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BioMed Central
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Harm Reduction Journal
Open Access
Review
Harm reduction-the cannabis paradox
Robert Melamede*
1,2
Address:
1
Biology Department, 1420 Austin Bluffs Parkway, University of Colorado, Colorado Springs, 80918, USA and
2
Bioenergetics Institute,
1420 Austin Bluffs Parkway, University of Colorado, Colorado Springs, 80918, USA
Email: Robert Melamede* - rmelamed@uccs.edu
* Corresponding author
Abstract
This article examines harm reduction from a novel perspective. Its central thesis is that harm
reduction is not only a social concept, but also a biological one. More specifically, evolution does
not make moral distinctions in the selection process, but utilizes a cannabis-based approach to
harm reduction in order to promote survival of the fittest. Evidence will be provided from peer-
reviewed scientific literature that supports the hypothesis that humans, and all animals, make and
use internally produced cannabis-like products (endocannabinoids) as part of the evolutionary harm
reduction program. More specifically, endocannabinoids homeostatically regulate all body systems
(cardiovascular, digestive, endocrine, excretory, immune, nervous, musculo-skeletal,
reproductive). Therefore, the health of each individual is dependant on this system working
appropriately.
Introduction
The concept of harm reduction is at the heart of conflict-
ing international drug policies. The Dutch pioneered this
approach. Today most European countries and Canada
have embraced the idea that society benefits most when
drug policy is designed to help people with drug problems
to live better lives rather than to punish them. In contrast,
the United States federal policy demands rigid zero toler-
ance with overwhelming emphasis on incarceration of
offenders (the Drug War). Although, seemingly reasona-
ble arguments can be made to support both sides of the
dispute, the recent global trend towards harm reduction
has resulted from the acknowledgement that drug use has
been a part of all societies throughout history and the real-
ization that repressive policies are expensive, ineffective,
and often harmful.
A dramatic example of the benefits that can result from a
harm reduction approach to drugs is seen with needle
exchange programs. While prohibitionists argue that pro-
viding clean injection equipment promotes drug use, the
facts do not support this contention. For example, the
Australian needle exchange program is credited with keep-
ing the HIV/AIDS infection rate very much lower than
what is typically found globally http://www.chr.asn.au/
about/harmreduction. Commonly cited examples of the
failed repressive policies championed by the United States
are the now repealed alcohol prohibition and the current
drug war. Crime, financial support for terrorism, disre-
spect for the law, and destruction of families, communi-
ties, and ecosystems can all be attributed to drug
prohibition. Yet, the staggering cost of the drug war,
driven by United States policy and taxpayers' money,
amounts to many billions of dollars a year.
Cannabis is the third most commonly used drug in the
world, following tobacco and alcohol. In the United
States, much of the drug war is focused on marijuana
Published: 22 September 2005
Harm Reduction Journal 2005, 2:17 doi:10.1186/1477-7517-2-17
Received: 19 November 2004
Accepted: 22 September 2005
This article is available from: http://www.harmreductionjournal.com/content/2/1/17
© 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.
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(over 700,000 people arrested last year alone). Is there jus-
tification for this policy? The gateway theory states mari-
juana use leads to the use of other drugs, and drives the
U.S. policy despite evidence that suggests alcohol and
tobacco use may foster the gateway effect [1,2]. In con-
trast, countries that support harm reduction focus their
enforcement and social support efforts on "hard drugs."
Consequently, many countries have effectively decrimi-
nalized marijuana. Holland, having the most liberalized
drug laws, does not have more cannabis users (over age
twelve) than do more repressive countries, and the per
capita number of heroin users is also lower http://
www.drugpolicy.org/global/drugpolicyby/westerneurop/
thenetherlan/. The Dutch Ministry of Justice estimates
that 0.16% of cannabis users are heroin users. This figure
does not support cannabis being a gateway drug. Data
from the 2000 National Household Survey on Drug
Abuse (U.S. Department of Health and Human Services,
Substance Abuse and Mental Health Services Administra-
tion) also shows that the vast majority of people who try
cannabis do not go on to use hard drugs.
A little explored question is what does harm reduction
specifically mean with respect to cannabis consumption?
This article will address cannabis harm reduction from a
biological perspective. Two directions will be examined:
what are the biological effects of cannabis use and what
are the social effects that emerge from the biological foun-
dation.
Like many substances that are put into the human body,
there can be positive or negative consequences that result
from cannabis consumption, depending on amount, fre-
quency, quality, and probably most importantly, the idio-
syncratic biochemistry of the user. Prohibitionists
concentrate their efforts on the negative effects of canna-
bis use, while anti-prohibitionists tend to focus on the
positive effects. If we assume that both sides have valid
arguments, the issue to be resolved is one of balance
between the negative and positive effects. Would a policy
of tolerance, or prohibition, be more likely to reduce
harm overall? Which policy would better serve society as
a whole, as well as problematic drug users?
