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Conducting Scientific research on Cannabinoids
Biology
1420 Austin Bluffs Parkway
PO Box 7150
Colorado Springs, CO 80918
INTRO
The
cannabis plant is an amazing source of medicinal chemicals, the reason being it
is the only plant that truly taps into our endocannabinoid
system. While marijuana has been used medicinally for thousands of years, it is
only within the past fifteen years that we have begun to understand why
marijuana has so many medicinal properties. As a result, research into this
area has exploded. One cannot understand medical marijuana without first
understanding the endocannabinoid system and the
fundamental role that it plays in the lives of all animals, especially man.
The endocannabinoid system is composed of receptors (CB1-nervous system and CB2-immune
system) on cells that bind exocannabinoids like THC,
and endocannabinoids that our bodies produce, like anandamide (AEA) and 2-arachidonyl glycerol (2AG). Both
of the latter chemicals are made from essential fatty acids such as are found
in hemp oil.
When cannabinoid receptors are activated, various
biochemical properties in cells are altered, and these cells then alter
communication with other cells. However, all body systems must be regulated,
therefore, enzymes exist that break down our endocannabinoids
to keep this system in balance (homeostasis, see below). The most studied
enzyme that breaks down some endocannabinoids is
fatty acid amino hydrolase (FAAH).
Specifically, FAAH breaks down anandamide,
thereby decreasing endocannabinoid activity. In order
to really appreciate the medicinal properties of this plant, we must understand
the basic properties of life itself. How ironic, after so many cannabis users
have been persecuted for believing that marijuana is the tree of life, in many
respects it is.
CREATIVE
ENERGY FLOW-LIFE
For
the first time in the history of mankind, we can look at life from a truly
scientific prospective and understand its basic properties. We will not go into
the details of the physics of life, but rather we will describe some of the
basic characteristics of life from the perspective of far from equilibrium
thermodynamics. For our purposes, these ominous terms can be easily understood.
Let’s start with equilibrium. Scientifically, equilibrium is a state of
maximum disorder (entropy), and simultaneously, a state of minimum potential
(the ability to do something). In other words, equilibrium is the opposite of
life. Thermodynamics refers to the flow of energy. It is, in fact, this flow
that keeps life away from equilibrium. The movement towards equilibrium is
characterized by aging, illness and death. On an organismic
level, living systems maintain the critical flow of organizing energy by
eating, sensing the environment, and getting rid of waste products. However,
the same principle of extracting potential from the environment is true at the
cellular level.
A unique characteristic of matter driven further from equilibrium,
is that it possesses a natural tendency to create new forms of organization.
From the human prospective, moving further from equilibrium can mean regaining
one’s health and increasing one’s organization and energy flow (as
occurs with physical training). Similarly, learning and enhanced thinking
skills (such as state of mind) can represent movement from equilibrium. Another
irony, our cannabinoid system is totally intertwined
with these processes.
HOMEOSTASIS
In
the biosphere, the creative process is evolution. As evolution proceeds, we see
increasing complexity, a property most obviously characteristic of man and his
society.
However, this complexity is not only between man and his environment, but within
man himself, existing at all levels of organization. Before going further into
the endocannabinoid system and the impact of
marijuana on it, a critical term that we must understand is homeostasis. It
essentially means biochemical balance, but dynamic balance not static balance.
A simplistic visual image of the dynamic character of biochemical homeostasis
would be a bunch of jugglers balanced on a bunch of seesaws that are balanced
on each other, while moving on a roller-coaster ride. The level of complexity
in this seemingly impossible task is readily accomplished biochemically
by living organisms all the time. In fact, the endocannabinoid
system plays a critical role in coordinating the many balancing acts associated
with life and does so across scales of organization. The impact of cannabinoids ranges in scale from controlling biochemistry
within cells to controlling social interactions and regulating political
thought [1].
EMERGENT
PHENOMENA
Another
fundamental characteristic of living systems is that the whole is greater than
the sum of its parts. Pieces of a system work together and create something new
and different, something that would not have been predicted from observing the
individual components in isolation. How does this phenomenon impact on the
health of cells, individuals, communities and society, and is the role cannabinoid system? Is consciousness an emergent
phenomenon, with the cannabinoid system being a
critical player in the emergence process?
Before we look at the endocannabinoid system,
let’s restate some of the physics of life.
All foods provide us with building blocks and the energy necessary for
organizing the building process. The chemicals that we call food can be viewed
as charged batteries.
They have potential to do things such as promoting growth, health and
evolution. Energy flow in a living system is similar to what occurs when a
battery is used to do something.
In both cases, energy comes from the flow of electrons. Living systems are
essentially rechargeable, biochemical batteries, and our biochemical pathways
constitute the wires.
Without going into details, the flow of biochemical electricity produces free
radicals, biochemical friction.
