Journal of the California Cannabis Research Medical
Harm Reduction: The Cannabis
By Robert Melamede
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 (endocan-nabinoids)
as part of the evolutionary harm-reduction program.
Endocannabinoids homeostatically regulate all body systems (cardiovascular,
digestive, endocrine, excretory, immune, nervous, musculo-skeletal,
reproductive). Therefore, the health of each individual is dependent
on this system working appropriately.
The concept of harm reduction is at the heart of conflicting 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
U.S. federal policy demands rigid zero tolerance with overwhelming
emphasis on incarceration of offenders (the “Drug War”).
Although, seemingly reasonable arguments can be made to support both
sides of the dispute, the recent trend towards harm reduction has resulted
from the acknowledgement that drug use has been a part of all societies
throughout history and the realization 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 providing clean injection equipment promotes drug use, the
facts do not support this contention. For example, the Australian needle
exchange program is credited with keeping 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by the United States are the now-repealed alcohol prohibition and the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, disrespect
for the law, and destruction of families, communities, and ecosystems
can all be attributed to drug prohibition. Yet the staggering cost
of the drug war, driven by U.S. 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 (over 700,000 people arrested last year alone).
Is there justification for this policy? The gateway theory states marijuana
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  . In contrast, countries that support harm reduction
focus their enforcement and social support efforts on “hard drugs.” Consequently,
many countries have effectively decriminalized marijuana. Holland,
having the most liberalized drug laws, does not have more cannabis
users over age 12 than do more repressive countries, and the per capita
number of heroin users is also lower.
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 Administration) also shows that the vast majority of
people who try cannabis do not go on to use hard drugs.
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 foundation.
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, frequency, quality, and probably most importantly,
the idiosyncratic biochemistry of the user.
Prohibitionists concentrate their efforts on the negative effects of
cannabis 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 a policy of 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.
Appropriate cannabis use reduces biological harm caused by biochemical
imbalances, particularly those that increase in frequency with age.
Proper cannabis use, as distinguished from misuse, may have significant
positive health effects associated with the way cannabis mimics natural
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 activities. 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?
Cannabis use can be divided into three categories: recreational, medical,
and religious. The latter will not be examined in this article.
Some, including those who favor and those who 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 said to have no medical
value, with the implication that those who use it are simply “getting
The former claim may be too extreme; the latter defies current scientific
understanding of the biological functions of the endocannabinoids.
While many people are reluctant to approve recreational cannabis use,
it appears that most people support medical use. The U.S. Federal Government
denies that there is any valid medical use for cannabis, 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.
Medical Marijuana Uses
Approved by the U.S. Government
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 treatment of glaucoma, chronic musculoskeletal pain, spasm
and nausea, and spasticity of multiple sclerosis .
Furthermore, 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. However, it is only relatively recently that
the active components have been identified and their mechanisms of
action have begun to be understood.
While delta-9-tetrahydrocannabinol (THC—molecular model at right)
was first synthesized by Mechoulam in 1967 , it was not until 1990
that the cannabinoid receptor was localized in the brain  and cloned
. Since then, discoveries in the field have proceeded at an ever-increasing
pace. The discovery of cannabinoid receptors on cells naturally prompted
the search for internal compounds (endogenous ligands) that would activate
the receptors since it seemed unlikely that cannabis receptors had
evolved so people could partake of cannabis.
In 1992, anandamide (model at right) was discovered . This lipid
metabolite was the first ligand of an ever-expanding class of molecules
known as endocan-nabinoids (internal marijuana-like compounds) to be
discovered. Endocan-nabinoid synthesis, degradation, transport, and
receptors together form the endocannabinoid system.
The broad therapeutic potential that can result from correctly manipulating
the endocannabinoid system is just beginning to be realized.