Biological science can be more objectively evaluated than
social science. The central theme that will be presented in
this article is that appropriate cannabis use reduces bio-
logical harm caused by biochemical imbalances, particu-
larly those that increase in frequency with age. Proper
cannabis use, as distinguished from misuse, may have sig-
nificant positive health effects associated with the way
cannabis mimics natural cannabinoids. In essence, it is
proposed that the endocannabinoid system, selected by
600 million years of evolution, is a central mediator of
biological harm reduction through its homeostatic activi-
ties. The social implications of cannabis use will be
viewed as emerging from the biological platform. Herein
lies the paradox of cannabis and harm reduction. Is
appropriate use of cannabis better than no use?
The Controversy
Cannabis use can be divided into three categories, recrea-
tional, medical, and religious. The latter will not be exam-
ined in this article. Some, including those who favor or
oppose cannabis use, presume recreational and medical
use are the same. On the one side, it is often claimed that
any cannabis use is justified by some underlying medical
need. On the other side, cannabis use is presumed to have
no medical value, with the implication that those who use
it are simply "getting stoned." While the former claim may
be too extreme, the latter defies current scientific under-
standing of the biological functions of the endocannabi-
noids. While many people are reluctant to approve
recreational cannabis use, it appears that most people
support medical use. The United States Federal Govern-
ment denies that there is any valid medical use for canna-
bis, while the National Institute of Drug Abuse (NIDA)
provides marijuana on a monthly basis to a few medical
users through the compassionate Investigatory New Drug
(IND) program of the Food and Drug Administration
(FDA). Nevertheless, a number of states, through either
legislative action or voter initiative, have approved the use
of medical marijuana[3].
Current Federally Approved Medical Marijuana
Uses
In order to better assess arguments for and against the
medical use of marijuana, the scientific evidence for the
health benefits of cannabis will be reviewed below. It
should be noted that the federally supplied cannabis users
have been receiving and using cannabis for 11 to 27 years
with clinically demonstrated effectiveness in the treat-
ment of glaucoma, chronic musculoskeletal pain, spasm
and nausea, and spasticity of multiple sclerosis [4]. Fur-
thermore, there is no evidence that these patients have
suffered any negative side effects from their cannabis use.
The Endocannabinoid System
Cannabis preparations have been used medically for
thousands of years for illnesses such as epilepsy, migraine
headaches, childbirth, and menstrual symptoms. How-
ever, it is only relatively recently that the active compo-
nents have been identified and their mechanisms of
action have begun to be understood. While delta-9-tet-
rahydrocannabinol (THC) was first synthesized by
Mechoulam in 1967 [5], it was not until 1990 that the
cannabinoid receptor was localized in the brain [6] and
cloned [7]. Since then, discoveries in the field have pro-
ceeded at an ever-increasing pace. The discovery of can-
nabinoid receptors on cells naturally prompted the search
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for internal compounds (endogenous ligands) that would
activate the receptors since it seemed unlikely that canna-
bis receptors had evolved so people could partake of can-
nabis. In 1992, anandamide was discovered [8]. This lipid
metabolite was the first ligand of an ever-expanding class
of molecules known as endocannabinoids (internal mar-
ijuana-like compounds) to be discovered. Endocannabi-
noid synthesis, degradation, transport, and receptors
together form the endocannabinoid system.
The broad therapeutic potential that can result from cor-
rectly manipulating the endocannabinoid system is just
beginning to be realized[9,10]. In fact, major pharmaceu-
tical companies, and university researchers all around the
world are now engaged in the cannabinoid-related
research [11]. Their efforts focus on learning how the
endocannabinoid system functions, and on how to
manipulate it in order to increase or decrease its activity,
depending on the illness or condition under considera-
tion. GW Pharmaceuticals in Britain has been developing
and testing a plant extract-based product line that is in
clinical trials in Britain and Canada [12]. The results thus
far have been positive to the extent that Bayer AG has
entered into a 25-million-dollar distribution agreement
for GW's product, Sativex which has recently been
approved in Canada. In contrast, Sanofi Research has
developed an antagonist that will inhibit the ability of
endocannabinoids to stimulate hunger and thus poten-
tially be useful for weight control.
Evolution of Endocannabinoids
The cannabinoid system appears to be quite ancient
[13,14], with some of its components dating back about
600 million years to when the first multicellular organ-
isms appeared. The beginnings of the modern cannabi-
noid system are found in mollusks [15] and hydra [16]. As
evolution proceeded, the role that the cannabinoid sys-
tem played in animal life continuously increased. It is
now known that this system maintains homeostasis
within and across the organizational scales of all animals.
Within a cell, cannabinoids control basic metabolic proc-
esses such as glucose metabolism [17]. Cannabinoids reg-
ulate intercellular communication, especially in the
immune [18] and nervous systems [19]. In general, can-
nabinoids modulate and coordinate tissues, organ and
body systems (including the cardiovascular [20], digestive
[16], endocrine [21], excretory [22,23], immune [18],
musculo-skeletal [24], nervous [19], reproductive [25],
and respiratory [26] systems). The effects of cannabinoids
on consciousness are not well understood, but are well
known, and underlie recreational cannabis use. These
effects also have therapeutic possibilities [27].
Cannabinoids: Homeostatic Regulators
The homeostatic action of cannabinoids on so many
physiological structures and processes is the basis for the
hypothesis that the endocannabinoid system is nothing
less than a naturally evolved harm reduction system.
