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Department of Health and Human Services, Food and Drug Administration

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 containing THC should not be reclassified. These
effects that are now well documented in the scientific literature include, alarmingly, harm
involving reproductive function 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 1-15
2) Effect on driving 16-26
3) Effect as a Gateway drug to other drug use including the opioid epidemic 27-30
4) Effect on developmental trajectory and failure to attain normal adult goals(stable
relationship, work, education) 17,31-43
5) Effect on IQ and IQ regression 13,44-48
6) Effect to increase numerous psychiatric and psychological disorders 49-62
7) Effect on respiratory system 63-85
8) Effect on reproductive system 7,86-91
9) Effect in relation to immunity and immunosuppression 92-108
10) Effect of now very concentrated forms of cannabis, THC and CBD which are widely
available 109,110
11) Outdated epidemiological studies which apply only to the era before cannabis became
so potent and so concentrated 110.
The University of Western Australia
M000, Perth WA 6009 Australia
T +61 7 3844-4000. E stuart.reece@uwa.edu.au
F +61 7 3844-4015 E stuart.reece@bigpond.com
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These issues are all well covered by a rich recent literature including reviews from such major
international authorities as Dr Nora Volkow Director of NIDA at NIH 1,3,5,110-112, Professor
Wayne Hall 113-117 and others 118.
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. My American liaisons advise that dronabinol
sales have climbed in recent times as patients use it as a ruse to avoid detection of
cannabinoid use at work in states where it is not yet legal. So when I call is a failed
therapeutic I mean in a traditional sense, not in the novel way it is now applied for flagrantly
flouting the law.
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 5,110,119-183. 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 5,110; a report from our own clinic in 2016 documenting the effect of cannabis to
increase cardiovascular aging to BMJ Open 183; a series of reports showing a fivefold
increase in the rate of heart attack within one hour after cannabis smoking 121-123;
several reports of cannabis related arteritis 162,163,168,170,171; other reports of the
cerebrovascular actions of cannabis 184-187; documentation that cannabis exposure
increases arterial stiffness and cardiovascular and organismal aging 183; and a recent
report showing that human endothelial vascular function – vasodilation – is
substantially inhibited within just one minute of cannabis exposure 188.
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 189.

14) Vascular aging, including both macrovascular and microvascular aging is a major
pathological feature not only because most adults in western nations die from
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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 190-192. 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 119.

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 193-198. 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) 199 and for cannabis alone was said by
these Canadian authors to be O.R.=3.0 200. 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 201,202;
17) Four congenital and thus inherited cancers (rhabdomyosarcoma, neuroblastoma,ALL,
AML and AMML) 201,202;
18) Sativex product insert in many nations carries standard warning against its use by
males or females who might be having a baby 203.
19) Cannabis – and likely also CBD – is known to be associated with epigenetic changes
30 some of which are believed to be inheritable for at least four generations 204;
20) Cannabis is known to interfere with tubulin synthesis 205-209 and binding and it also
acts via Stathmin so that microtubule function is impeded 210. This leads directly to
micronucleus formation 113,211,212. Cannabis has been known to test positive in the
micronucleus assay for over fifty years 113,117,211. 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 –
and is known to be associated with cell death, cancerogenesis and major foetal
abnormalities 202,213-215.
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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
216, 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 217 . Indeed, one study showed that paternal cannabis use was
the strongest risk factor of all for preventable congenital cardiac defects 218.
22) Cannabis has also been linked with gastroschisis in at least seven cohort and case
control studies 199,219-224 some of which are summarized in a Canadian Government
Report 200. In that report the geographic incidence of most major congenital anomalies
closely paralleled the use of cannabis as described in other major Canadian reports
225. The overall adjusted odds ratio for cannabis induction of gastroschisis was
quoted by these authors as 3.0 200.