In fact, major pharmaceutical companies, and university researchers
all around the world are now engaged in the cannabinoid-related research
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 consideration. GW Pharmaceuticals
in Britain has been developing and testing a plant extract-based product
line that is in clinical trials in Europe and Canada . The results
thus far have been positive to the extent that Bayer AG has entered
into a $25 million distribution agreement for GW’s product, Sativex
which has recently been approved in Canada.
In contrast, Sanofi Aventis has developed an antagonist that will inhibit the
ability of endocannabinoids to stimulate hunger and thus potentially be useful
for weight control.
Evolution of Endocannabinoids
The cannabinoid system appears to be quite ancient , with some
of its components dating back about 600 million years to when the
first multicellular organisms appeared. The beginnings of the modern
cannabinoid system are found in mollusks  and hydra . As
evolution proceeded, the role that the cannabinoid system 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
processes such as glucose metabolism .
Cannabinoids regulate intercellular communication, especially in the
immune  and nervous systems .
In general, cannabinoids modulate and coordinate tissues, organ and
body systems (including the cardiovascular , digestive , endocrine
, excretory , immune , musculo-skeletal , nervous
, reproductive , and respiratory  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 .
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.
Endo-cannabinoids protect by fine-tuning and regulating dynamic biochemical
steady states within the ranges required for healthy biological function.
The endocannabinoid system itself appears to be up- or down-regulated
as a function of need.
Endocannabinoid levels naturally increase in the case of head injury
and stroke , and the number of cannabinoid receptors increases
in response to nerve injury and the associated pain . In contrast,
the number of cannabinoid receptors is reduced when tolerance to cannabinoids
is induced .
of Living Systems
To illustrate the multidimensional biochemical balancing act performed
by cannabinoids, a variety of endo- and exocannabinoid activities will
be reviewed below. A brief introduction to cell biology may provide
the context for this review.
All life is dependent upon the maintenance of its dynamic organization
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 communication. Cells communicate by thousands
of different, but specific, receptors on cell surfaces that respond
to thousands 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 cannabis indicates that its use is often bad for the former
but good for the latter (see Immunology section below).
Cannabinoids and Brain Disorders
Numerous disease states associated with the nervous system will be
seen as potential targets for cannabinoid-based therapy . The
nervous system is composed of nerve and supporting cells. In addition
role cannabinoids play in a healthy nervous system , the regulatory
effects of cannabinoids in cases of stroke , Parkinson’s
disease , Huntington’s disease , amyotrophic lateral
sclerosis (ALS) , Alzheimer’s disease , glioma (a type
of brain tumor),  multiple sclerosis , seizures, and pain
 will be examined.
Cannabinoids & 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 . This function essentially regulates the sensitivity
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 neurotransmitters (excitotoxins) such as glutamate.
Cannabinoids can reduce the level of stimulation and protect against
this form of cell death .
In addition to their down-regulatory 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) . For example,
cannabinoids were shown to modulate the release of UK-1ra, thereby
protecting against IL-1 assisted cell death .
The role of cannabinoids in neurological health and disease goes beyond
the prevention of cell death and regulates neuronal differentiation.
Cannabinoid receptors are functionally coupled to the fibroblast growth
factor receptor (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) .
2AG is an endocannabinoid shown to be important for axon growth and
guidance.. This function is critical for nerves to innervate their
target effectors. The ability to control these fundamental neurological
activities, in conjunction with the anti-inflammatory properties of
cannabinoids, is likely to have important regenerative health benefits
for people suffering from neurological damage as occurs with stroke
or injury .
Both animal and human studies provide strong evidence of the therapeutic
potential of cannabinoids to provide relief from a number of neurological
disease states . 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.
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.
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, or CREAE) . However, the involvement
of the cannabinoid system in the etiology of MS goes much deeper. MS
is in reality an autoimmune disease. In order to appreciate why cannabinoids
can have a major role in treating MS on a mechanistic level , a
brief introduction to immunology is required.
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 . This function is inhibited by cannabinoids.