Endocannabinoids protect by fine-tuning and regulating
dynamic biochemical steady states within the ranges
required for healthy biological function. The endocan-
nabinoid system itself appears to be up- or down-regu-
lated as a function of need. As will be detailed later in this
article, endocannabinoid levels naturally increase in the
case of head injury and stroke [28], and the number of
cannabinoid receptors increases in response to nerve
injury and the associated pain [29]. In contrast, the
number of cannabinoid receptors is reduced when toler-
ance to cannabinoids is induced [30].
Physical Characteristics of Living Systems
To illustrate the multidimensional biochemical balancing
act performed by cannabinoids, a variety of endo- and
exocannabinoid activities will be reviewed below. In order
to appreciate these activities a brief introduction to cell
biology may provide the context for this review. All life is
dependant upon the maintenance of its dynamic organi-
zation through sufficient input of nutrients and removal
of wastes. The more complicated an organism is, the more
complex the coordination required to accomplish the
essential tasks necessary to maintain this vital flow of
inputs and outputs. Coordination requires communica-
tion. Cells communicate by thousands of different, but
specific, receptors on cell surfaces that respond to thou-
sands of different, but also specific, molecules (ligands)
that bind to the receptors. A receptor that is bound to its
activating ligand causes biochemical changes to occur in
the cell. In response to such regulatory signals on the
membrane, biochemical regulation within the cell occurs
at the level of gene expression as well as at the level of
enzyme action and other processes outside the nucleus.
Ultimately these changes, through complex biochemical
pathways, allow cells to divide, carry out specialized tasks,
lie dormant, or die. Any of these cellular activities, when
not properly coordinated, can result in illness. Two major
categories of disease states are those that result from acute
illness commonly caused by infections and those that are
age-related. Historically, in the United States, the cause of
death has transitioned from being pathogen-induced to
age-related. Current scientific literature regarding canna-
bis indicates that its use is often bad for the former but
good for the latter (see Immunology section below).
Cannabinoids and Brain Disorders
Since cannabis' action on the brain is most widely known
due to its recreational use, the nervous system will serve as
the starting point for examining cannabinoid activity as
an example of a natural biological harm reduction system.
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Numerous disease states associated with the nervous sys-
tem will be seen as potential targets for cannabinoid-
based therapy [31]. The nervous system is composed of
nerve and supporting cells. In addition to the role cannab-
inoids play in a healthy nervous system [32], the regula-
tory effects of cannabinoids in cases of stroke [28],
Parkinson's disease [33], Huntington's disease [34],
amyotrophic lateral sclerosis (ALS) [35], Alzheimer's dis-
ease [36], glioma (a type of brain tumor), [37] multiple
sclerosis [38], seizures[39], and pain [40,41] will be exam-
ined.
Cannabinoids and the Healthy Brain
In a healthy individual, cannabinoids play a direct role in
neurotransmission of many nerve cell types. They exhibit
the unusual property of retrograde transmission, in which
the cannabinoid neurotransmitter diffuses backwards
across the neural cleft to inhibit the presynaptic action
potential [42]. This function essentially regulates the sen-
sitivity of a nerve cell by acting as a feedback mechanism
that prevents excessive activity. Some nerve cells die when
they are excessively stimulated by excitatory neurotrans-
mitters (excitotoxins) such as glutamate. Cannabinoids
can reduce the level of stimulation and protect against this
form of cell death [43,44]. In addition to their down-reg-
ulatory effect on neurotransmission, cannabinoids play
other roles in reducing this type of cell death (biological
harm reduction) by regulating the role of interleukin-1
(IL-1, an inflammatory cytokine) and the IL-1 receptor
antagonist (IL-1ra) [45]. For example, cannabinoids were
shown to modulate the release of IL-1ra thereby protect-
ing against IL-1 assisted cell death [46].
The role of cannabinoids in neurological health and dis-
ease goes beyond the prevention of cell death and regu-
lates neuronal differentiation. Cannabinoid receptors are
functionally coupled to the fibroblast growth factor recep-
tor (FGF). The FGF receptor, when stimulated, activates
lipid catabolism via diacylglerol (DAG) lipase which
causes the hydrolysis of DAG to produce 2-arachidonyl
glycerol (2AG) [47]. 2AG is an endocannabinoid shown
to be important for axon growth and guidance[48]. This
function is critical for nerves to innervate their target effec-
tors. The ability to control these fundamental neurologi-
cal activities, in conjunction with the anti-inflammatory
properties of cannabinoids, is likely to have important
regenerative health benefits for people suffering from neu-
rological damage as occurs with stroke or injury [28].
Multiple Sclerosis
Both animal and human studies provide strong evidence
of the therapeutic potential of cannabinoids to provide
relief from a number of neurological disease states [49].
The use of cannabinoids to treat people suffering from
multiple sclerosis (MS) is an excellent example of the
importance of "medical marijuana" as an agent of harm
reduction[50] MS is a neurodegenerative disease in which
the immune system attacks components of the nervous
system. The axons of many central nervous system (CNS)
neurons are surrounded by a myelin sheath that acts
much like an insulator around a wire. MS is associated
with the degradation of the myelin sheath that leads to
loss of axon function and cell death, thus producing the
disease symptoms.
