Journal of the California Cannabis Research Medical
Cannabinoid Antagonist Will
be Sold as Diet Drug
By Fred Gardner
Sanofi, a multinational pharma-cuetical company based in France, is planning
to market a weight-loss drug called Rimonabant that works by blocking part
of the cannabinoid receptor system.
Scientists employed by Sanofi reported at the 2004 meeting
of the International Cannabinoid Research Society that Rimonabant has
proven safe and effective in clinical trials involving 13,000 patients.
Sanofi expects FDA approval within the year. The fact that Rimonabant blocks
the “euphoric” effects of marijuana is a big plus in the eyes of U.S. government
Sanofi researchers Murielle Rinaldi-Carmona,
Francis Barth, and Gerald Le Fur were honored at the 2004 ICRS
meeting for developing a drug that blocks cannabinoid receptors.
The marketing is already done, in a sense, because everybody knows
that marijuana induces the munchies, and it seems logical that
blocking the cannabinoid receptors
would reverse the effect.
But the advent of Rimonabant troubles California doctors who have made a
specialty of monitoring their patients’ cannabis use, as well as some scientists who
are studying the basic nature of the cannabinoid system. Jeffrey Hergenrather,
MD, of Sebastopol —one of the few clinicians to attend this year’s ICRS meeting— says, “We
are only now becoming aware of the modulating effects the cannabinoids have
on the body and mind. The consequences of interfering with the cannabinoid
receptor system have not been evaluated in normal human physiology.”
Cannabinoid receptors are proteins on the surface of certain cells to which
certain compounds bind, setting off molecular cascades within the cells that
produce effects in the body such as reduced inflammation, increased appetite,
etc. Two kinds of cannabinoid receptors have been discovered —CB1 , which is
highly concentrated in the brain and central nervous system, and CB2, found
mainly in tissues associated with the immune system.
There are three different kinds of cannabinoids, or chemical “agonists” that
activate the cannabinoid receptors. They are, in order of evolutionary appearance:
compounds made in the body for purposes of neurotransmission, compounds unique
to the cannabis plant (the most famous being delta-9 THC), and compounds made
in the lab —synthetics.
Cannabinoids made in the body are called “endocannabinoids” (the prefix is
a contraction of “endogenous,” just as the body’s endogenous morphine-like
chemicals are called “endorphins”).
The first endocannabinoid to be identified —by Raphael Mechou-lam and William
Devane in 1992— was named “anandamide” after the Sanskrit word for “bliss.”
It has since been learned that endocannabinoids help regulate the cardiovascular,
digestive, endocrine, excretory, immunological, nervous, reproductive, and
Rimonabant is SR-141716 redefined as a “therapeutic drug”
Rimonabant is an “antagonist” drug that engages the CB1 receptors
so they can’t be activated. Originally called SR-141716, it was developed
by Sanofi in the early ’90s as a research tool. If a given effect is
blocked by SR-141716, that effect is said to be mediated by CB1 receptors.
Rimonabant is SR-141716 redefined as a “therapeutic drug” that counteracts
unwanted effects —like overeating— mediated by the cannabinoid receptor
In a talk at the ICRS meeting entitled “Clinical Results with Rimonabant in
Obesity,” Sanofi researcher Gerard Le Fur reported that the drug had done well
in phase-three clinical trials involving 13,000 patients. The trials were conducted
at numerous sites in the U.S. Obese patients were treated with Rimonabant for
52 weeks. “Over 72% of patients at 1 year showed a weight loss of greater than
5 percent, with over 44% showing a weight loss of greater than 10%,” according
to Le Fur. “There was also an increase in HDL-cholesterol values, a reduction
in triglyceride values and reductions in glucose and insulin values... The
general tolerance of the compound was excellent.”
Le Fur and other Sanofi researchers were asked how a drug could block the CB1
receptor system without adversely affecting mood, sleep, pain relief, and other
CB1 -mediated aspects of well-being. The answers were vague —other neurotransmitters
may play compensatory roles. We were told that no pattern of adverse effects
had been observed during the clinical trials, and that such effects are probably
so rare that they won’t be detectable until Rimonabant has been used by millions
of people over a period of years.