Thus cannabinoids are important homeostatic modulators of the immune
system. While often classified as immune inhibitors, cannabinoids actually
promote the Th2 response while they inhibit the Th1 response. Therefore
cannabinoids are immune system modulators. A specific cannabinoid receptor
(Cb2)  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 cannabis
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 perspective, in that a cluster of new
tuberculosis casee was traced to a shared water pipe . Free radical
production, inflammation and cell-mediated immunity are characteristic
of the Th1 response. The targeting of infectious 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
In contrast to the Th1 immune response, the Th2 immune response promotes
the humoral arm of the immune system. It turns down the Th1 response,
is characterized by antibody production, and is typically anti-inflammatory.
Ideally, the Th1 and Th2 pathways are functionally balanced 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
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 .
In a study that involved both guinea pigs
and rats, 98% of the EAE animals that were not treated with THC died.
In contrast, more 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 spectrum 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  and one of the participants in a clinical trial unexpectedly
developed multiple sclerosis .
The brief interludes into cell biology, neurology, and immunology provide
a biological platform for considering how cannabinoids might impact
a variety of other disease 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
organism’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 .
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 perspective, these
observations demonstrate the critical importance of dose-dependent,
disease-dependent, state-dependent, and individually tailored approaches
to cannabis therapeutics .
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 neurons that produce levo-dopamine
(L-dopa). In an animal model of Parkinson’s disease, L-dopa producing
cells are killed with 6-hydroxy-dopamine. Rats so treated exhibit spontaneous
glutamatergic activity that can be suppressed by exo- as well as endocannabinoids
The standard treatment for Parkinson’s disease involves L-dopa
replacement 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 , as well
as L-dopa induced rotations in 6-hydroxydopamine-lesioned rats .
In contrast to the potential benefits of cannabinoid agonists just
cited, using a different animal model, the cannabis antagonist SR141716A
reduced reserpine-induced suppression of locomotion . Thus, in
this model locomotion was restored by inhibiting the endocannabinoid
Cannabinoids and Cancer
Possibly the greatest harm-reducing potential afforded by cannabinoids
comes from their use by cancer patients. Cannabinoids possess numerous
pharmacological properties that are often beneficial to cancer patients.
Many people are aware of the anti-emetic and appetite-stimulating
effects of cannabinoids .
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 . 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 negative side effects.
The cancer-cell killing  and pain- relieving properties of cannabinoids
are less well known to the general public. Cannabinoids may prove to
be useful chemotherapeutic agents . Numerous cancer types are killed
in cell cultures and in animals by cannabinoids. For example, cannabinoids
kill the cancer cells of various lymphoblastic malignancies such as
leukemia and lymphoma , skin cancer , glioma , breast and
prostate cancer , pheochromocytoma , thyroid cancer , and
colorectal cancer. Since 2002 THC has been used in a clinical trial
in Spain for the treatment of glioma .
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
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 .
Although much has been learned about the therapeutic value of cannabinoid
agonists and antagonists in different situations, scientific understanding
of how to appropriately modulate 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 cannabinoids, for both cancer
 and non-cancer patients . Medicine based on cannabis extract
has demonstrated positive effects for pain relief .
Recently, an intrinsic role for cannabinoids in pain circuitry was
discovered: the endocannabinoid AEA was identified as the natural ligand
for the vanilloid receptors . Vanilloid receptors, which are ligand-gated
cation channels, are primary targets for the treatment of pain .
The cannabinoids seem to function in a pathway parallel to the opioid
pathway  and are thought to exert anti-nociceptic activity at the
level of the spinal cord and the brain , although they can also
act peripherally by inhibiting mast cell degranulation .
In recognition of the pain-relieving properties of cannabinoids, England
 and Canada  are using cannabis 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 neurogenic symptoms
where other treatments have failed .
The topical application of the synthetic cannabinoid WIN 55,212-2 has
been found to significantly enhance the antinociceptive activity of
morphine, opening the door for possible cannabis-induced pain relief
with reduced cognitive side effects .
