Issue 4 • 1000219 Mol Biol, an open access journal Dawson

Abstract

This disquisition is designed to be an exploration of the controversies, contentions, and consternations with regard to the efficacy and potential of a newly devised CAM approach which entails modulating the endocannabinoid system and is considered to be a potentially useful technique for the treatment of obesity and diabetes. This paper is constructed to provide the reader with an understanding of the principles underlying a form of Complimentary Alternative Medicine (CAM) which has existed for millennia but has only recently attained credibility and acceptance within the scientific community. It provides a historical analysis of the perceived equivalency between synthetic cannabinoids and organic cannabinoids as well as the unknowns of each in their potential treatment of obesity and diabetes.

Full text

Volume 7 • Issue 4 • 1000219
Mol Biol, an open access journal
ISSN: 2168-9547
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ISSN: 2168-9547
Molecular Biology
Dawson, Mol Biol 2018, 7:4
DOI: 10.4172/2168-9547.1000219
Perspective Article Open Access
Synthetic Cannabinoids, Organic Cannabinoids, the Endocannabinoid
System, and Their Relationship to Obesity, Diabetes, and Depression
David A Dawson*
Director of Endocannabinoid Research & Development, Helping End the Opiate Addiction (HEOE), Biology, Clearwater, Florida 33763, United State
Abstract
This disquisition is designed to be an exploration of the controversies, contentions, and consternations with regard
to the efcacy and potential of a newly devised CAM approach which entails modulating the endocannabinoid system
and is considered to be a potentially useful technique for the treatment of obesity and diabetes. This paper is constructed
to provide the reader with an understanding of the principles underlying a form of Complimentary Alternative Medicine
(CAM) which has existed for millennia but has only recently attained credibility and acceptance within the scientic
community. It provides a historical analysis of the perceived equivalency between synthetic cannabinoids and organic
cannabinoids as well as the unknowns of each in their potential treatment of obesity and diabetes.
*Corresponding author: David A Dawson, Director of Endocannabinoid
Research & Development, Helping End the Opiate Addiction (HEOE), Biology,
Clearwater, Florida 33763, United States, Tel: 1 (458) 229-2021, E-mail:
d.dawson8352@o365.ncu.edu
Received September 05, 2018; Accepted September 12, 2018; Published
September 22, 2018
Citation: Dawson DA (2018) Synthetic Cannabinoids, Organic Cannabinoids,
the Endocannabinoid System, and Their Relationship to Obesity, Diabetes, and
Depression. Mol Biol 7: 219. doi: 10.4172/2168-9547.1000219
Copyright: © 2018 Dawson DA. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited.
Keywords: Cannabinoids; Diabetes; Obesity; Depression;
Rimonabant; CAM; Receptors
Introduction
e following disquisition is designed to be an exploration of
the controversies, contentions, and consternations with regard to the
ecacy and potential of a newly devised CAM approach which entails
modulating the endocannabinoid system and is considered to be a
useful technique for the treatment of obesity and diabetes. By necessity,
this exploration becomes rather convoluted because in the year 2006
traditional medicine took a shot at incorporating this CAM approach
into their world-view by attempting to integrate their synthetic, single
molecule paradigm into a system of incredible molecular diversity.
Although the attempt failed dramatically and resulted in a large
number of major depressive episodes as well as two suicides, the
endeavor provided some valuable knowledge applicable to the eld of
bimolecular psychology.
Two ailments will be discussed, one physical and one emotional.
As will be demonstrated, both are intricately interrelated, although
not in a way that is immediately and intuitively apparent. e areas
where our knowledge is lacking and the necessity of research in the
eld of biomolecular psychology will be explored which will further
our understanding of the endocannabinoid system as well as how this
knowledge can be incorporated into this next frontier of medicine.
is paper is constructed to provide the reader with an understanding
of the principles underlying a form of Complimentary Alternative
Medicine (CAM) which has existed for millennia but has only recently
attained credibility and acceptance within the scientic community.
e approach based on the biological system was discovered less than
two decades ago, and therefore the paradigm is still in its infancy.
