserable lives they actually felt happy. Do not under estimate the importance of happiness in contributing to our physical and psychological health. Laugh often, laugh loud.

Biokei-Gorzo and his collegues said that the greatest hurdle for moving forward with their research are the social and political challenges.
That is true. The rest of the news article, while not saying so pointedly, goes on to suggest that concerning the dangers of marijuana we are being conned by the authorities. I accept that and have known for 20 years now that most of the purported risks of marijuana consumption belong in the propaganda basket. For example many people still believe that smoking marijuana must be causing lung and respiratory tract cancers. Read the research, there isn't even a compelling association let alone a statistically based argument. It should increase the risk but I suspect the nil results reflect the anti-inflammatory and anti-carcinogenic properties of cannabinoids cancel out the risks of inhaling burnt plant products.

Marijuana and Schizophrenia - Again!
If we choose to look at ALL the data on this subject the most parsimonious conclusion is:

We conclude that there is insufficient knowledge to determine the level of risk associated with cannabis use in relation to psychotic symptoms and that more information is needed on both the risks of cannabis use and the benefits of preventive interventions to support evidence-based approaches in this area.
An overview of systematic reviews on cannabis and psychosis: discussing apparently conflicting results. 2010 May;29(3):304-17.
I'm not going to address the "marijuana causes psychosis" subject because whilst the literature consistently demonstrates a "marijuana precipitates earlier onset psychosis in vulnerable individuals" the media presentation is absolute and unequivocal that "marijuana causes psychosis". I'll trust the literature and leave the politics to those so inclined. However there is a very strange paradox in relation to marijuana and schizophrenia.

One of the strangest findings in relation to cannabis and schizophrenia is that the premorbid iq of cannabis smokers who develop schizophrenia is above average. The finding of generally higher premorbid iq is consistent with other studies demonstrating that the higher the intelligence, the more inclined the person is to experiment with being a psychonaut.  There is also a statistical association between psychosis and creative intellects. Numerous studies highlight how schizophrenics who smoke cannabis demonstrate greater cognitive preservation. However they also tend to have more severe psychosis.

On the other hand there have been a number of studies that show how marijuana can actually reduce brain power and impair working memory. The amount of studies that show the potential benefits of marijuana is outstanding, and the potential harmful effects are in the few, if any at all.
There is a huge number of studies consistently pointing towards poor academic performance in chronic marijuana users. On the other hand, judicious use of psychonaut drugs can also enhance creativity. Thus:

Ecstasy users did not differ from controls on the behavioral measures of creativity, although there was a borderline trend for self-assessment of greater creativity. Cannabis users produced significantly more "rare-creative" responses, but did not rate themselves as more creative.
Jones KA, Blagrove M, Parrott AC, Cannabis and Ecstasy/ MDMA: empirical measures of creativity in recreational users., J Psychoactive Drugs. 2009 Dec;41(4):323-9.
 And ...
Cannabis increased state psychosis-like symptoms in both groups and the high creativity group were significantly higher in trait schizotypy, but this does not appear to be linked to the verbal fluency change. Acute cannabis use increases divergent thinking as indexed by verbal fluency in low creatives.
Schafer G, Fielding A, Morgan CJ, Agathangelou M, Freeman TP, Valerie Curran H., Investigating the interaction between schizotypy, divergent thinking and cannabis use.Conscious Cogn. 2012 Mar;21(1):292-8. doi: 10.1016/j.concog.2011.11.009. Epub 2012 Jan 9.

Obviously there are harmful effects. The loss of motivation, a recent study suggesting chronic use lowers dopamine tone, couch potato syndrome, working memory dysfunction. Don't get too carried away by the creativity issue, for 99.5% of people creativity is not required at work and can get you into trouble. The creativity benefits probably only produce useful creativity for individuals who have been working long and hard on particular problems, the change in thinking induced by cannabis and other psychoactive drugs can help. Nonetheless smoking marijuana is fun and that has to be considered a huge plus in this all too often dreary world.

Should We All Get Stoned?

I can think of many people I wish would get stoned, it might disavow them of all the nonsense the media and politicians push about being high and how dangerous it is. The hypocrisy of so many people on this issue is quite astounding because there is now unequivocal evidence that some sports are inducing brain damage and these same people often enjoy and celebrate brain damaging games like Grid Iron and Rugby League. The simple truth is that sport constitutes a far greater risk to our cerebral health than marijuana.

The prohibition against marijuana is ridiculous, it is driven by moralising politicians who know there are votes in prohibition and don't give a damn about empirical evidence. In my country Australia alcohol is the big drug problem, it causes more deaths and grief than all other drugs combined. If we legalised marijuana tomorrow it would not lead to a big increase in marijuana consumption, it may even reduce alcohol related violence because when stoned and drunk you just can't be bothered to be violent. You're too happy to be violent.

There needs to be much more research into the neuroprotective effects of cannabinoids for the treatment of neurodegenerative conditions. A recent study found that very low dose THC, well below where it becomes psychoactive, is neuroprotective. That has been in the literature for a decade but only now is becoming important because there is a desperate need to find agents which can prevent neurodegeneration. There are other potentially very important benefits:

  • Asthmatics appear to benefit from marijuana, possibly because it impedes inflammatory mediators. 
  • A Nature Medicine study found that very low doses of oral THC significantly impeded the development of atherosclerosis in the rabbit atherosclerosis prone species. 
  • Cannabinoids demonstrate remarkable efficacy across a range of cancers. 
  • Cannabinoids are very useful for neuropathic pain and given that that USA now has an epidemic or prescription related opioid deaths it seems a policy change might save many lives.
  • Cannabinoids, especially cannabidol, could be very useful in the treatment of autoimmune conditions. 
  • The world needs much more Happy Happy Joy Joy and cannabis helps. 

If you wish to be a hard working productive person, especially in the intellectual sphere, be very prudent in your use of marijuana. If you don't give a damn about smarts and work to live rather than live to work marijuana is a much safer choice than alcohol. If you are one of those hyper productive types then marijuana probably won't make you happy because it will slow you down. It's your choice, or rather it should be your choice.

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