Harm Reduction Journal

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Harm Reduction Journal
Review Open Access
Cannabis and tobacco smoke are not equally carcinogenic
Robert Melamede*1,2
Address: 1Biology Department, 1420 Austin Bluffs Parkway, University of Colorado, Colorado Springs, 80918, USA and 2Bioenergetics Institute,
1420 Austin Bluffs Parkway, University of Colorado, Colorado Springs, 80918, USA
Email: Robert Melamede* – rmelamed@uccs.edu
* Corresponding author
marijuanatobaccocancersmokecannabinoidscarcinogensnicotine
Abstract
More people are using the cannabis plant as modern basic and clinical science reaffirms and extends
its medicinal uses. Concomitantly, concern and opposition to smoked medicine has occurred, in
part due to the known carcinogenic consequences of smoking tobacco. Are these reactions
justified? While chemically very similar, there are fundamental differences in the pharmacological
properties between cannabis and tobacco smoke. Cannabis smoke contains cannabinoids whereas
tobacco smoke contains nicotine. Available scientific data, that examines the carcinogenic
properties of inhaling smoke and its biological consequences, suggests reasons why tobacco smoke,
but not cannabis smoke, may result in lung cancer.
Tobacco has dramatic negative consequences for those
who smoke it. In addition to its high addiction potential
[1], tobacco is causally associated with over 400,000
deaths yearly in the United States, and has a significant
negative effect on health in general [2]. More specifically,
over 140,000 lung-related deaths in 2001 were attributed
to tobacco smoke [3]. Comparable consequences would
naturally be expected from cannabis smoking since the
burning of plant material in the form of cigarettes generates
a large variety of compounds that possess numerous
biological activities [4].
While cannabis smoke has been implicated in respiratory
dysfunction, including the conversion of respiratory cells
to what appears to be a pre-cancerous state [5], it has not
been causally linked with tobacco related cancers [6] such
as lung, colon or rectal cancers. Recently, Hashibe et al [7]
carried out an epidemiological analysis of marijuana
smoking and cancer. A connection between marijuana
smoking and lung or colorectal cancer was not observed.
These conclusions are reinforced by the recent work of
Tashkin and coworkers [8] who were unable to demonstrate
a cannabis smoke and lung cancer link, despite
clearly demonstrating cannabis smoke-induced cellular
damage.
Furthermore, compounds found in cannabis have been
shown to kill numerous cancer types including: lung cancer
[9], breast and prostate [10], leukemia and lymphoma
[11], glioma [12], skin cancer [13], and pheochromocytoma
[14]. The effects of cannabinoids are complex and
sometimes contradicting, often exhibiting biphasic
responses. For example, in contrast to the tumor killing
properties mentioned above, low doses of THC may stimulate
the growth of lung cancer cells in vitro [15].
The genotoxic effects of partially oxidized hydrocarbons
created by burning either cannabis or tobacco have been
Published: 18 October 2005
Harm Reduction Journal 2005, 2:21 doi:10.1186/1477-7517-2-21
Received: 30 November 2004
Accepted: 18 October 2005
This article is available from: http://www.harmreductionjournal.com/content/2/1/21
© 2005 Melamede; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Harm Reduction Journal 2005, 2:21 http://www.harmreductionjournal.com/content/2/1/21
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widely examined as the likely source of genetic changes
that lead to the carcinogenic state [16]. As a result, the
medical potential of cannabis has been obscured by the
potential negative impact of using a smoked medicine
[17]. Those who deny the validity of “medical marijuana,”
cite that marijuana smoke contains four fold more tars
than does tobacco smoke [18]. Nevertheless, smoking is
often the preferred route of intake by medical cannabis
users because rapid action allows self-titration [19]. Are
the biological consequences of smoking cannabis and
tobacco similar?