FREE
RA
Free
radicals are highly reactive chemicals that modify life’s chemicals. Free
radicals have three critical biological functions. On the one hand, due to
their reactivity, free radicals alter the chemical properties of
EVOLUTION
Over
500 million years ago, cells began to communicate with one another and to
develop new levels of cooperation that, in turn, allowed for increased levels
of complexity (spatially, temporally, and physically). These primitive,
communicating, multi-cellular organisms began the evolutionary process that
lead to the body systems that we’re familiar with today: circulatory,
digestive, endocrine, immunological, musculoskeletal, nervous, reproductive,
respiratory and tegumentary (skin). Interestingly, it
was at this critical time in life’s history that the endocannabinoid
system had its origins and found its place as a critical modulator of
biological activities. As evolution proceeded, and systems and their
interactions grew more complicated, the endocannabinoid
system increasingly played an important role in the dynamic balancing acts that
characterize not only life, but also economic, social, political, and religious
institutions. As our understanding of the magnitude and diversity of cannabinoid biology increases, it naturally extends beyond
the biological realm through its regulation of complex human behavior.
All cells exhibit basic biological properties. Typically they are replicating,
performing some differentiation related task, resting or dying, all the while
communicating with their neighbors, ideally, for the good of the organism as a
whole. Cannabinoids regulate all of these basic
activities as a function of cell type, dose, etc. What are the implications of
this broad cannabinoid based activity that spans from
sub-cellular activities to consciousness and beyond? We will examine some of
the cannabinoid-based scientific discoveries that
occurred in 2006 and see what picture is painted regarding the essential role
of cannabinoids in human health.
SCIENCE
NOT POLITICS
First,
let’s clarify our starting point. Cannabis plant material is highly
variable in composition. Therefore, even in the absence of governmental
interference, the plant material is not ideally suited for most scientific
experimental studies (which need not limit its medicinal usefulness). Accurate
dosing and reproducibility are critical components of scientific inquiry. These
constraints are met experimentally by using agonists, chemicals that stimulate
specifically the CB1 or CB2
receptors, and antagonists, chemicals that inhibit specifically the CB1 or CB2 receptors. Today, we
know that many of the activities produced by cannabinoids
occur via cannabinoid receptor independent
mechanisms, further demonstrating how complex cannabinoid
activities are. In addition to the new synthetic cannabinoids,
naturally occurring THC and CB
NERVOUS
SYSTEM
A
good place to begin examining cannabinoid discoveries
of 2006 is the nervous system.
Current knowledge clearly shows that the brain has robust regenerative
capacities. One of the newly discovered surprises is that nerve regeneration, that develops from neural progenitor cells, is
regulated by endocannabinoids [2]. In other words,
when there is brain injury, as occurs from head injury or stroke, the brain
produces marijuana-like compounds [3] that are important limiters of damage and
promoters of healing.
The ability to feel pain is a critical biological response to injury (it helps
us avoid it). We now know that the level of cannabinoid
receptors is turned up in response to chronic inflammation and its associated
pain. The body, apparently in effort to reduce pain [4], enhances endocannabinoid activity. This response is not surprising
since endocannabinoids are direct regulators of pain
receptors [5].
Superoxide dismutase (SO
A source of pain for many individuals involves trigeminal vascular neurons,
which are thought to be involved with initiating migraine headaches. Ackerman
et al [7] conclude "CB receptors may have therapeutic potential in migraine,
cluster headache or other primary headaches, although the potential hazards of
psychoactive side-effects that accompany cannabinoid
treatments may be complex to overcome." This type of strange
commentary is pervasive in the scientific literature. The default perspective
found in the scientific literature is that one should endure pain and suffering
rather than bare the terrible psychological effects of cannabis consumption.
The mind-altering properties of narcotic pain-killers, antidepressants, tranquilizers
and sleep medications are okay, just stay away from the killer weed.
With cannabinoids intimately involved with so many
biological processes, what other diseases might be associated with cannabinoid deficiencies? Both anecdotally and
experimentally, cannabinoids seem to benefit those suffering
from multiple sclerosis. In one study, the synthetic cannabinoid
Nabilone was shown to significantly reduce spasticity-related pain [9]. In another study with multiple
sclerosis patients, cannabinoids decreased the
frequency of urination [10]. In a commentary on a newly published article [11]
Raphael Mechoulam, the father of cannabinoids
chemistry, writes that multiple sclerosis may disrupt the endocannabinoid
protection mechanism [12].
CAR
A
general theme of cannabinoid activity is inhibition
of inflammation and related free radical damage. In the immune system, cannabinoids regulate the balance between free radical
production and their inhibition [13]. Inflammation and free radical production
are important defense mechanisms used by the immune system to fight infectious
invaders.