Cannabis-based therapies for the treatment of MS can
provide symptomatic and true therapeutic relief. On the
one hand, cannabinoids help to reduce spasticity in an
animal model of MS (chronic relapsing experimental
autoimmune encephalomyelitis (CREAE) [51]. However,
the involvement of the cannabinoid system in the etiol-
ogy of MS goes much deeper. MS is in reality an autoim-
mune disease. In order to appreciate why cannabinoids
can have in important role, beyond what has already been
mentioned, in treating MS on a mechanistic level [52], a
brief introduction to immunology is required.
Cannabinoids and the Immune System
The role of the immune system is simplistically thought of
as protecting us from foreign attack. More inclusively,
however, the immune system has the biological function
of modulating the life, death, and differentiation of cells
in order to protect us. The immune system accomplishes
these tasks, in part, by balancing two mutually opposed
pathways known, respectively, as the "Th1" and "Th2"
response. The Th1 immune response is critical for fighting
infections caused by specific infectious agents [53]. This
function is inhibited by cannabinoids. Thus cannabinoids
are important homeostatic modulators of the immune
system. While often classified as immune inhibitors, can-
nabinoids actually promote the Th2 response while they
inhibit the Th1 response. Therefore cannabinoids are
immune system modulators. A specific cannabinoid
receptor (Cb2) [54] is found on most cells of the immune
system.
Th1 Immune Response
The Th1 pathway is proinflammatory and functions by
inducing the defensive production of free radicals that are
vital for fending off pathogens, especially intracellular
pathogens, such as those that cause Legionnaire's disease,
Leishmania, and tuberculosis. Accordingly, the use of can-
nabis should be avoided when the Th1 arm of the
immune system is needed to fight a particular disease.
Although contagion as well as immune suppression may
have been involved, a recent study supports this perspec-
tive, in that a cluster of new tuberculosis cases was traced
to a shared water pipe [55]. Free radical production,
inflammation and cell-mediated immunity are character-
istic of the Th1 response. The targeting of infectious
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organisms, or infected cells, by a Th1 immune response
results in healthy surrounding cells being exposed to free
radicals. Much as if radiation had been applied, there is
collateral damage that occurs with a targeted Th1 immune
response.
Cannabinoids and Th1 Mediated Auto-Immune
Diseases
In contrast to the Th1 immune response, the Th2 immune
response promotes the humoral arm of the immune sys-
tem. It turns down the Th1 response, is characterized by
antibody production, and is typically anti-inflammatory.
Ideally, the Th1 and Th2 pathways are functionally bal-
anced to optimally meet the survival needs of an organism
in its environment. In reality however, many autoimmune
diseases, and other age related diseases, are characterized
by an excessive Th1-driven immune response at the site of
the of the tissue damage involved. Multiple sclerosis,
arthritis, Crohn's disease, and diabetes are all diseases that
fall into this category.
The therapeutic impact of cannabinoids on these diseases
can be dramatic. For example, when rodents were given
experimental autoimmune encephalomyelitis (EAE) as an
MS animal model and were treated with cannabinoids,
the results were profound [56]. In a study that involved
both guinea pigs and rats, 98% of the EAE animals that
were not treated with THC died. In contrast, greater than
95% of THC-treated animals survived. They had only
mild symptoms with a delayed onset or no symptoms at
all. The capacity of cannabinoids to down-regulate a spec-
trum of auto-immune diseases should serve as a warning
against the long term use of CB1 inhibitors for weight
control. Such drugs are currently in the regulatory pipeline
[57] and one of the participants in the clinical trial unex-
pectedly developed multiple sclerosis [58].
Cannabinoid Actions-Biphasic Responses
The brief interludes into cell biology, neurology, and
immunology provide a biological platform for consider-
ing how cannabinoids might impact a variety of other dis-
ease states. It is important to keep in mind that in its role
as a general homeostatic modulator, too much or too little
cannabinoid activity can be harmful. Cannabinoid levels
or concentration ranges vary as a function of an organ-
ism's genetics, the cell types under consideration, and
their health and environment. Care must be taken when
evaluating the scientific literature on cannabinoids and
their effects. Cannabinoids often exhibit biphasic
responses [59]. Low doses of cannabinoids may stimulate
the Th2 immunological response, whereas high doses
may inhibit the Th2 response and shift the balance in
favor of a Th1 response. From a harm reduction perspec-
tive, these observations demonstrate the critical impor-
tance of dose-dependent, disease-dependent, state-
dependent, and individually tailored approaches to can-
nabis therapeutics [60].
The use of cannabinoids in the treatment of Parkinson's
disease is an example of a condition where excessive or
deficient cannabinoid activity may prove problematic.
