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Tetrahydrocannabinol and Cannabidiol Related Arteriopathy, Genotoxicity and Teratogenesis

I am very concerned about the potential for increased cannabis availability in USA implied
by full drug legalization however a comprehensive and authoritative submission of the
evidence would take weeks and months to prepare. Knowing what we know now and indeed
what has been available in the scientific literature for a growing number of years concerning
a myriad of harmful effects of marijuana, marijuana should not be reclassified. These effects
that are now well documented in the scientific literature include, alarmingly, harm involving
reproductivity and birth anomalies as a result of exposure to or use of marijuana with THC.
In addition to all of the usual concerns which you will have heard from many sources
including the following I have further particular concerns:
1) Effect on developing brains
2) Effect on driving
3) Effect as a Gateway drug to other drug use including the opioid epidemic 1-4
4) Effect on developmental trajectory and failure to attain normal adult goals (stable
relationship, work, education)
5) Effect on IQ and IQ regression
6) Effect to increase numerous psychiatric and psychological disorders
7) Effect on respiratory system
8) Effect on reproductive system
9) Effect in relation to immunity and immunosuppression
10) Effect of now very concentrated forms of cannabis, THC and CBD which are widely
available
11) Outdated epidemiological studies which apply only to the era before cannabis became
so potent and so concentrated.
Cannabinoid Therapeutics
In my view the therapeutic effects of cannabinoids have been wildly inflated by the press.
Moreover with over 1,000 studies listed for cannabinoids on clinicaltrials.gov, the chance of a
type I experimental error, or studies being falsely reported to be positive when in fact they are
not, is at last 25/1,000 at the 0.05 level.
THC as dronabinol is actually a failed drug from USA which has such a high incidence of
side effects that it was rarely used as superior agents are readily available for virtually all of
its touted and alleged therapeutic applications.
In considering the alleged benefits of cannabis one has to be particularly mindful of cannabis
addiction in which cannabinoids will alleviate the effect of drug withdrawal as they do in any
other addiction. Moreover the fact that cannabis itself is known to cause both pain and
nausea, greatly complicates the interpretation of many studies.
I also have the following concerns which relate in sum to the arteriopathy and
vasculopathy and the genotoxicity of cannabis, tetrahydrocannabinol and LIKELY
INCLUDING CANNABIDIOL AND VARIOUS OTHER CANNABINOIDS:
Cannabinoid Arteriopathy
12) Cannabis is now known to have an important arteriopathic effect and cardiovascular
toxic effect 5-71. Particularly noteworthy amongst these various reports are two
reports by Dr Nora Volkow in 2014, the Director of the National Institute of Drug
Abuse at NIH to the New England Journal of Medicine which together document the
adverse cardiovascular and cerebrovascular effects of cannabis at the epidemiological
level 5,6; a report from our own clinic in 2016 documenting the effect of cannabis to
increase cardiovascular ageing to BMJ Open 71; a series of reports showing a fivefold
increase in the rate of heart attack within one hour after cannabis smoking 9-11; several
reports of cannabis related arteritis 50,51,56,58,59; other reports of the cerebrovascular
actions of cannabis 72-75; documentation that cannabis exposure increases arterial
stiffness and cardiovascular and organismal aging 71; and a recent report showing that
human endothelial vascular function – vasodilation – is substantially inhibited within
just one minute of cannabis exposure 76.
13) It is also relevant that a synthetic cannabinoid was recently shown to directly induce
both thromboxane synthase and lipoxygenase, and so be directly vasoconstrictive,
prothrombotic and proinflammatory 77.
14) Vascular aging, including both macrovascular and microvascular aging is a major
pathological feature not only because most adults in western nations die from
myocardial infarction or cerebrovascular accidents, but also because local blood flow
and microvascular function is a key determinant of stem cell niche activity in many
stem cell beds. This has given rise to the vascular theory of aging which has been
produced by some of the leading researchers at the National Health Lung and Blood
Institute at NIH, amongst many others 78-80. It can thus be said not only that “You are
as old as your (macrovascular) arteries”, but also that “you are as old as your
(microvascular) stem cells.” Hence the now compelling evidence for the little known
arteriopathic complications of cannabis and cannabinoids, carry very far reaching
implications indeed. This was confirmed directly in the clinical study of arterial
stiffness from my clinic mentioned above 7.
15) Whilst aging, myocardial infarction and cerebrovascular accidents are all highly
significant outcomes and major public health endpoints, these effects assume added
significance in the context of congenital anomalies. Some congenital defects, such as
gastroschisis, are thought to be due to a failure of vascular supply of part of the
anterior abdominal wall 81-86. Hence in one recent study the unadjusted odds ratio of
having a gastroschisis pregnancy amongst cannabis users (O.R.=8.03, 95%C.I. 5.63-
11.46) was almost as high as that for heroin, cocaine and amphetamine users (O.R.=
9.35, 95%C.I. 6.64-13.15), and the adjusted odds ratio for any illicit drug use (of
which was 84% cannabis) was O.R.=3.54 (95%C.I. 2.22-5.63) 87 and for cannabis
alone was said by these Canadian authors to be O.R.=3.0 88. Hence cannabis related
vasculopathy – arteriopathy beyond its very serious implications in adults also carries