The immune system regulates the level of inflammation in the circulatory
system. A chronic pro-inflammatory response is a prime determinant in the
development of arteriosclerosis, and can be reversed by cannabinoids
in mice [14]. Unfortunately, the comparable experiment in humans has not yet
been done. However, mice often serve as a good model for human immunology.
SKELETAL
SYSTEM
The
global homeostatic role of the endocannabinoid system
is again demonstrated by their control of the skeletal system. Earlier
publications lead to some confusion in that some data indicated that cannabinoids might promote osteoporosis, whereas others
suggested the opposite. Experiments published in 2006 provided new insights
into the regulation of bone mass by the endocannabinoid
system. Mice that have had their CB2 receptor
genetically "knocked out," develop age associated loss of bone mass,
a condition that appears similar to osteoporosis in humans [15]. Thus, CB2 simulation appears to prevent bone loss. Similar
results were found with CB1 knock out mice [16].
CONSCIOUSNESS
Many
people use and enjoy marijuana because of the effects that it has on
one’s consciousness. The year 2006 has produced some interesting new
science in this area, in general, supporting the anti-depressive effects of
cannabis. A study by Parish and Nicols [17] showed
that stimulation of the serotonin receptor (5-HT2a)
produced the endocannabinoid 2-arachidonylglycerol.
The obvious question is how much of the antidepressive
effects produced by serotonin uptake inhibitors is due
to the production of endocannabinoids? Similarly,
another study demonstrated that cannabinoids reduce
anxiety by stimulating another class of serotonin receptors (5-HT1a) [18].
BEATING
AROUN
The
possibility of increasing the levels of endocannabinoids
by decreasing their rate of breakdown is an exciting new area of drug
development. In agreement with earlier findings [19], elevating anandamide levels by inhibiting FAAH
with an inhibitor "elicits significant, anxiolytic-like,
antidepressant-like and analgesic effects" [20]. These findings, of
course, provide unmentioned support for the use of cannabis for these same
conditions.
We know that elevating endocannabinoid levels has
affects that are similar to consuming THC [21].
CANCER
Cancer
is one of the most exciting areas under investigation for the therapeutic
application of cannabinoids. For many years the
anti-nausea properties of cannabinoids was thought to
be the primary use of cannabis for cancer therapy. Over the past few years, the
greater potential for cannabinoids in the treatment
of cancer has been revealed.
Cannabinoids have been demonstrated to kill the
variety of tumor cells, as well as to inhibit activities associated with
metastasis (spreading) [22].
Since cannabis is frequently used by cancer patients to relieve nausea, lack of
appetite, depression, and difficulty sleeping [27], a concern has been its
possible effect on chemotherapeutic drug sensitivity. A recent study
demonstrated that a variety of plant derived cannabinoids
inhibited a protein that pumps therapeutic drugs out of cancer cells and is
typically associated with drug resistance [28], thus providing another possible
significant benefit to cancer patients who consume cannabis.
Since smoking is the most widely used route of cannabis administration, a
long-term concern has been its possible carcinogenic effects. A recent
epidemiological study demonstrated that cannabis smoking does not seem to cause
cancers of the respiratory tract [29], confirming my earlier prediction [30].
All
humans suffer from a common biochemical imbalance. We are all aging, and aging
is believed to be a consequence of accumulated free radical damage. With
respect to the biochemistry of aging, cannabinoids
appear to be beneficial. They not only appear to inhibit age related illnesses
such as multiple sclerosis [31] and diabetes [32], but their absence increases
the probability of premature death [33]. However, with respect to the
body’s method of defense against certain infectious diseases, an excess
of cannabinoids could be harmful or even lethal, in
particular, when fighting intracellular parasites such as those responsible for
Legionella disease [34] and tuberculosis [35].
Another possible danger that may result from cannabis consumption involves the
liver. On the one hand, recent data shows that hepatitis C patients who consume
cannabis are more likely to successfully complete there treatment regime [36].
On the other hand, turning off the CB1 receptors may
be beneficial for treatment of liver fibrosis [37] since CB1
activation seems to be involved in this pathology [38].
CONCLUSION
In
the marijuana plant, nature has provided us with a well-stocked medicinal
chemistry set. Everyday new peer reviewed scientific publications support and
extend the benefits that this plant can provide mankind. When you couple the
scientific data with the observations of medical marijuana users, the support
for medical marijuana use is overwhelming. How then is it possible that there
remains resistance to the medicinal use of marijuana? A possible answer may be
found in the simple truth that in any population of people there will be those
who are cannabinoid endowed and others who are cannabinoid deficient. When the deficiency involves the
areas of the brain that allow us to change our minds and replace out dated
information with new information, change becomes difficult. These individuals
unfortunately lack some of the necessary cannabinoid-based
biochemistry. This scenario raises the question: are cannabinoid
deficient people selected for by our political process? [1]
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websites:
Robert Melamede Ph.D.
cannabuzz.net
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