Parkinson's disease results from the loss of levo-
dopamine (L-dopa) producing neurons. In an animal
model of Parkinson's disease, L-dopa producing cells are
killed with 6-hydroxydopamine. Rats so treated exhibit
spontaneous glutamatergic activity that can be suppressed
by exo- as well as endocannabinoids [61]. The standard
treatment for Parkinson's disease involves L-dopa replace-
ment therapy. Unfortunately, this treatment often results
in dyskinesia (abnormal voluntary movements). Recent
clinical trials have shown that cannabinoid treatment
reduces the reuptake of gamma-aminobutyric acid
(GABA) and relieves the L-dopa-induced dyskinesia [33],
as well as L-dopa induced rotations in 6-hydroxy-
dopamine-lesioned rats [62]. In contrast to the potential
benefits of cannabinoid agonists just cited, using a differ-
ent animal model, the cannabis antagonist SR141716A
reduced reserpine-induced suppression of locomotion
[63]. Thus, in this model locomotion was restored by
inhibiting the endocannabinoid pathway.
Cannabinoids and Cancer
Possibly the greatest harm-reducing potential afforded by
cannabinoids comes from their use by cancer patients.
Cannabinoids possess numerous pharmacological prop-
erties that are often beneficial to cancer patients. Many
people are aware of the anti-emetic and appetite stimulat-
ing effects of cannabinoids [64]. A systemic study
designed to quantify the efficacy of cannabinoids as an
anti-emetic agent examined data from 30 randomized
controlled studies that were published between 1975 and
1997 and included 1366 patients who were administered
non-smoked cannabis [65]. For patients requiring a
medium level of control, cannabinoids were the preferred
treatment (between 38% and 90%). This preference was
lost for patients requiring a low or a high level of control.
Sedation and euphoria were noted as beneficial side
effects, whereas dizziness, dysphoria, hallucinations, and
arterial hypotension were identified as harmful side
effects.
The cancer cell killing [66] and pain relieving properties of
cannabinoids are less well known to the general public.
Cannabinoids may prove to be useful chemotherapeutic
agents [67]. Numerous cancer types are killed in cell cul-
tures and in animals by cannabinoids. For example, can-
nabinoids kill the cancer cells of various lymphoblastic
malignancies such as leukemia and lymphoma [68], skin
cancer [69], glioma [70], breast and prostate cancer [71],
pheochromocytoma [72], thyroid cancer [73], and color-
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ectal cancer[74]. Since 2002 THC has been used in a clin-
ical trial in Spain for the treatment of glioma [75].
However, not all cancers are the same, and cannabinoid-
induced biochemical modifications, while effective in
killing the cells of some cancers, as indicated above, can
have the opposite effect on the cells of other types of can-
cer. For example, recent work has shown that the synthetic
cannabinoid, methanandamide, can promote the growth
of lung cancer cells by a receptor independent pathway
that involves the up-regulation of COX2 [76]. Although
much has been learned about the therapeutic value of can-
nabinoid agonists and antagonists in different situations,
scientific understanding of how to appropriately modu-
late the endocannabinoid pathways remains preliminary,
with much remaining to be learned.
Cannabinoids and Pain
One area of current research that has begun attracting
public interest is the pain relieving potential of cannabi-
noids, for both cancer [77] and non-cancer patients [78].
Medicine based on cannabis extract has demonstrated
positive effects for pain relief [79]. Recently, an intrinsic
role for cannabinoids in pain circuitry was discovered: the
endocannabinoid AEA was identified as the natural ligand
for the vanilloid receptors [80]. Vanilloid receptors, which
are ligand-gated cation channels, are primary targets for
the treatment of pain [81]. The cannabinoids seem to
function in a pathway parallel to the opioid pathway [82]
and are thought to exert anti-nociceptic activity at the level
of the spinal cord and the brain [83], although they can
also act peripherally by inhibiting mast cell degranulation
[84]. In recognition of the pain relieving properties of can-
nabinoids, England [11] and Canada [41] are using can-
nabis preparations to provide relief to citizens suffering
from a variety of disorders. Human trials have established
that co-administration of cannabinoids can dramatically
lower opioid use and can provide pain relief for neuro-
genic symptoms where other treatments have failed [85].
Recently, the topical application of the synthetic cannabi-
noid WIN 55,212-2 significantly enhanced the antinocic-
eptive activity of morphine, opening the door for possible
cannabis-induced pain relief with reduced cognitive side
effects [86]. The intrinsic role of endocannabinoids in
modulating pain is further supported by the up-regulation
of the CB1 receptor in rats following nerve damage [29].
Once again, nature has selected cannabinoids to reduce
harm.
Smoking and Lung Cancer
Fundamental to any consideration of cannabis-based
harm reduction, as a biological phenomenon or as a pol-
icy, is how to best administer the drug. Smoking cannabis
preparations, in contrast to oral administration [87], has
the benefit of rapid action that allows self-titration of the
drug's activity [88,89]. Unfortunately, cannabis smoke
contains numerous carcinogenic compounds [90]. In fact,
cannabis smoke may contain more tars than tobacco
smoke [91]. However, despite the fact that cannabis
smoke does produce cellular changes that are viewed as
precancerous, a major epidemiological study does not
find that cannabis smoking is associated with tobacco
related cancers [92]. A number of recent studies provide a
scientific foundation for the clear relationship between
tobacco smoking and lung cancer, a relationship that does
not hold true for cannabis smoke (manuscript submitted
to HRJ). For example nicotine, acting via nicotine recep-
tors, is critical in the development of tobacco related can-
cer by inhibiting the death of genetically damaged cells
[93]. Tobacco also promotes the development of blood
vessels needed to support tumor growth [94] whereas can-
nabis inhibits tumor vascularization in nonmelanoma
skin cancer [69] and glioma [95]. Although conclusions
derived from an oft-cited study examining the carcino-
genic effects of cannabis, tobacco, and cannabis com-
bined with tobacco claims to show a link between
cannabis smoking and head and neck cancer [96]. But
these results do not hold up under scrutiny. The study
does support a link between tobacco use that is exacer-
bated by concurrent cannabis use and the development of
head and neck cancer. However, the "cannabis use only"
group was composed only of two subjects, undermining
the statistical relevance of conclusions regarding this
group.