Smoke from tobacco and cannabis contains many of the
same carcinogens and tumor promoters [20,21]. However,
cannabis and tobacco have additional pharmacological
activities, both receptor-dependent and independent,
that result in different biological endpoints. Polycyclic
aromatic hydrocarbons found in smoke are pro-carcinogens
that are converted to carcinogens by the enzymatic
activity of the cytochrome P4501A1 oxidase protein
(CYP1A1 gene product). Benzo [a] pyrene is converted to
its carcinogenic metabolite diol epoxide, which binds to
specific hyper-mutable nucleotide sequences in the K-ras
oncogene and p53 tumor suppressor [22]. Recent work by
Roth et al. demonstrates that THC treatment of murine
hepatoma cells caused a dose dependent increase in
CYP1A1 gene transcription, while at the same time
directly inhibiting the enzymatic activity of the gene product
[23]. Thus, despite potentially higher levels of polycyclic
aromatic hydrocarbons found in cannabis smoke
compared to tobacco smoke (dependent on what part of
the plant is smoked), the THC present in cannabis smoke
should exert a protective effect against pro-carcinogens
that require activation. In contrast, nicotine activates
some CYP1A1 activities, thus potentially increasing the
carcinogenic effects of tobacco smoke [24].
It is worth noting that cytochrome P4501A1 oxidase has
numerous substrates including biologically active lipid
metabolites such as arachidonic acid, and eicosinoids
[25]. These molecules are components of metabolic pathways
that are interwoven with the synthesis and degradation
of endocannabinoids such as
arachidonylethanolamine (anandamide) [26]. Hence, the
inhibition of cytochrome P4501A1 oxidase by THC is
likely to have multiple biological effects such as possibly
enhancing cannabinoid activities by decreasing their
catabolism.
The need to better understand the biological consequences
of tobacco compared to cannabis smoke has been
underscored by recent studies that demonstrate a unique
role for nicotine in the pathogenesis of lung cancer [27].
In order to appreciate potential biological differences
between tobacco and cannabis smoke, the molecular
basis of signal transduction must be considered with
respect to the life and death of cells. Evolution has provided
cells with biochemical feedback loops, checkpoints
that monitor genetic integrity and the overall state of the
cell. Under conditions of sufficient cellular damage, apoptotic
cell death is induced [28]. While a variety of different
biochemical states are consistent with a cell either living
or dying, constant communication between a cell and its
environment is critical for survival of the cell and ultimately
the organism.
Cells communicate with each other via specific cell surface
receptors. When bound with their appropriate ligand, the
receptors initiate signaling cascades that alter cellular biochemistry
[29]. THC found in cannabis [30] and nicotine
found in tobacco [31] both have specific receptors by
which their corresponding ligands modulate cellular
functions. Interestingly, both cannabinoid [32] and nicotine
receptors [27] are coupled to the AKT (PKB) signaling
pathway. Activation of either receptor type can induce an
anti-apoptotic state that prevents cell death. However, it is
the context in which the AKT pathway is activated that
determines whether an organism benefits or is harmed by
this anti-apoptotic activity.
Nicotine receptors are widely distributed and are found in
the epithelial cells lining respiratory passages. Cannabinoid
receptors are also widely distributed, but have not
been reported in respiratory epithelial cells. The differential
expression of receptors may account for the apparent
difference in carcinogenic activity that results from smoking
tobacco compared to cannabis. Both types of smoke
contain a complex mixture of compounds, some of which
are carcinogenic. They both contain hot gasses and irritating
particulate matter (tars). However, the anti-apoptotic
response that results from the stimulation of the nicotine
receptors, under mutagenic conditions, creates a worstcase
scenario. The very cells that have accumulated sufficient
genetic damage to normally initiate the apoptotic
cascade are prevented from going down this suicidal path
[33] even though it would be best for the organism as a
whole. In contrast, when the AKT pathway is activated in
the brain after head injury [34] or stroke, [35] cannabinoids
protect against cell death to the organism’s benefit.
