Harm Reduction Journal

1477-7517-2-21.pdf (application/pdf Object).

Page 1 of 4
(page number not for citation purposes)
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
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
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
Page 2 of 4
(page number not for citation purposes)
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
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
Page 3 of 4
(page number not for citation purposes)
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
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.
1. Khurana S, Batra V, Patkar AA, Leone FT: Twenty-first century
tobacco use: it is not just a risk factor anymore. Respir Med
2003, 97(4):295-301.
2. Thun MJ, Henley SJ, Calle EE: Tobacco use and cancer: an epidemiologic
perspective for geneticists. Oncogene 2002,
3. Alavanja MC: Biologic damage resulting from exposure to
tobacco smoke and from radon: implication for preventive
interventions. Oncogene 2002, 21(48):7365-7375.
4. Novotny M, Merli F, Weisler D, Fencl M, Saeed T: Fractionation
and capillary gas chromatographic-mass spectrometric
characterization of the neutral components in marijuana
and tobacco smoke condensates. J Chromatogr 1982,
5. Tashkin DR, Baldwin GC, Sarafian T, Dubinett S, Roth MD: Respiratory
and immunologic consequences of marijuana smoking.
J Clin Pharmacol 2002, 42(11 Suppl):71S-81S.
6. Sidney S, Beck JE, Tekawa IS, Quesenberry CP, Friedman GD: Marijuana
use and mortality. Am J Public Health 1997, 87:585-590.
7. Hashibe M, Straif K, Tashkin DP, Morgenstern H, Greenland S, Zhang
ZF: Epidemiologic review of marijuana use and cancer risk.
Alcohol 2005, 35:265-275.
8. Tashkin DP: Smoked marijuana as a cause of lung injury.
Monaldi Arch Chest Dis 2005, 63:93-100.
9. Munson AE, Harris LS, Friedman MA, Dewey WL, Carchman RA:
Antineoplastic activity of cannabinoids. J Natl Cancer Inst 1975,
10. Sanchez C, de Ceballos ML, del Pulgar TG, Rueda D, Corbacho C,
Velasco G, Galve-Roperh I, Huffman JW, Ramon y, Cajal S, Guzman
M: Inhibition of glioma growth in vivo by selective activation
of the CB(2) cannabinoid receptor. Cancer Res 2001,
11. McKallip RJ, Lombard C, Fisher M, Martin BR, Ryu S, Grant S, Nagarkatti
PS, Nagarkatti M: Targeting CB2 cannabinoid receptors as
a novel therapy to treat malignant lymphoblastic disease.
Blood 2002, 100:627-634.
12. Sanchez C, Galve-Roperh I, Canova C, Brachet P, Guzman M:
Delta9-tetrahydrocannabinol induces apoptosis in C6 glioma
cells. FEBS Lett 1998, 436:6-10.
13. Casanova ML, Blazquez C, Martinez-Palacio J, Villanueva C, Fernandez-
Acenero MJ, Huffman JW, Jorcano JL, Guzman M: Inhibition of
skin tumor growth and angiogenesis in vivo by activation of
cannabinoid receptors. J Clin Invest 2003, 111:43-50.
Publish with BioMed Central and every
scientist can read your work free of charge
“BioMed Central will be the most significant development for
disseminating the results of biomedical research in our lifetime.”
Sir Paul Nurse, Cancer Research UK
Your research papers will be:
available free of charge to the entire biomedical community
peer reviewed and published immediately upon acceptance
cited in PubMed and archived on PubMed Central
yours — you keep the copyright
Submit your manuscript here:
Harm Reduction Journal 2005, 2:21 http://www.harmreductionjournal.com/content/2/1/21
Page 4 of 4
(page number not for citation purposes)
14. Sarker KP, Obara S, Nakata M, Kitajima I, Maruyama I: Anandamide
induces apoptosis of PC-12 cells: involvement of superoxide
and caspase-3. FEBS Lett 2000, 472:39-44.
15. Hart S, Fischer OM, Ullrich A: Cannabinoids induce cancer cell
proliferation via tumor necrosis factor alpha-converting
enzyme (TACE/ADAM17)-mediated transactivation of the
epidermal growth factor receptor. Cancer Res 2004,
16. Godschalk R, Nair J, van Schooten FJ, Risch A, Drings P, Kayser K,
Dienemann H, Bartsch H: Comparison of multiple DNA adduct
types in tumor adjacent human lung tissue: effect of cigarette
smoking. Carcinogenesis 2002, 23:2081-2086.
17. Watson SJ, Benson JAJ, Joy JE: Marijuana and medicine: assessing
the science base: a summary of the 1999 Institute of Medicine
report. Arch Gen Psychiatry 2000, 57(6):547-552.
18. Wu TC, Tashkin DP, Djahed B, Rose JE: Pulmonary hazards of
smoking marijuana as compared with tobacco. N Engl J Med
1988, 318:347-351.
19. Grotenhermen F: Pharmacokinetics and pharmacodynamics
of cannabinoids. Clin Pharmacokinet 2003, 42(4):327-360.
20. Nebert DW, Gonzalez FJ: P450 genes: structure, evolution, and
regulation. Annu Rev Biochem 1987, 56:945-993.
21. Hecht SS, Carmella SG, Murphy SE, Foiles PG, Chung FL: Carcinogen
biomarkers related to smoking and upper aerodigestive
tract cancer. J Cell Biochem Suppl 1993, 17F:27-35.
22. Tretyakova N, Matter B, Jones R, Shallop A: Formation of
