Another article from Using Medical Cannabis - this one looking at the promise of manipulating the cannabinoid system to produce better results in concussion, stoke and degenerative neurological disorders.

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THE NATIONAL FOOTBALL LEAGUE HAS BEEN STRUCK A HEAVY BLOW WITH RECENT CONCERNS over
concussions and chronic traumatic encephalopathy (CTE). In parallel to this, league officials have
come under increased scrutiny over their drug policy for players, which effectively encourages
the use of alcohol and opiates over cannabis. These two issues have come together with
increasing evidence that cannabinoids can play a protective role in traumatic head injury.
Interest in the endocannabinoid system as part of head injury care has been long-standing.
This is founded on multiple threads of investigation that come together to make a compelling
case. At each level of investigation, the results have been in a consistent direction and following
ENDOCANNABINOIDS AND
NEUROPROTECTION
Ian Mitchell, MD
EndocannabinoidsandNeuroprotection/IanMitchell,MD
Ian Mitchell is an emergency physician practising in
Kamloops, British Columbia. His area of interest is
reducing opiate deaths with the use of take-home
Naloxone and the substitution of opiates with cannabis
for chronic pain. He is a qualified investigator for an RCT
of cannabis for PTSD and is also involved with research
as the site scholar for the Kamloops Family Medicine
program. He blogs less often than he should at
www.clinicalcannabisincontext.tumblr.com.

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a similar pattern to other neurodegenerative diseases
such as Alzheimer’s and Parkinson’s.
In traumatic brain injury (and also in stroke), the death
of brain cells leads to the release of a complex cascade of
neurotoxic chemicals including calcium and glutamate.
Research in the past has focused on reducing harms
from these, as is the use of calcium channel blockers in
stroke. This research was promising based on etiology,
but failed to make a difference in clinical practice.
The literature around cannabinoids is extensive, but a
good place to begin is with a review of An endogenous
cannabinoid (2-AG) is neuroprotective after brain injury
fromanIsraeliresearchgroupincludingRaphael Mechoulam
and Esther Shohami.This group’s initial research involved
liposaccharide (LPS) models of brain injury and two
contributors to brain inflammation, tumor necrosis factor
(TNF) and reactive oxygen species (ROS). They had
previously reported on lipopolysaccharide models of
brain injury showing decreased release of ROS and TNF
from mouse macrophages after exposure to LPS and lower
levels ofTNF in the serum of LPS treated mice.3
In their paper published in Nature the authors describe a
further series of experiments linking endocannabinoids
to neuroprotection.4
1. Head trauma was associated with an increase of 2-AG
in the serum of mice, which peaks at around 4 hours
2. Intravenous administration of exogenous 2-AG was
associated with decreased brain edema. This effect
was blocked by prior administration of a specific
antagonist of the CB1 receptor
EndocannabinoidsandNeuroprotection/IanMitchell,MD
3. There was decreased cell death after head trauma in
those mice pretreated with 2-AG, both in total brain
volume and in the hippocampus
4. The administration of 2-AG was associated with
decreased motor deficits after head injury, especially
when given within 24 hours
5. Lastly (from a previous study by the same group), 2-AG
opposes the effects of endothelin-1, a potent vasocon-
strictor that is involved in reducing cerebral blood flow
Certainly, there is little question that endocannabinoids are
involved with neuroprotection; however the more relevant
question is what effect does supranormal stimulation of the
endocannabinoid system have in head injury, particularly
from THC and CBD? Much of the literature in this area is
directed at stroke research, leaving us to infer effects of the
phytocannabinoids on head injury.
Cannabidiol has piqued more interest as a neuroprotectant
and is much easier to access for research. Mori et al.
recently made the case that Cannabidiol reduces neuroin-
flammation and promotes neuroplasticity.
Using an ischemic injury model of brain injury in mice,
this group demonstrated decreased damage in those
mice treated with cannabidiol.The specific findings were:
1. Protection from cognitive deficits and emotional
dysfunction
2. Decreased degeneration of brain cells in the
hippocampus and white matter
3. Decreased neuroinflammation in the hippocampus
3
Panikashvili et al., “An Endogenous Cannabinoid (2-AG) Is Neuroprotective after Brain Injury.”
4
Ibid.
5
Mori et al., “Cannabidiol Reduces Neuroinflammation and Promotes Neuroplasticity and Functional Recovery after Brain Ischemia.”
6
Fishbein et al., “Long-Term Behavioral and Biochemical Effects of an Ultra-Low Dose of Δ9-Tetrahydrocannabinol (THC).”
“CANNABIDIOLISRELATIVELYINNOCUOUSANDIFIWASMAKING
SEVERAL MILLION US DOLLARS A SEASON ENGAGED IN
REPETITIVEHEADTRAUMA,IWOULDWANTTODOEVERYTHING
ICOULDTOPROTECTMYBRAIN”