Traditionally, new paradigms in science are met with resistance
even though it is a scientist’s responsibility to design studies which
potentially challenge the dominant world-view. However, traditionally
scientists that challenge dominant paradigms are oen persecuted
[1]. For example, Albert Einstein struggled when attempting to gain
acceptance of his theory of relativity. Galileo died under house arrest for
proering the paradigm of a heliocentric universe, and Charles Darwin
is still being persecuted 160 years aer he established the paradigm on
which the science of biology is now based. e point is scientists at the
forefront of paradigm shis have to expect resistance from purveyors
of the dominant ideology, and imaginative methods are at times
utilized to combat the perceived threat of attaining new knowledge.
is resistance manifested itself as a ban being imposed on the research
of organic cannabinoid molecules (phytocannabinoids) in 1971, and
because of this, there are gaps in our knowledge and understanding
of the intersection of the endocannabinoid system with the study
of psychology and medicine. Ironically, our understanding of this
intersection has been greatly enhanced by the study of pharmacology
and an attempt by a French pharmaceutical company called Sano-
Aventis to treat obesity and diabetes by creating a synthetic cannabinoid
designed to dominate the biological system which controls virtually
every aspect of the way our minds and bodies function.
Obesity and diabetes have become health problems of epidemic
proportions in the industrialized world [2,3]. More than a million and
a half studies have been penned about obesity alone, and the condition
is still considered extremely dicult to control in the modern world.
Traditional treatments of low-calorie diets and appetite-suppressing
drugs frequently fail [4]. e majority of studies reporting weight loss
resulting from merely low-calorie diets report that most subjects regain
the weight back either partially or completely within three to ve years
aer treatment ends, and long-term studies present a less favorable
outcome with 49.5% of subjects regaining or surpassing their previous
weight [5]. ese issues with traditional treatment ecacy indicate the
necessity for the development of new strategies of both losing weight
and maintaining that weight loss.
In a study examining the relationship between obesity and diabetes
conducted by the National Health and Nutrition Examination Survey
(NHANES), researchers found the prevalence of diabetes increased
with escalating weight classes [6]. Other researchers also weigh in
on intervention approaches for treating diabetes. “Nearly half of
adult diabetics are considered obese suggesting that weight loss is an
important intervention in an eort to reduce the impact of diabetes
on the healthcare system.” [7]. In 2012, the total healthcare cost for
diagnosed cases of diabetes in the United States was 245 billion dollars.
At that time it was expected the cost would soar to half a trillion dollars
by the year 2020 and we as a nation are well on our way to achieving those

Volume 7 • Issue 4 • 1000219
Mol Biol, an open access journal
ISSN: 2168-9547
Citation: Dawson DA (2018) Synthetic Cannabinoids, Organic Cannabinoids, the Endocannabinoid System, and Their Relationship to Obesity,
Diabetes, and Depression. Mol Biol 7: 219. doi: 10.4172/2168-9547.1000219
Page 2 of 4
projections. e total estimated cost of diagnosed diabetes in 2017 was
327 billion dollars in direct medical costs plus an additional 90 billion
dollars in reduced productivity. Aer adjusting for ination, economic
costs of diabetes rose by 26% from 2012 to 2017 due to its increased
prevalence and the increased cost per aicted person [8]. Traditional
approaches for treating diabetes involve the patient keeping close watch
over their blood sugar levels and maintaining them within parameters
set by their doctor, and by employing a combination of diet, synthesized
medications, and exercise [9]. People with diabetes frequently use
complementary and alternative medicine (CAM) techniques of
multiple varieties ranging from dietary approaches to herbal and
vitamin therapies, and massage. e endocannabinoid system has
lately received considerable attention as a potential therapeutic target
in combating obesity as well as its associated metabolic abnormalities
[10]. Studies by Sano-Aventis Pharmaceuticals demonstrated that a
simple synthetic CB1 receptor antagonist (Rimonabant) corrected the
deleterious eects of diet-induced obesity by restoring insulin sensitivity
and normalizing fat cell size and distribution [11]. is antagonist
also prevented visceral fat accumulation and decreased subcutaneous
fat. Other investigations showed similar ndings and concluded that
blockage of the CB1 receptors with Rimonabant decreased body weight
and adiposity, independent of sustained reductions in food intake in
humans, canines, and rodents [12-16].
By the year 2006 Sano-Aventis had conducted numerous studies
which indicated the central cannabinoid (CB1) receptors played a
signicant role in controlling food consumption and dependence. To
develop suitable synthetic medicines against this target, compounds
with potential activity against this receptor were screened for inhibitory
activity. Rimonabant emerged from this screening process as a potent
CB1 receptor antagonist. Preclinical animal trials subsequently showed
that it reduced consumption of fats and sugars which are signicant
contributors to weight gain. ese preclinical ndings were conrmed
in a series of clinical studies involving over 6,000 obese subjects and
carried out in both the Americas and Europe. In the United States,
the FDA requires two years of safety data before approving anti-
obesity medicines, and as part of their patent application process,
the pharmaceutical company conducted those trials. e conclusion
of the FDA meta-analysis of Rimonabant safety data indicated an
increased risk for suicidal ideation in patients and two suicides were
recorded across the two-year Rimonabant clinical trial program.