implications for paediatric and congenital disorders and may also constitute a major
teratogenic mechanism.
Cannabinoid Genotoxicity and Teratogenesis
16) Cannabis is associated with 11 cancers (lung, throat, bladder, airways, testes, prostate,
cervix, larynx) including 89,90;
17) Four congenital and thus inherited cancers (rhabdomyosarcoma, neuroblastoma, ALL,
AML and AMML) 89,90;
18) Sativex product insert in many nations carries standard warning against its use by
males or females who might be having a baby 91;
19) Cannabis – and likely also CBD – is known to be associated with epigenetic changes 4
some of which are believed to be inheritable for at least four generations 92;
20) Cannabis is known to interfere with tubulin synthesis 93-97 and binding and it also acts
via Stathmin so that microtubule function is impeded 98. This leads directly to
micronucleus formation 99-101. Cannabis has been known to test positive in the
micronucleus assay for over fifty years 99,100,102. This is a major and standard test for
genotoxicity. Micronucleus formation is known to lead directly to major
chromosomal toxicity including chromosomal shattering – so-called chromothripsis
90,103-105.
21) Cannabis has also been linked definitively with congenital heart disease is a statement
by the American Heart Association and the American Academy of Pediatrics in 2007
106, on the basis of just three epidemiological studies, all done in the days before
cannabis became so concentrated. Congenital heart defects have also been linked
with the father’s cannabis use 107 . Indeed one study showed that paternal cannabis
use was the strongest risk factor of all for preventable congenital cardiac defects 108.
22) Cannabis has also been linked with gastroschisis in at least seven cohort and case
control studies 87,109-114 some of which are summarized in a Canadian Government
Report 88. In that report the geographic incidence of most major congenital anomalies
closely paralleled the use of cannabis as described in other major Canadian
reports. The overall adjusted odds ratio for cannabis induction of gastroschisis
quoted as 3.0 88.
23) Moreover outbreaks of both congenital heart disease 115 and gastroschisis in North
Carolina also paralleled the local use of cannabis in that state as described by
Department of Justice Reports 116. The incidence of gastroschisis was noted to double
in North Carolina 1999-2001 in the same period the cannabis trade there was rising
117. Figures of cannabis use in pregnant women in California by age were also
recently reported to JAMA 118, age group trend lines by age group which closely
approximate those reported by CDC for the age incidence of gastroschisis in the USA
119. Importantly much of the cannabis coming into both North Carolina and Florida is
said to originate in Mexico 116. An eight-fold rise in the rate of gastroschisis has been
reported from Mexico 120. Gastroschisis has also risen in Washington state 121.
24) Cannabis has also been associated with 17 other major congenital defects by major
Hawaiian epidemiological study reported by Forrester in 2007 when it was used alone
111. When considered in association with other drug use – which in many cases
cannabis leads to – cannabis use was associated with a further 19 major congenital
defects.
25) In addition to the effect of cannabinoids on the epigenome and microtubules,
cannabinoids have been firmly linked to a reduction of the ability of the cell to
produce energy from their mitochondria 122. An extensive and robust evidence base
123 now links cellular energy generation to the maintenance and care of cellular DNA
124-127. Moreover as the cellular energy charge falls so too DNA maintenance
collapses, and indeed the cell can spiral where its remaining energy resources,
particularly as NAD+, are routed into failing and futile DNA repair, the cell slips into
pseudohypoxic metabolism like the Warburg effect well known in cancerogenesis 128,
NAD+ falls below the level required for further energy generation and cellular
metabolism collapses. Hence this well established collapse of the mitochondrial
energy charge and transmembrane potential forms a potent engine of continuing and
accelerating genotoxicity 129.
26) All of which points to major teratogenic activity for both THC and CBD.
27) The genotoxicity of THC, CBD and CBN has been noted against sperm since at least
1999 (Zimmerman and Zimmerman in Nahas “Marijuana and Medicine” 1999,
Springer). This is clearly highly significant as sperm go directly into the formation of
the zygote and the new human individual.
28) CB1R receptors are known to exist intracellularly on both the membranes of
endoplasmic reticulum and mitochondria. In both locations they can induce
organellar stress and major cell toxicity including disruption of DNA maintenance.
Interestingly mitochondrial CB1R’s signal via a complex signalling chain involving
the G-protein transduction machinery, protein kinase A and cyclic-AMP. This
machinery is also implicated in mitonuclear signalling, and the mitonuclear DNA
balance between mitochondrial DNA and nuclear DNA transcriptional control, which
has long been implicated in cell aging, stem cell behaviour and DNA genotoxic
mechanisms 130,131.
29) You are no doubt aware that human sperm are structured like express outboard motors
behind DNA packets with layers of mitochondria densely coiled around the rotating
flagellum which powers their progress in the female reproductive tract (illustrated
below). These mitochondria also carry CB1R’s and are significantly inhibited even at
100 nanomolar THC. The acrosome reaction is also inhibited 132.
30) Cannabidiol is known to act via the PPARγ system 133-140. PPARγ is known to have a
major effect on gene expression, reproductive and embryonic and zygote function
during development 141-164 so that significant genotoxic and / or teratogenic effects
seem inevitable via this route.