The developer of another antagonist drug, a rival of Sanofi’s, claimed that
Rimonabant induced “food aversion” in five percent of the test subjects. Le
Fur responded that obesity was such a widespread and serious health problem
that five percent seems like an acceptable rate of anorexia.
Other criticisms and misgivings were only whispered. A multiple sclerosis specialist
told of a case in which Rimonabant apparently caused an immediate, extreme
exacerbation. A physician wondered —since the body’s own cannabinoids have
neuropro-tectant and anti-oxidant functions—if Rimonabant users would be at
increased risk for stroke and cancer. But the negative remarks were anecdotal
or speculative; the positive data belonged to Sanofi.
Le Fur and two colleagues accepted the ICRS’s 2004 achievement award on behalf
of their company. It was presented by Mechoulam himself, the grand old man
of the field, who observed that Sanofi had shown great foresight in developing
a weight-loss drug in the 1990s, because it has since swallowed up two much
larger drug companies, Synthelabo and Aventis.
From the perspective of the scientists in the ICRS —mainly employees of universities
or pharmaceutical companies who get funding from the U.S. National Institute
on Drug Abuse— it’s a win-win-win to honor Sanofi for developing CB-receptor
antagonists as “new therapeutic drugs.” NIDA is eager to sponsor research involving
cannabinoid antagonists. A lot will be learned about the cannabinoid system,
its mechanism of action, etc. And a therapeutic effect is a therapeutic effect,
whether it’s produced by activating or blocking the cannabinoid receptors.
But common sense and a few cautious clinicians say DANGER DANGER DANGER! CB1
receptors are concentrated in the cerebellum and the basal ganglia (responsible
for motor control, which may help explain why marijuana eases muscle spasticity
in disorders like multiple sclerosis), the hippocampus (responsible for storage
of short-term memory), and the limbic system (emotional control). Although
other neurotransmitters may play compensatory roles when the cannabinoid receptors
are blocked, the longterm impacts will not be known until years after Sanofi
gets approval to market Rimonabant to the pizza-loving masses. Before marketing
commences, says Hergenrather, “It would be ethical to design longitudinal studies
to assess the consequences of interfering with the cannabinoid system.”
Other uses for cannabinoid-antagonist drugs are being studied with active encouragement
from NIDA. Walter Fratta of the University of Cagliari gave a paper in Paestum
[see story at bottom of page] proposing antagonists “as therapeutic agents
to prevent relapse to heroin abuse.” Carl Lupica of NIDA discussed Rimonabant
as a “potential treatment” for food, alcohol and nicotine cravings. “It is
also clear that marijuana craving may be successfully treated by this drug,” he
G.W. still waiting for approval
Alas, this was supposed to be the year that G.W. Pharmaceuticals won the ICRS
achievement award and hosted the big party. G.W. is the British firm that in
1998 got government approval to develop and test an extract of the cannabis
plant which it formulated as an oral spray and dubbed “Sativex.”
Clinical trials of Sativex as a treatment for neuropathic pain, multiple sclerosis
and other conditions were conducted and favorable results reported to the regulators.
Bayer agreed to market Sativex in Europe when the approval came through. G.W.
generously made Sativex and other plant extracts with different cannabinoid
contents available to investigators who previously could experiment only with
synthetics or plant material from NIDA.
But the marketing approval that Guy said he expected by the end of 2003, and
then by spring ’04, has yet to be granted. So he and his associates had to
walk a bit of a tightrope in Paestum, reassuring all concerned that Sativex
certainly will get approved, while not risking any more misstatements about
Guy cited favorable data produced in recent trials of Sativex as a treatment
for pain in rheumatoid arthritis and spasticity in multiple sclerosis. G.W.
researcher Ethan Russo presented a paper showing that patients taking Sati-vex
achieve beneficial effects without requiring increasingly large doses, i.e.,
tolerance does not build up.
Unfortunately, in the U.K. as in the U.S., favorable trial results can count
for less than the establishment connections of the doctors who conduct them.
And so the British regulatory authorities continue to ponder G.W.’s dossier,
while the banquet at this year’s ICRS meeting was hosted by Sanofi.