Furthermore, an analysis of data collected from four double-blind,
randomized controlled trials demonstrated that 20 mg per day of this
synthetic cannabinoid increased the risk of psychiatrically adverse
events, specically, depressed mood disorders and anxiety [17-20].
ese ndings resulted in marketing authorization being withdrawn
for Rimonabant because the adverse psychological eects could not
be addressed [21]. ese results beg two questions. First, what is the
mechanism causing these emotional disorders? Second, would an
organic phytocannabinoid CB1 receptor antagonist produce similar
results? Analyzing these questions individually brings up other questions
indicative of how little we know about the correlation of synthetic
cannabinoid medicines with organic phytocannabinoid supplements.
A comprehensive review of the literature also indicates how little
we understand about Rimonabant. 2,980 studies published within
the last ve years classify the synthetic cannabinoid as an antagonist
at the receptor, while 1,327 studies identify it as an inverse agonist.
Scientic truth is not determined democratically, and the manufacturer
of Rimonabant stopped answering questions about the synthetic
cannabinoid in 2009 with the claim that the information is proprietary.
is distinction between antagonist and inverse agonist is critical
because it speaks to the mechanism causing the adverse reaction. An
inverse agonist serves as a receptor blocker, precluding the attachment
of anandamide, the body’s natural antidepressant endocannabinoid
[22]. eoretically, blocking the attachment of anandamide to the CB1
receptor could conceivably result in depression. If merely blocking the
CB1 receptor is enough to produce depression, any inverse agonist that
attaches to that receptor would prohibit the attachment of anandamide.
If the1327 studies are correct, and Rimonabant merely acts as a receptor
blocker, its phytocannabinoid equivalent would be CBD, providing
an accessible population in the United States for survey depression
studies. According to data obtained by the National Conference of
State Legislators (2018), only four states remain that ban access to
natural CBD. Cannabinoids derived from hemp are legally marketed
in the remaining states as treatment for a variety of ailments despite
the long-held FDA contention that the synthetic cannabinoids are
medicinal and the organic cannabinoids are among the most addictive
and dangerous molecules humans can ingest. Coincidently, 20 mg is
the usual suggested dose of most phytocannabinoid supplements
suggested by marketers of these products in the United States, although
many recommend multiple doses per day. No studies exist on whether
naturally produced CBD isolates increase the risk of these adverse
psychiatric reactions. ere are two schools of thought on this. e rst
is that synthetic cannabinoids and cannabinoids produced naturally
(organic cannabinoids) act on the CB1 receptors in the same way, and
therefore the eects of each should be similar. e question becomes,
do both the synthetic and natural CBD act on the receptors in the same
way? If they do, organic CBD should also be expected to be associated
with depressed mood disorders, and physicians should be alerted to
these potentially severe adverse psychiatric reactions by the US Food
and Drug Administration. e second school of thought advances the
notion that while naturally produced CBD acts as an inverse agonist
at the CB1 receptor, the enzyme Fatty Acid Amide Hydrolase (FAAH)
breaks down the organic molecule faster than the synthetic, thereby
reducing the depressive eects. e most useful analogy to view this
way of thinking is imagining the enzyme eating something organic as
opposed trying to eat something plastic.
However, no studies have been conducted comparing degradation
rates of organic cannabinoids with synthetic cannabinoids and
therefore, staying true to the paradigm as presented, all indications lead
to the conclusion that naturally produced CBD would increase the risk
of psychiatric adverse events in the same way the synthetic cannabinoid
does. Dierences in degradation rates between phytocannabinoids and
synthetic cannabinoids is an area in which further research is necessary.
Evidence obtained from the multiple studies of Rimonabant and
its depressive properties suggests that other inverse agonists at the
CB1 would have depressive properties as well. However, due to the
ban on research of phytocannabinoids in the United States, this has
never been studied. Given the proliferation of companies marketing
isolate organic phytocannabinoid supplements throughout the nation,
studies looking for possible deleterious eects of these products on a
population are necessary. With 92% of the nation allowing medicinal
cannabinoid use, clinical and policy concerns regarding the mental
health eects of organic cannabinoids should be examined regardless
of the federal mandate that such studies not be allowed. Analyzing
this mandate from the paradigm of synthetic cannabinoid/organic
cannabinoid equivalency, it becomes apparent that a survey study of
possible depressive properties of CBD isolates could easily be conducted
without Federal approval. Given the fact that the population is already
legally intromitting these supplements, it seems appropriate to study
their eects.
e National Institute of Drug Abuse subsidizes studies designed

Volume 7 • Issue 4 • 1000219
Mol Biol, an open access journal
ISSN: 2168-9547
Citation: Dawson DA (2018) Synthetic Cannabinoids, Organic Cannabinoids, the Endocannabinoid System, and Their Relationship to Obesity,
Diabetes, and Depression. Mol Biol 7: 219. doi: 10.4172/2168-9547.1000219
Page 3 of 4
to prove the deleterious eects of cannabis while blocking inquiry
into its potential benets (National Institute of Drug Abuse, 2018).