3. 134. Increased levels of brain-derived neurotrophic
factor, important in neuroplasticity and recovery of
brain function2
In contrast, the literature on THC as a neuroprotectant
is sparse. There are older studies showing general
neuroprotection, however recent trends in research
have focused on studies using very low doses of THC.
These low doses are held to be neurotoxic in themselves,
but thought to act as protection for further neurological
insults. The most recent study in this vein is from 2012
and is entitled Long-term behavioral and biochemical
effects of an ultra-low dose of D9-tetrahydrocannabinol
(THC): neuroprotection and ERK signaling.
Whatever the mechanism, the researchers showed
that this low dose of THC could protect against the
cognitive dysfunction induced in mice who were subject
to treatment with pentylenetetrazole, phenobarbital
anaesthesia, carbon monoxide, and repeated exposure
to MDMA. These effects were found when the THC
was delivered either 1-7 days before the neurological
insult or 1-3 days after.1
Moving into humans, there is only one clinical study
that has examined the link between cannabis use
and traumatic head injury. Effect of Marijuana Use on
Outcomes in Traumatic Brain Injury looked at trauma
registry data on head-injured patients who had a positive
urine test for THC and compared them with those who
tested negative for THC. The most startling result was
an almost five-fold decrease in mortality, from 11.5% in
those who were THC negative to 2.4% in those who
were THC positive.3
The two cohorts were not exactly identical. The THC-
positive cohort had a population that was significantly
younger and were also more likely to be intoxicated or
black.To help control for this disparity, the investigators
used logistic regression to look for variables that would
predict survival from head trauma. As expected, both
older age and head injury severity lead to increased
mortality. The most startling result was a marked
decrease in mortality, from 11.5% in those who were
THC negative to 2.4% in thoseTHC positive, independent
of age, alcohol and other variables.
EndocannabinoidsandNeuroprotection/IanMitchell,MD
This report can only be viewed as tentative and tempting;
causality cannot be assumed from a retrospective
study-only association. However, this follows the narrative
of the preclinical evidence so far and should be compelling
enough to prompt prospective human trials for THC
and CBD as neuroprotectants on the field and in the
hospital. While none of this evidence is enough to justify
a recommendation for treatment, cannabidiol is relatively
innocuous and if I were making several million US dollars
a season engaged in repetitive head trauma, I would want
to do everything I could to protect my brain.
As far as the NFL is concerned, calls for reform have so far
fallen on deaf ears, as cynics point to competing interests
from alcohol companies. Despite the weight of their
sponsors, the NFL must get rid of their complete ban on
THC and focus on misuse. Moving forward, cannabinoids
should be part of the NFL’s concussion-research funding, on
top of encouraging the substitution of cannabis for opiates
for pain relief.
REFERENCES
1. Fishbein, Miriam, Sahar Gov, Fadi Assaf, Mikhal Gafni, Ora Keren, and
Yosef Sarne. “Long-Term Behavioral and Biochemical Effects of an Ultra-
Low Dose of Δ9-Tetrahydrocannabinol (THC): Neuroprotection and ERK
Signaling.” Experimental Brain Research 221, no. 4 (September 2012):
437–48. doi:10.1007/s00221-012-3186-5.
2. Mori, Marco Aurélio, Erika Meyer, Ligia Mendes Soares, Humberto
Milani, Francisco Silveira Guimarães, and Rúbia Maria Weffort de Oliveira.
“Cannabidiol Reduces Neuroinflammation and Promotes Neuroplasticity
and Functional Recovery after Brain Ischemia.” Progress in Neuro-
Psychopharmacology & Biological Psychiatry 75 (April 3, 2017): 94–105.
doi:10.1016/j.pnpbp.2016.11.005.
3. Nguyen, Brian M., Dennis Kim, Scott Bricker, Fred Bongard, Angela Neville,
Brant Putnam, Jennifer Smith, and David Plurad. “Effect of Marijuana Use
on Outcomes in Traumatic Brain Injury.” The American Surgeon 80, no. 10
(October 2014): 979–83.
4. Panikashvili, D., C. Simeonidou, S. Ben-Shabat, L. Hanus, A. Breuer, R.
Mechoulam, and E. Shohami. “An Endogenous Cannabinoid (2-AG) Is
Neuroprotective after Brain Injury.” Nature 413, no. 6855 (October 4, 2001):
527–31. doi:10.1038/35097089.
7
Nguyen et al., “Effect of Marijuana Use on Outcomes inTraumatic Brain Injury.”