“Beneficial Effects” Takes Back Seat
Russo’s talk was one of three given on “Beneficial Effects” at the end of the
last day. The auditorium in which more than 400 conference participants had
listened to earlier speakers held about 50. Beneficial effects seemed more
like a quaint afterthought than an urgent goal.
Russo’s report was significant. He and three colleagues had looked at data
from various trials in which subjects had used Sativex, GW’s 50-50 mixture
of high-THC and CBD plants formulated for spraying under the tongue for 600
patient-years. “Consistent maintenance of symptom control (pain, spasm, sleep,
bladder disturbances) with stable or even diminishing CBME dosages was noted.
Sativex in chronic adminsitration demonstrates a favorable side-effect profile
in comparison with standard medicines for neurogenic symptoms, with no tolerance
developing to its clinical benefits.”
Sebastopol general practitioner Jeffrey Hergenrather, MD, described the health
history questionnaire developed by the California Cannabis Research Medical
Group [previewed in the Spring 2004 O’Shaughnessy’s] to facilitate data collection
and research. California patients have reported that cannabis helped ease the
symptoms of more than 100 conditions not referred to in the pre-1937 medical
Tomi Jarvinen of the University of Kuopio, Finland, reported that THC, anandamide
and other natural cannabinoid agonists could be made more water soluble by
formulating them as phosphate esters or cyclodextrins. As in so many of the
earlier talks, the beneficial effects Jarvinen was referring to will be delivered
at some time in the future. And people are hurting in the now.
Scientific conferences are divided into talks and posters. The talks are 15
minutes; speakers can use all their time to describe their research or leave
a few minutes for questions. Everyone shows slides, and many simply read the
same text that’s being shown on the slides.
When we first attended an ICRS meeting in ‘98, there were 63 posters; this
year there were 155, which shows how the field is burgeoning. As in previous
years, the brilliant young researchers we talked to expressed confidence that
relying on the U.S. National Institute of Drug Abuse for funding won’t undermine
their objectivity or induce them to search for adverse effects. They’re conducting
useful basic research that will explain the body’s endogenous cannabinoid system
and lead to useful new drugs.
And yet the net effect of virtually all the funding going to people who are
trying to develop synthetics, or “elucidate the basic mechanism” by which the
receptor gets activated, inducing a chain of chemical events inside the cell...
is to deflect research away from the plant itself.
As a biochemistry postdoc at UCSF (where not a single investigator studied
plants) told us in ‘98, “If you care about cost-effective treatment for individuals,
then you would be in favor of the classic natural cannabinoids. However, if
you care about drugs that optimally treat the various conditions, then you
start looking at receptor distribution and maximizing activity and things like
Being partial to those classic natural cannabinoids, we were interested in
a poster by Benjamin J. Whalley and co-workers at the University of London’s
School of Pharmacy: “A Novel Component of Cannabis Extract Potentiates Excitatory
Synaptic Transmission in Rat Olfactory Cortex In Vitro.”
Whalley et al. worked with a “standard cannabis extract” —meaning whole buds
turned into a liquid by a strong blender— from which they removed the delta-9
THC by chemical means. They found that whereas THC has a suppressive effect,
the THC-free extract had an excitatory effect on nerve cells taken from the
olfactory cortex (of a rat), an ancient part of the brain. They know that the
mystery component is working through CB1 receptors because its effect can be
blocked by the cannabinoid antagonist SR141716A. The authors infer that a “novel
compound” is active in the plant, it does not appear to be CBD, and its potentiating
effect at the synapse appears to be greater than THC’s.
Federico Massa's group showed that the endogenous
cannabinoid system protects against colonic inflamation.
The authors conclude, “The potentiating effects and enhancement of
cell excitability of the unkown extract constituent(s) on neurotransmission
were capable of over-riding
the predominantly suppressive effects of delta-9-THC on excitatory neurotransmitter
release. This phenomenon may possibly explain the preference by some patients
for herbal cannabis rather than isolated delta-9-THC (due to attenuation
of some of the central delta-nine-THC side effects) and even account
for the rare incidence of seizure episodes in some individuals taking
It may turn out that one of the terpenes that give cannabis flowers
their smell is also exerting an effect on the mind and body! Smell
matters —and not just
Krysztina Monory was a co-author on a poster by Federico Massa and lead author
on another, “Mechanism of Cannabinoid Receptor-Dependent Protection Against
Excitotoxicity.” She is trying to figure out exactly how anadamide and CB1
receptors are involved in protecting against nerve damage in mice.