Smoking Alternatives
Regardless of whether or not smoking cannabis can cause
lung cancer, smoking anything containing partially oxi-
dized hydrocarbons, carcinogens, and irritants a priori, is
not healthy and will have negative health consequences.
Fortunately, harm-reducing alternatives exist. While often
touted as a problem, the availability of high THC cannabis
with high levels of THC permits less cannabis to be
smoked for therapeutic effects. Additionally, methods of
vaporizing the active ingredients of cannabis have been
shown to successfully remove most compounds of con-
cern while efficiently delivering the desired ones [97].
These results contrast with a recent Australian study that
found that the use of a water pipe, or bong, failed to
reduce tars or carbon monoxide delivered to the smoker
[98]. GW Pharmaceuticals is developing an oral spray that
should prove to be an additional safe and effective alter-
native delivery system [12] and valuable to medical can-
nabis users. The company has also identified strains with
defined ratios of various cannabinoids for which specific
medicinal value will be determined.
Cannabinoids Affect Drug Metabolism
Another important cannabis and harm reduction topic
that must be considered is that of how the use of cannabis
impacts on the pharmacokinetics of other drugs [99]. A
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number of drugs are metabolized by the P450 family of
isoenzymes, including numerous cannabinoids [100].
Even though cannabinoids stimulate the transcription of
P450 (2A and 3C), they also directly inhibit the activity of
this enzyme [101]. There are likely to be pros and cons
associated with P450 inhibition. P450 activity activates
procarcinogens in tobacco smoke to create active cancer-
causing mutations [102]. Thus, the inhibition of these
enzymes by cannabinoids may minimize some of the neg-
ative consequences of smoke inhalation. On the other
hand, many pharmaceutical drugs are metabolized by
these enzymes. The reduction of the rate of drug metabo-
lism by cannabinoids with pharmokinetic consequences
has been shown for cocaine [103], barbiturates [104], opi-
ates [105], alcohol, the antipsychotic haloperidol [106],
and others [107].
Thus far, both endo- and exocannabinoids are seen to
reduce harm in numerous circumstances. Cannabinoid-
based therapies have been especially helpful for the treat-
ment of a variety of neurological and immunological dis-
orders. Yet, we have only scratched the surface of the
scientific literature on cannabinoids and their biological
effects. Nevertheless, it should be apparent that cannabi-
noids have enormous medical potential as we learn to
manipulate the natural cannabinoid harm reduction sys-
tem that has evolved in the animal kingdom.
A fundamental question that remains unanswered is how
basic, complex biochemical phenomena, as touched on
briefly in this article, collectively emerge as substantial
contributors to health and behavior. In far-from-equilib-
rium thermodynamic systems, such as living organisms,
there are discontinuities between underlying molecular
dynamics and associated emergent macroscopic phenom-
ena [108]. In such systems, small changes (called "pertur-
bations") can amplify with consequences for the
organization of the whole system. The cannabinoids help
to regulate an amazingly broad range of biochemical
events. All of these effects have genetic foundations. As
such, natural genetic/biochemical variation in a popula-
tion can be expected to have significant effects on health
and behavior. It should be expected that in a population
distribution of cannabinoid levels and sensitivities, as a
function of an individual's health/disease status, some
individuals would naturally need to increase their can-
nabinoid activity while others would need theirs lowered.
Although the focus of this paper has been to suggest the
many circumstances in which higher cannabinoid activity
would be beneficial, these circumstances will necessarily
differ among individuals with different congenital can-
nabinoid levels and sensitivities. Therefore, reduced can-
nabinoid activity would be beneficial under some
conditions. A prime example of potential harmful effects
of excess cannabinoids is their effects on pregnancy where
low levels are needed but high levels are harmful [109].
Behavioral Effects: Self-administration and
Reward
The broad homeostatic activities of cannabinoids that
have been developed in this article have been rooted in
hard science. The extension of these ideas to the psycho-
logical and behavioral levels is intrinsically more specula-
tive, but remains consistent with the literature. For years,
researchers have looked into the possible addictive quali-
ties of cannabis. The lack of significant reward behavior
was indicated by the lack of self-administration in pri-
mates. Experiments examining preference in rats demon-
strated that low doses of THC could induce place
preference but that higher doses produced drug aversion
[110], again demonstrating the homeostatic nature of
cannabinoids. Self-administration is typical of most psy-
choactive drugs of abuse. Hence, one could conclude that
marijuana has a low potential for abuse.