23) Moreover, outbreaks of both congenital heart disease 226 and gastroschisis in North
Carolina also paralleled the local use of cannabis in that state as described by
Department of Justice Reports 227. The incidence of gastroschisis was noted to double
in North Carolina 1999-2001 in the same period the cannabis trade there was rising
228. Figures of cannabis use in pregnant women in California by age were also
recently reported to JAMA 229, age group trend lines by age group which closely
approximate those reported by CDC for the age incidence of gastroschisis in the USA
230 (Figure 1). Importantly much of the cannabis coming into both North Carolina
and Florida is said to originate in Mexico 227,231. An eight-fold rise in the rate of
gastroschisis has been reported from Mexico 232. Gastroschisis has also risen in
Washington state 233.
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
221. 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 78,82,91,234-249. An extensive and robust
evidence base 244 now links cellular energy generation to the maintenance and care of
cellular DNA 250-253. 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 254, 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 255.
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26) Moreover, the well documented decline in mitochondrial respiration induced by
cannabinoids, including tetrahydrocannabinol, cannabidiol and anandamide 78,82,91,234-
242,244-248 achieves particular significance in the light of the robustly documented
decline in cellular energetics including NAD+ which not only occurs with age 251,256-
268 but indeed, has now been shown to be one of the primary drivers of cellular and
whole organismal aging 250-254,263,269-289. This close parallel is illustrated in Figure
2. It follows therefore that cannabinoid administration (including THC andCBD)
necessarily phenocopies cellular aging. This implies of course that cannabinoid
dependent patients are old at the cellular level. Indeed, normal human aging is
phenocopied in the clinical syndrome of cannabinoid dependence which includes
(most references are provided above):
1) Neurological deficits in:
i) attention,
ii) learning and
iii) memory;
iv) social withdrawal and disengagement and
v) academic and
vi) occupational underachievement
2) Psychiatric disorders including
i) Anxiety,
ii) Depression,
iii) Mixed Psychosis
iv) Bipolar Affective disorder and
v) Schizophrenia,
3) Respiratory disorders including:
i) Asthma
ii) Chronic Bronchitis (increased sputum production)
iii) Emphysema (Increased residual volume)
iv) Probably increased carcinomas of the aerodigestive tract
4) Immune suppression which generally implies
i) segmental immunostimulation in some parts of the immune system
since
the innate and adaptive immune systems exert profound homeostatic
mechanisms in response to suppression of one of its parts;
A Substantial literature on immunostimulation
5) Reproductive effects generally characterized by reduced
i) Male and
ii) Female fertility
6) Cardiovascular toxicity with elevated rates of
i) Myocardial infarction
ii) Cerebrovascular accident
iii) Arteritis
iv) Vascular age – vascular stiffness 119
7) Genotoxicity in
i) Respiratory epithelium and
ii) Gonadal tissues.
8) Osteoporosis 290-300
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9) Cancers of the
i) Head and neck
ii) Larynx
iii) Lung
iv) Leukaemia
v) Prostate
vi) Cervix
vii) Testes
viii) Bladder
ix) Childhood neuroblastoma
x) Childhood acute lymphoblastic leukaemia
xi) Childhood Acuter Myeloid and myelomonocytic leukaemia
xii) Childhood rhabdomyosarcoma 201,202.
The issue here of course is that cannabinoid dependence therefore copies without
exception all of the major disorders of old age, each of which is also faithfully
phenocopied by cannabis dependence.
The most prominent disorders of older age include:
1) Alzheimer’s disease
2) Cardiovascular and cerebrovascular disease
3) Osteoporosis
4) Systemic inflammatory syndrome
5) Changes in lung volume and the mechanics of breathing
6) Cancers
Hence this provides one powerful pathway by which cannabinoid exposure can replicate and
phenocopy the disorders of old age.
This is not of course to suggest that this is the only such pathway. Obviously changes of the
general level of immune activity, or alterations of the level of DNA repair occurring directly
or indirectly associated with cannabis use can form similar such pathways: both are well
documented in cannabis use and also in the aging literature as major pathways implicated in
systemic aging. Nevertheless, the decline in mitochondrial energetics together with its
inherent genotoxic implications does seem to be a particularly well substantiated and robustly
demonstrated pathway which must give serious pause to cannabinoid advocates if the
sustainability of the health and welfare systems is to be factored in together with any
consideration of individual patient, advocate and industrial-complex rights.