Massa’s group showed that the endogenous cannabinoid system protects against
colonic inflammation “both by dampening smooth muscular irritation caused by
inflammation and by controlling cellular pathways leading to inflammatory responses.”
ICRS 2004: 10 Talks of Special Interest
to Dr. X
1. “Physical Interactions of CB1 Cannabinoid and D2 Dopamine Receptors” by
Christopher Kearn et al. was the favorite of Patricia Reggio and other
researchers I surveyed. CB receptors form homodimers (CB receptors
oligomeriz-ing with themselves in pairs or more) and even heterodimers
(CB receptors linking with other receptors such as dopamine receptors).
The system IS complex and dynamic. We’re only beginning to understand...
2. Niehaus et al and Elphick et al. described CRIPs, and Breivogel
described beta-arrestins —proteins associating with CB receptors— more
complexity. These partners modulate CB constitutional activity (CRIPs)
and response to THC (beta-arrestin). From a phylogenetic viewpoint,
these associative proteins may be the reason why CB receptors function
differently in humans versus rodents.
3. Pryce and Baker was a talk you rarely hear: “Hey, we got it wrong.
Our landmark study published in Nature 2000 was not right.” They suggested
no physiology study can be entirely trusted if the workers limited
their methods to the use of “selective” agonists and antagonists. There
is no such thing as “selective” in the CB world - all the current drugs
are dirty and lack specificity. Pryce and Baker say the way to go with
CB physiology research is knockout mice. See next paragraph.
4. Cravatt, Lichtman, et al. designed a “partial” knockout, expressing
FAAH in the central nervous system but not in peripheral tissues. This
will enable physiologists to look closer at the difference between
CB1 (central) and CB2 (peripheral).
5. Okamoto et al. and Bisogno et al. have discovered the enzymes that
synthesize (cleave) anandamide and 2-AG (respectively). These studies
complete the molecular characterization of the endocannabinoid system.
(We already knew the genes for CB receptors and catabolic enzymes like
FAAH.) Maybe we can find out WHY animals synthesize endocannabinoids,
which to me is the million dollar question.
Van der Stelt et al. and De Petrocellis delve into the million dollar
question — the raison d’etat for anandamide (at least its function
at vanilloid receptors). It functions as intracellular messenger, signaling
to vanilloid receptors to gate extracellular calcium ions, controlling
basic cellular function, with therapeutic implications regarding inflammatory
7. Malan et al. Another presentation keeping with the complexity theme.
CB2 receptors in the skin [hey, I didn’t know that, for starters],
when activated, reduce nociception [pain before it reaches the brain]
by stimulating the release of endorphins in skin cells. Far out.
8. Bab et al. and Karsak et al. continue to build on their research
concerning CB2s expressed in osteoblast cells - CB knockout mice have
a low bone mass —could THC be a cure for osteoporosis? They are on
to something, big I think— Karsak was very cagey with me when I asked
her some questions after her talk.
9. Varvel and Cannich continue working upon “active forgetting” —the
endocannabinoid system’s role in the suppression and extinction of
learned behavior, especially fear behavior— the reason why so many
Nam vets medicate their PTSD with pot. Perhaps this approach would
also help people with phobias, and even help addicts forget about their
lingering jones (but wait, I thought CB antagonists were supposed to
help with drug addiction, not CB agonists...).
10. Last but not least, all the studies about CBD! The difference
a decade makes: I presented a poster about CBD in 1994 and mine was
the only mention of CBD at the conference. In 2004 we heard a dozen.
The most noteworthy: Costa re: CBD modulating neuropathic pain via
vanilloid receptors, Fadda et al. re: CBD reversing impaired memory
caused by THC, Ligresti et al. re: CBD’s anti-tumor activity, Liou
et al. re: CBD preventing vascular permeability with therapeutic implications
regarding diabetes; Cluny et al. re: CBDic acid attenuating emesis.
The difference between 1994 and 2004? GW Pharmaceuticals sparking the
interest and supplying the drug to researchers.