If Rimonabant is an antagonist at the CB1 receptor the depression
mechanism is dierent, but a study would t into NIDA’s wheelhouse.
NIDA contracts with the University of Mississippi to produce
phytocannabinoids for research purposes, and from a biomolecular
perspective, one of the most important studies this supply could be used
for is an analysis of the mechanism by which CB1 antagonism causes
depression. eoretically, the depression could either be the byproduct
of the antagonism of the CB1 directly, or the result of blocking the CB1
receptor, thereby prohibiting the binding of anandamide, the body’s
natural antidepressant endocannabinoid [23].
Evidence indicates that most, if not all, of the central nervous system
actions of cannabinoids, whether they be plant-derived, endogenous, or
synthetic are related to an anity for binding with the CB1 receptor.
If Rimonabant is an antagonist, the phytocannabinoid equivalent
has been determined to be THCV [24-26]. In the phytocannabinoid
world, Tetrahydrocannabivarin (THCV) appears to be an anomaly as
the only known phytocannabinoid antagonist at the CB1 receptor. Of
course, there are 112 other known phytocannabinoids and information
is still lacking about how each acts on the body’s various receptors.
What we do know has to do with the “nature of science.” In scientic
research, it is generally the anomalies that end up being important. is
has particular signicance with regard to devising a CAM approach
utilizing the principles of biomolecular psychology in the treatment of
diabetes [27].
Manipulation of CB1 receptors with Rimonabant resulted in a
signicant reduction in body weight, waist circumference, triglyceride
concentrations, an increase in HDL cholesterol and adiponectin
concentrations and a reduced number of subjects with type 2 diabetes
[28]. However, as already discussed, in 2008, marketing authorization
for Rimonabant was withdrawn due to a signicant increase in
incidences of adverse psychiatric events [29].
Two possible phytocannabinoids equivalents to Rimonabant have
been discussed, and both have signicant implications concerning
proper regulation of the endocannabinoid system in addition to
obesity, diabetes, and depression. Cannabidiol (CBD) provides an
astonishing benet with respect to hyperglycemia, mainly through
its anti-inammatory and antioxidant properties, and modulates
cardiovascular response to stress [30].
D9-Tetrahydrocannabivarin (THCV) is a naturally occurring
analog of THC, but with dierent pharmacological eects. As with
many of the phytocannabinoids it acts on the receptors dierently
depending on the amount intromitted. At low dose (5-7.5 mg) it
antagonizes the CB1 receptors resulting in an inhibition of appetite,
while at moderate to high doses (10-20mg) it acts as an inverse agonist
CB2 receptor blocker and full agonist at the GPR55 receptors resulting
in a regulation of blood sugar levels while reducing the body’s resistance
to insulin. ese properties make the potential benet of THCV and
CBD, alone or in combination, very interesting molecules for study
in regard to the treatment of obesity and diabetes as they have very
distinct pharmacological proles, and therefore dierent side eects to
Rimonabant [31-33].
Recently the American Diabetes Association published a meta-
analysis indicating that there may be ethnic dierences of the optimal
states in the relationship between insulin sensitivity and insulin response.
e genetic background of Africans and East Asians makes them more
and dierentially susceptible to diabetes than Caucasians [34-37], and
ethnic groups are more likely to use CAM as a treatment option than
Caucasians [38-41]. is indicates the necessity of further study and
development of CAM approaches for the treatment of diabetes which
are based on sound scientic methodology, and an argument could be
proered that further studies of the endocannabinoid system could
lead to methods of balancing its environment through the judicious
supplementation of naturally occurring cannabinoids.
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Volume 7 • Issue 4 • 1000219
Mol Biol, an open access journal
ISSN: 2168-9547
Citation: Dawson DA (2018) Synthetic Cannabinoids, Organic Cannabinoids, the Endocannabinoid System, and Their Relationship to Obesity,
Diabetes, and Depression. Mol Biol 7: 219. doi: 10.4172/2168-9547.1000219
Page 4 of 4
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