 


31) CBD has also been noted to be a genotoxic in other studies 165-167.
Since cannabis is now more concentrated than formerly, this implies that another major
genotoxin, akin to THALIDOMIDE is about to be unleashed on the USA and the world
– which is clearly a very grave – and indeed entirely preventable – occurrence.
Dr Frances Kelsey of FDA is said to have the public servant based at FDA who saved
American from the thalidomide scandal which devastated so many other English speaking
nations including my own 168. This occurred because the genotoxicity section of the file
application with FDA was blank. It was blank because thalidomide tested positive in various
white rabbit and guinea pig assays. It is these same tests which cannabis is known to have
failed 169-172. Dr Kelsey’s photograph has been published in the medical press with President
Kennedy for her service to the nation 168. The challenge to FDA at this time seems whether
Science can triumph over agenda driven populism, and its primary vehicle, the mass media.
Since FDA is the Federal agency par excellence where Health Science is weighed,
commissioned and thoughtfully considered the challenge in our time would appear to be no
less.
Indeed even from the other side of the world I have heard many exceedingly adverse reports
from US states in which cannabis has been legalized including Colorado, Washington,
Oregon, Florida and California 121,173-176. Taken together the above evidence suggests that
these negative reports stem directly from the now known actions of cannabis and
cannabinoids, and are by no means incidental epiphenomena somehow related to social
constructs surrounding cannabis use or the product forms, dosages, or routes of
administration involved 177.
Dr Bertha Madras, Professor of Addiction Psychiatry at Harvard Medical School has recently
argued against re-scheduling of cannabis. Her comments include the following:
Why do nations schedule drugs? …… Nations schedule psychoactive drugs because
we revere this three-pound organ (of our brain) differently than any other part of our
body. It is the repository of our humanity. It is the place that enables us to write
poetry and to do theater, to conjure up calculus and send rockets to Pluto three
billion miles away, and to create I Phones and 3 D computer printing. And that is the
magnificence of the human brain. Drugs can influence (the brain) adversely. So, this
is not a war on drugs. This is a defense of our brains, the ultimate source of our
humanity 178.


I look forward to seeing the comments that you post concerning the reasons why the
classification for marijuana should not be changed and that, indeed, the public should be
alerted to the very harmful effects of marijuana with THC, especially in light of the wide
range of marijuana’s harmful effects and the high potency of THC in today’s marijuana and
in light of the idiosyncratic effects of marijuana of even low doses of THC and owing to the
certain risk of harm to progeny and babies born to users of marijuana.

Please feel free to call on me if you would like further information concerning the research to
which I have referred herein.
Thankyou so much,
Assoc. Prof. Dr. Stuart Reece,
University of Western Australia,
Edith Cowan University,
Perth,
Western Australia,
Australia.
P: +617 3844 4000.