benzo[a]pyrene diol epoxide-DNA adducts at specific
guanines within K-ras and p53 gene sequences: stable isotope-
labeling mass spectrometry approach. Biochemistry 2002,
23. Roth MD, Marques-Magallanes JA, Yuan M, Sun W, Tashkin DP, Hankinson
O: Induction and regulation of the carcinogen-metabolizing
enzyme CYP1A1 by marijuana smoke and delta (9)-
tetrahydrocannabinol. Am J Respir Cell Mol Biol 2001, 24:339-344.
24. Price RJ, Renwick AB, Walters DG, Young PJ, Lake BG: Metabolism
of nicotine and induction of CYP1A forms in precision-cut
rat liver and lung slices. Toxicol In Vitro 2004, 18:179-185.
25. Nebert DW, Russell DW: Clinical importance of the cytochromes
P450. Lancet 2002, 360(9340):1155-1162.
26. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin
G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R: Isolation and
structure of a brain constituent that binds to the cannabinoid
receptor. Science 1992, 258:1946-1949.
27. West KA, Brognard J, Clark AS, Linnoila IR, Yang X, Swain SM, Harris
C, Belinsky S, Dennis PA: Rapid Akt activation by nicotine and a
tobacco carcinogen modulates the phenotype of normal
human airway epithelial cells. J Clin Invest 2003, 111:81-90.
28. Woo RA, Poon RY: Cyclin-Dependent Kinases and S Phase
Control in Mammalian Cells. Cell Cycle 2003, 2:316-324.
29. Bockaert J, Pin JP: Molecular tinkering of G protein-coupled
receptors: an evolutionary success. EMBO J 1999,
30. Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA,
Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee
RG: International Union of Pharmacology. XXVII. Classification
of cannabinoid receptors. Pharmacol Rev 2002,
31. Itier V, Bertrand D: Neuronal nicotinic receptors: from protein
structure to function. FEBS Lett 2001, 504(3):118-125.
32. Gomez del Pulgar T, Velasco G, Guzman M: The CB1 cannabinoid
receptor is coupled to the activation of protein kinase B/Akt.
Biochem J 2000, 347:369-373.
33. Minna JD: Nicotine exposure and bronchial epithelial cell nicotinic
acetylcholine receptor expression in the pathogenesis
of lung cancer. J Clin Invest 2003, 111(1):31-33.
34. Panikashvili D, Simeonidou C, Ben-Shabat S, Hanus L, Breuer A,
Mechoulam R, Shohami E: An endogenous cannabinoid (2-AG)
is neuroprotective after brain injury. Nature 2001,
35. Leker RR, Shohami E, Abramsky O, Ovadia H: Dexanabinol; a
novel neuroprotective drug in experimental focal cerebral
ischemia. J Neurol Sci 1999, 162:114-119.
36. Iuvone T, Esposito G, Esposito R, Santamaria R, Di Rosa M, Izzo AA:
Neuroprotective effect of cannabidiol, a non-psychoactive
component from Cannabis sativa, on beta-amyloid-induced
toxicity in PC12 cells. J Neurochem 2004, 89:134-141.
37. Kihara T, Shimohama S, Sawada H, Honda K, Nakamizo T, Shibasaki
H, Kume T, Akaike A: alpha 7 nicotinic receptor transduces signals
to phosphatidylinositol 3-kinase to block A beta-amyloid-
induced neurotoxicity. J Biol Chem 2001, 276:13541-13546.
38. Heeschen C, Jang JJ, Weis M, Pathak A, Kaji S, Hu RS, Tsao PS, Johnson
FL, Cooke JP: Nicotine stimulates angiogenesis and promotes
tumor growth and atherosclerosis. Nat Med 2001,
39. Galve-Roperh I, Sanchez C, Cortes ML, del Pulgar TG, Izquierdo M,
Guzman M: Anti-tumoral action of cannabinoids: involvement
of sustained ceramide accumulation and extracellular signalregulated
kinase activation. Nat Med 2000, 6:313-319.
40. Blazquez C, Gonzalez-Feria L, Alvarez L, Haro A, Casanova ML, Guzman
M: Cannabinoids inhibit the vascular endothelial growth
factor pathway in gliomas. Cancer Res 2004, 64:5617-5623.
41. Sarafian TA, Magallanes JA, Shau H, Tashkin D, Roth MD: Oxidative
stress produced by marijuana smoke. An adverse effect
enhanced by cannabinoids. Am J Respir Cell Mol Biol 1999,
42. Chung HY, Kim HJ, Kim JW, Yu BP: The inflammation hypothesis
of aging: molecular modulation by calorie restriction. Ann N
Y Acad Sci 2001, 928:327-335.
43. Raha S, Robinson BH: Mitochondria, oxygen free radicals, and
apoptosis. Am J Med Genet 2001, 106:62-70.
44. Halliwell B: Role of free radicals in the neurodegenerative diseases:
therapeutic implications for antioxidant treatment.
Drugs Aging 2001, 18:685-716.
45. Drew B, Leeuwenburgh C: Aging and the role of reactive nitrogen
species. Ann N Y Acad Sci 2002, 959:66-81.
46. Yuan M, Kiertscher SM, Cheng Q, Zoumalan R, Tashkin DP, Roth
MD: Delta 9-Tetrahydrocannabinol regulates Th1/Th2
cytokine balance in activated human T cells. J Neuroimmunol
2002, 133:124-131.
47. Mirken B: Vaporizers for medical marijuana. Aids Treat News No
327 1999; Sect. 1, 5. .
48. Gieringer D, St Laqurent J, Goodrich S: Cannabis Vaporizer Combines
Efficient Delivery of THC with Effective Suppression of
Pyrolytic Compounds. In Journal of Cannabis Therapeutics 4th edition.
Edited by: Dr. Ethan Russo. Binghamton, New York: Haworth
Press; 2004:7-27.

Leave a Reply