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.
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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 outer membrane CB1R’s signal via a complex signaling chain
involving the G-protein transduction machinery, protein kinase A and cyclic-AMP
across the intermembrane space to the inner membrane and cristae, in a fashion
replicating much of the G-protein signaling occurring at the cell membrane. This
machinery is also implicated in mitonuclear signaling, and the mitonuclear DNA
balance between mitochondrial DNA and nuclear DNA transcriptional control, which
has long been implicated in inducing the mitochondrial unfolded protein cellular stress
response cell aging, stem cell behaviour and DNA genotoxic mechanisms 248,301.
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 (Figure 3).
These mitochondria also carry CB1R’s and are significantly inhibited even at 100
nanomolar THC. The acrosome reaction is also inhibited 239.
30) A similar arrangement is shown in Figure 4, where mitochondria are shown in green
surrounding the mitotic spindle (pink, with the chromosomes shown in blue), which
is the cellular machinery and apparatus of cell division. Mitosis and meiosis, the
classical processes of cell division, are highly energy dependent and mitochondria are
clearly positioned strategically to supply the required energy for this process, just as
they are positioned in proximity to the root of the sperm flagellum rotor in that
situation.
31) Cannabidiol is known to act via the PPARγ system 101,302-308. PPARγ is known to have
a major effect on gene expression, reproductive and embryonic and zygote function
during development 309-332 so that significant genotoxic and / or teratogenic effects
seem inevitable via this route. Drugs which act in this class, known as the
thiazolidinediones, are classed as category B3 in pregnancy and caution is indicated in
their use in pregnancy and lactation.
32) The Report of the Reproductive and Cancer Hazard Assessment Branch of the Office
of Environmental Health Hazard Assessment of the Health Department of California
was mentioned above in connection with the carcinogenicity of marijuana smoke 333.
Since virtually all mutagens are also teratogens it follows therefore from the basic
tenets of mutagenesis that if cannabis is unsafe as a known carcinogen it must also be
at the very least a putative teratogen.
33) CBD has also been noted to be a genotoxic in other studies 334-336.
34) All of which points to major teratogenic activity for both THC and CBD.
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Some of the quotations from Professor James Graham’s classical book on the effects of THC
in hamsters and white rabbits, the best animal models for human genotoxicity, bear repeating
337 :
a) “The concentration of THC was relatively low and the malignancy severe.”
b) “40-100μg resin/ml there occurred marked inhibition of cell division.
c) “large total dose, Hamsters, 25-300mg/kg …“oedema, phocomelia,omphalocoele,
spina bifida, exencephaly, multiple malformations and myelocoele. This is a
formidable list.”
d) “It is to this anti-mitotic action that the authors attribute the embryotoxic action of
cannabis.”
e) “By such criteria resin or extract of cannabis would be forbidden to women during
the first three months of pregnancy.” 337
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 231,233,338-342. 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 343.
Cannabis that contains increasingly high levels of THC is now widely available,
particularly in the jurisdictions where the use of cannabis has been legalized. This means
that another major genotoxin, akin to Thalidomide, is being unleashed on the USA and
the world. This is clearly a very grave, and. indeed, an 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 344. 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 88,337,345,346. Dr Kelsey’s photograph has been published in the medical press with
President Kennedy for her service to the nation (Figure 5) 344. The challenge to FDA at this
time seems whether Science can triumph over agenda driven populism, its primary vehicle,
the mass media, and its primary proximate driver the burgeoning cannabis industry. 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.
Evidence to date does not suggest that major congenital malformations are as common after
prenatal cannabis exposure as they are after prenatal thalidomide exposure. Nevertheless the
qualitative similarities remain and indeed are prominent. It is yet to be seen whether the rate
of congenital anomalies after cannabis are quantitatively as common: epidemiological studies
in a high potency era have not been undertaken; and even the birth defects rates from most
birth defects registers in western nations including that held by CDC, Atlanta appear to be
seriously out of date at the time of writing. Moreover the non-linear dose response curve in