The intrinsic role of endocan-nabinoids in modulating pain is further
supported by the up-regulation of the CB1 receptor in rats following
nerve damage . Once again, nature has selected cannabinoids to
Smoking and Lung Cancer
Fundamental to any consideration of cannabis-based harm reduction as
a biological phenomenon or as a policy, is how to best administer
the drug. Smoking cannabis preparations, in contrast to oral administration
, has the benefit of rapid action that allows self-titration
of the drug’s activity .
Unfortunately, cannabis smoke contains numerous carcinogenic compounds
. In fact, cannabis smoke may contain more tars than tobacco smoke
. 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
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.
For example nicotine, acting via nicotine receptors, is critical in
the development of tobacco-related cancer by inhibiting the death of
genetically damaged cells . Tobacco also promotes the development
of blood vessels needed to support tumor growth , whereas cannabis
inhibits tumor vascularization in nonmelanoma skin cancer  and
Regardless of whether or not smoking cannabis can cause lung cancer,
smoking anything containing partially oxidized hydrocarbons, carcinogens,
and irritants a priori, is not healthy and will have negative health
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 concern while efficiently
delivering the desired ones .
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 . GW Pharmaceuticals is developing an oral
spray that should prove to be an additional safe and effective alternative
delivery system  and valuable to medical cannabis users. The company
has also identified strains with defined ratios of various cannabinoids
for which specific medicinal value will be determined.
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 . A number of drugs are metabolized by the P450
family of isoenzymes, including numerous cannabinoids . Even though
cannabinoids stimulate the transcription of P450 (2A and 3C), they
also directly inhibit the activity of this enzyme . 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 . Thus, the inhibition of these enzymes by cannabinoids
may minimize some of the negative consequences of smoke inhalation.
On the other hand, many pharmaceutical drugs are metabolized by these
enzymes. The reduction of the rate of drug metabolism by cannabinoids
with pharmokinetic consequences has been shown for cocaine , barbiturates
, opiates , alcohol, the antipsychotic haloperidol ,
and others .
Thus far, both endo- and exocan-nabinoids are seen to reduce harm
in numerous circumstances. Cannabinoid-based therapies have been especially
helpful for the treatment of a variety of neurological and immunological
disorders. Yet, we have only scratched the surface of the scientific
literature on cannabinoids and their biological effects. Cannabinoids
have enormous medical potential as we learn to manipulate the natural
cannabinoid harm reduction system 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-equilibrium thermodynamic systems, such as living organisms,
there are discontinuities between underlying molecular dynamics and
associated emergent macroscopic phenomena . In such systems, small
changes (called “perturbations”) 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 population 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 cannabinoid 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 cannabinoid
levels and sensitivities. Therefore, reduced cannabinoid 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 .
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 psychological and behavioral levels is intrinsically
more speculative, but remains consistent with the literature.
researchers have looked into the possible addictive qualities of cannabis.
The lack of significant reward behavior was indicated
by the lack of self-administration in primates. Experiments examining
preference in rats demonstrated that low doses of THC could induce
place preference but that higher doses produced drug aversion ,
again demonstrating the homeostatic nature of cannabinoids. Self-administration
is typical of most psychoactive 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-administration behavior was maintained using THC .
Interestingly, 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 . Thus, in
this animal model a controlled dose is chosen. To further 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. 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 . This pathway is shared by other major drugs of
abuse including, morphine, ethanol, and nicotine . However, the
production of glucocorticoid hormones that are normally produced in
response to stress , are suppressed by cannabinoids . Are
cannabinoids addictive, is pleasure addictive, or is a low stress state
Cannabinoids and Stress
Stress and reward are complicated components of addictive 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 .
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, thalamic, and basal ganglia
In contrast, glucose utilization 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 temperature and locomotor activity
become resistant to repeated THC administration, those areas involved
in many higher brain functions remain responsive to THC. This differential
adaptation to THC administration is consistent with a low addictive
potential. The best evidence that demonstrates 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 promote stress relief is through their effects on
memory. Cannabinoids control the extinction of painful memories .