Likewise, nicotine can also activate the AKT pathway in
the brain in a beneficial manner. For example, activation
of the nicotine receptors, as is also true of cannabinoid
receptors [36], can prevent the brain cell death that results
from exposure to beta amyloid protein [37] as occurs in
Alzheimer’s disease.
The impact of receptor and downstream activation is complicated.
Both nicotine and cannabinoids have been
shown to effect angiogenesis in a receptor-mediated manner
[13]. However, nicotine and tobacco have opposite
Harm Reduction Journal 2005, 2:21 http://www.harmreductionjournal.com/content/2/1/21
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effects on angiogenesis. Nicotine promotes neo-vacularization
along with associated tumor growth, atheroma, upregulation
of VEGF, and cell migration [38]. In contrast,
cannabinoids promote tumor regression in rodents and
inhibit pro-angiogenic factors [39]. In fact, clinical trials
to treat human glioma with THC have resulted in
decreased levels of VEGF [40].
The signal transduction pathway described above represents
one means by which the carcinogenic affects of
tobacco are amplified in a contrasting manner to what
occurs with cannabis. The immunological effects resulting
from smoking tobacco or cannabis are also distinctive and
result in opposite end-points. Again, the carcinogenic
potential of smoke is increased by tobacco, whereas it is
uniquely reduced by the specific immune regulatory activity
of cannabinoids in cannabis smoke. The introduction
of hot gaseous material containing both carcinogens and
particulate material into the respiratory passages produces
pro-inflammatory immune responses [41]. The inflammatory
state is a double-edged sword that can serve to
protect or kill an organism. A functional characteristic of
the pro-inflammatory state is the production of free radicals
[42]. These reactive chemical species are essential
armaments in the body’s defense against various pathogens,
in particular against intracellular parasites and bacteria.
Free radicals are thought to be contributing
etiological agents behind a number of pathological states
[43] including cardiovascular and neuro-degenerative diseases
[44], cancers, and aging in general [45]. Endocannabinoids
are specific immunological homeostatic
modulators when acting on “peripheral” CB2 receptors
[30]. Both endo- and exo-cannabinoids push the immune
system towards the relatively anti-inflammatory Th2
cytokine profile [46]. Thus, cannabinoids inhaled in cannabis
smoke physiologically reduce the potential amplification
of carcinogens in smoke that results from
biologically produced free radicals. This response is not
induced by tobacco smoke.
In conclusion, while both tobacco and cannabis smoke
have similar properties chemically, their pharmacological
activities differ greatly. Components of cannabis smoke
minimize some carcinogenic pathways whereas tobacco
smoke enhances some. Both types of smoke contain carcinogens
and particulate matter that promotes inflammatory
immune responses that may enhance the
carcinogenic effects of the smoke. However, cannabis typically
down-regulates immunologically-generated free
radical production by promoting a Th2 immune cytokine
profile. Furthermore, THC inhibits the enzyme necessary
to activate some of the carcinogens found in smoke. In
contrast, tobacco smoke increases the likelihood of carcinogenesis
by overcoming normal cellular checkpoint
protective mechanisms through the activity of respiratory
epithelial cell nicotine receptors. Cannabinoids receptors
have not been reported in respiratory epithelial cells (in
skin they prevent cancer), and hence the DNA damage
checkpoint mechanism should remain intact after prolonged
cannabis exposure. Furthermore, nicotine promotes
tumor angiogenesis whereas cannabis inhibits it. It
is possible that as the cannabis-consuming population
ages, the long-term consequences of smoking cannabis
may become more similar to what is observed with
tobacco. However, current knowledge does not suggest
that cannabis smoke will have a carcinogenic potential
comparable to that resulting from exposure to tobacco
smoke.
It should be noted that with the development of vaporizers,
that use the respiratory route for the delivery of carcinogen-
free cannabis vapors, the carcinogenic potential of
smoked cannabis has been largely eliminated [47,48].
Competing interests
The author(s) declare that they have no competing interests.
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