Some may question the conclusion that cannabis has a
low abuse potential since an animal model using squirrel
monkeys was recently developed in which self-adminis-
tration behavior was maintained using THC [111]. Inter-
estingly, and consistent with the notion that the
cannabinoid system is a biological homeostatic harm
reduction mechanism, the self-administration of THC
ranges from 2 to 8 ug/kg and peaks at 4 ug/kg [112]. Thus,
in this animal model a controlled dose is chosen. To fur-
ther put these experiments in perspective, the dose used
must be examined more closely. A 1-gram joint of 10%
THC content would contain 100 mg of THC. The self-
administered dose schedule chosen by the animal of 4 ug/
kg would correspond to 360 ug of THC (if absorption was
complete, approximately 1/278 of the joint) for a 200-
pound human. Similarly, in rats, the intravenous self-
administration of the synthetic cannabinoid Win 55,212-
2 also occurred in a biphasic manner, with a maximum
response occurring at 12 ug/kg[113] The self-regulated,
controlled use of low drug doses is not characteristic of
addictive drugs of abuse.
Additional cannabinoid involvement in reward behavior
is suggested by the increased activity of dopaminergic
neurons stimulated with psychoactive cannabinoids
[114]. This pathway is shared by other major drugs of
abuse including, morphine, ethanol, and nicotine [115].
However, the production of glucocorticoid hormones that
are normally produced in response to stress [116], are
suppressed by cannabinoids [117]. Are cannabinoids
addictive, is pleasure addictive, or is a low stress state
addictive?
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Cannabinoids and Stress
Stress and reward are complicated components of addic-
tive behavior. How does repeated use of THC influence
these states? A recent study examines this question by
measuring glucose utilization in different areas of the rat
brain following repeated treatment with THC [118]. After
7 and 21 days of THC treatment, THC no longer resulted
in reduced glucose utilization in many areas of the brain
typically affected by a single THC dose (most cortical, tha-
lamic, and basal ganglia regions). In contrast, glucose uti-
lization in other areas of the brain remained unaltered
(nucleus accumbens, mediodorsal thalamus, basolateral
amygdala, portions of the hippocampus and median
raphe). Thus while the effects of THC on body tempera-
ture and locomotor activity become resistant to repeated
THC administration, those areas involved in many higher
brain functions remain responsive to THC. This differen-
tial adaptation to THC administration is consistent with a
low addictive potential. The best evidence that demon-
strates the absence of an addictive response to cannabis
use is the fact that most people who use it do not continue
to use it, and stop using it without any effort.
The stress-relieving properties of cannabinoids are an
important aspect of their pharmacological activity. An
interesting mechanism by which cannabinoids may pro-
mote stress relief is through their effects on memory. Can-
nabinoids control the extinction of painful memories
[119]. What a blessing for those suffering from debilitat-
ing or life threatening illnesses: cannabinoids may help
them to forget their misfortune.
Independent of the direct addictive or non-addictive
properties of cannabis, the cannabis-opioid connection
will be examined in more detail. Both drug families func-
tion (not necessarily exclusively) through biochemical
pathways that are regulated by specific receptor-ligand
interactions. However, there appears to be, as yet not fully
defined, crosstalk between these pathways [120]. For
example, CB1 receptor knockout mice are non-responsive
to CB1 cannabinoid activities and show reduced addictive
effects of opiates [121]. Similarly, Lewis rats showed
enhanced sensitivity to morphine self-administration
after treatment with the synthetic cannabinoid CP55040
[122]. Examining the cannabis-opioid connection from
the other direction, chronic morphine administration
results in some down-regulation of cannabinoid receptors
along with a significant reduction in 2AG [123]. These
results show both positive and negative feedback relation-
ships between the endocannabinoid and opiate systems.
They also suggest that cannabinoids might serve to reduce
the symptoms of opiate withdrawal [124].
The possibility that cannabinoids could serve as an addic-
tion interrupter was demonstrated in rats where the syn-
thetic cannabinoid agonist Win 55-212,2 reduced
intravenous self-administration of cocaine [125]. Simi-
larly, recent studies indicate that THC may facilitate nico-
tine withdrawal in mice [126] and inhibit alcohol
preference in a model of alcoholism [127]. The opposite
indications, that blocking cannabinoids receptors could
serve as an addition interrupter has also been made [128].
Behavioral Complexity
Behavioral processes and their complexities set humans
apart from other animals. Can we simply extrapolate from
animal to human behavior? It is one thing to compara-
tively examine the molecular and cell biology of animals
and extrapolate to humans. However, the behavioral rep-
ertoire of humans appears to be dramatically enhanced
over other animals and is therefore more difficult to con-
nect between the species. Evolutionary relationships show
that the cannabinoid receptors are located in the more
advanced areas of our brains. Again, any population is
always a spread around the average value of any parame-
ter. A subset of the human population will inevitably
retain a more primitive behavioral repertoire. Is this sub-
set more susceptible to addictive behavior or psychologi-
cal problems that could result from cannabis
consumption? Has the cannabinoid system been opti-
mized for the regulation of more primitive behavior or,
alternatively, is it better optimized for the behavioral flex-
ibility required of modern humans? Indeed, is there any
evidence that the cannabinoid system, like our cortical
capacity, may enable even greater behavioral flexibility in
the more complex societies and altered environments of
the future?