What a blessing for those suffering from debilitating 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 function (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 .
For example, CB1 receptor knockout mice are non-responsive to CB1 cannabinoid
activities and show reduced addictive effects of opiates . Similarly,
Lewis rats showed enhanced sensitivity to morphine self-administration
after treatment with the synthetic cannabinoid CP55040 . 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 . These results show
both positive and negative feedback relationships between the endocannabinoid
and opiate systems. They also suggest that cannabinoids might serve
to reduce the symptoms of opiate withdrawal .
The possibility that cannabinoids could serve as an addiction interrupter
was demonstrated in rats where the synthetic cannabinoid agonist Win
55-212,2 reduced intravenous self-administration of cocaine .
Similarly, recent studies indicate that THC may facilitate nicotine
withdrawal in mice  and inhibit alcohol preference in a model
of alcoholism . Conversely, it has been proposed that blocking
cannabinoids receptors could serve as an addiction interrupter .
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 comparatively examine the molecular and cell biology
of animals and extrapolate to humans. However, the behavioral repertoire
of humans appears to be dramatically enhanced over other animals
and is therefore more difficult to connect 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 parameter. A subset
of the human population will inevitably retain a more primitive behavioral
repertoire. Is this subset more susceptible to addictive behavior or
psychological problems that could result from cannabis consumption?
Has the cannabinoid system been optimized for the regulation of more
primitive behavior or, alternatively, is it better optimized for the
behavioral flexibility 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 cannabis 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 without
ever having become heroin users, schizophrenic, or motivationally compromised.
These facts indicate that for the majority of people who try marijuana,
it is not addictive, 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 foster
problems. The biology presented in this paper suggests that such individual
differences should be expected. We must learn to identify individuals
who would be negatively 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
A link to schizophrenia?
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 , especially in susceptible
It has been suggested that schizo-phrenics (or potential schizophrenics)
fall into two categories with respect to cannabis use . 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
complexities of this issue are illuminated by the unpredictable behavior
of interacting complex systems such as the nervous and immune systems,
as will be considered below.
In an important recent study, De Marchi et al , examined 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 normal individuals or patients in
clinical remission. Might these elevated cannabinoid levels be contributing
to the disease symptoms, and what might be causing them?
Cannabinoids act homeostatically across biological subsystems. 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 rheumatoid arthritis;
an individual generally does not get both illnesses .
Interestingly, schizophrenia has been correlated with HLA type, Toxoplasma
gonodii infection, and exposure to cats . Toxoplasma gonodii infects
brain neurons, and is best controlled with a strong pro-inflammatory
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.
Evolution has selected the endocan-nabinoids to homeo-statically
regulate numerous biological phenomena that can be found in every
system in the body, and to counteract biochemical imbalances that
are characteristic of numerous damaged or diseased states, in particular
those associated with aging.
Starting from birth, cannabinoids are present in mother’s milk
, where they initiate the eating process. If the activity of endocannabinoids
in the mouse milk is inhibited with a cannabinoid antagonist, the newborn
mice die of starvation.
As life proceeds, endocannabinoids continuously regulate appetite,
body temperature, reproductive activity, and learning capacity. When
a body is physically damaged, the endocannabinoids are called on
to reduce inflammation, protect neurons , regulate cardiac rhythms
 and protect the heart form oxygen deprivation . In humans
suffering from colorectal cancer, endocan-nabinoid levels are elevated
in an effort to control the cancer . They help relieve emotional
suffering by reducing pain and facilitating movement beyond the fears
of unpleasant memories .
There is a pattern to all the cannabinoid-mediated activities described
in this review. 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 stability, fertility, or more regulated
I thank Suzanne Stradley, Jenell Forschler, and Carolyn Rogers, graduate
students in Laura Fillmore’s electronic publishing course, Writing
and Publishing Program (Emerson College), for creating the text links
used in this article.
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