Answers to these questions are suggested by the data of
human cannabis consumption. Most people who use can-
nabis in their youth stop using it as their lives progress.
Most do so as a natural part of their development. They do
so without outside intervention or help. They do so with-
out ever having become heroin users, schizophrenic, or
motivationally compromised. These facts indicate that for
the majority of people who try marijuana, it is not addic-
tive, does not lead to heroin use, nor is it a trigger for the
onset of psychological problems. However, due to the
complexity of cannabinoid activities, it is likely that in a
small percentage of the population, cannabis use may fos-
ter problems. The biology presented in this paper suggests
that such individual differences should be expected. We
must learn to identify individuals who would be nega-
tively affected by cannabis use; they are the people that an
intelligent drug policy would help to identify and assist.
In contrast, our policy criminalizes the majority of users
and further harms them, perhaps psychologically as well
as medically, through its repercussions.
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The use of cannabis – and any mind-altering drug – by
young developing minds rightfully remains an area of
focus and concern. For example, is there a relationship
between cannabis use and schizophrenia? Schizophrenia
is characterized by distortions of reality, disturbances of
language and thought processes, and social withdrawal.
Certainly, aspects of cannabis intoxication parallel these
symptoms. It is feared that cannabis can precipitate this
state [129], especially in susceptible individuals [130]. It
has been suggested that schizophrenics (or potential
schizophrenics) fall into two categories with respect to
cannabis use [131]. One group may find symptomatic
relief in the use of cannabis, while the other may actually
take the risk of inducing the onset of the disease. The com-
plexities of this issue are illuminated by the unpredictable
behavior of interacting complex systems such as the nerv-
ous and immune systems, as will be considered below.
In an important recent study, De Marchi et al [132], exam-
ined the endocannabinoid levels in healthy volunteers
and compared them to that of schizophrenic patients,
both before and after successful antipsychotic treatment.
Patients suffering with acute disease had significantly
higher anandamide levels in their blood than did the nor-
mal individuals or patients in clinical remission. Might
these elevated cannabinoid levels be contributing to the
disease symptoms, and what might be causing them? Can-
nabinoids act homeostatically across biological subsys-
tems. A possible immune involvement in schizophrenia
has long been suspected, and immunological parameters
have been implicated in the disease. For example, there is
an inverse correlation between schizophrenia and rheu-
matoid arthritis; an individual generally does not get both
illnesses [133]. Interestingly, schizophrenia has been cor-
related with HLA type, Toxoplasma gonodii infection, and
exposure to cats [133]. Toxoplasma gonodii infects brain
neurons, and is best controlled with a strong pro-inflam-
matory immune response. Endocannabinoids modulate
the pro-inflammatory TH1 response by up-regulating the
anti-inflammatory Th2 response. Hence, it is likely that
some individuals idiosyncratically respond to Toxoplasma
gonodii infections by producing excess endocannabinoids
and suffering the associated abnormal mental state.
Antipsychotic drugs have actually improved the outcome
of infection with this parasite[134].
Conclusion
Evolution has selected the endocannabinoids to homeo-
statically regulate numerous biological phenomena that
can be found in every organized system in the body, and
to counteract biochemical imbalances that are characteris-
tic of numerous damaged or diseased states, in particular
those associated with aging. Starting from birth, cannabi-
noids are present in mother's milk [135], where they ini-
tiate the eating process. If the activity of
endocannabinoids in the mouse milk is inhibited with a
cannabinoid antagonist, the newborn mice die of starva-
tion. As life proceeds, endocannabinoids continuously
regulate appetite, body temperature, reproductive activity,
and learning capacity. When a body is physically dam-
aged, the endocannabinoids are called on to reduce
inflammation, protect neurons [136], regulate cardiac
rhythms [137] and protect the heart form oxygen depriva-
tion [20]. In humans suffering from colorectal cancer,
endocannabinoid levels are elevated in an effort to con-
trol the cancer [74]. They help relieve emotional suffering
by reducing pain and facilitating movement beyond the
fears of unpleasant memories [119].
While this review is far from complete, it attempts to pro-
vide a conceptual overview that supports the endocannab-
inoid system as being nature's method of harm reduction.
There is a pattern to all the cannabinoid-mediated activi-
ties described. Many of the biochemical imbalances that
cannabinoids protect against are associated with aging.
Aging itself is a system-wide movement towards chemical
equilibrium (away from the highly regulated far-from-
equilibrium state) and as such is an imbalance from
which all living organisms suffer. In contrast, the harmful
consequences of cannabis use, however exaggerated they
often appear to be, are likely to represent significant
potential risk for a minority of the population for whom
reduced cannabinoid levels might promote mental stabil-
ity, fertility or more regulated food consumption.
Additional material
Acknowledgements
I thank Suzanne Stradley, Jenell Forschler, and Carolyn Rogers, graduate
students in Laura Fillmore's electronic publishing course: Writing and Pub-
lishing Program (Emerson College), for creating the text links used in this
article (see additional file 1).
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