Tuesday, April 7, 2009

Combating Obesity with the Anti-Munchies: Are CB1 Inhibitors Any Good?

ResearchBlogging.orgIn a nice bit of synchronicity, I just found a study by Dr. John McPartland in PLoS ONE examining conflicts of interest in academic medicine with respect to the cannabinoid (CB1) receptor antagonist, rimonabant (aka Acomplia). We actually discussed this drug in my Cellular and Developmental Neuroscience class yesterday, as we've been learning about long-term potentiation, long-term depression, and other forms of synaptic plasticity that can be mediated by endogenous cannabinoids. I've also been hearing a lot about conflicts of interest lately as I move through the coursework in scientific ethics that I'm required to complete. (And, of course, Emory has gotten some press about an academic physician's major conflicts of interest recently. The university is making a substantial effort to ensure that things like this don't happen again, but it's a big deal.) So, this paper seemed like a good one for me to blog about.

First, a little background on endogenous cannabinoids, or endocannabinoids. You're probably all familiar with an exogenous cannabinoid -- that is, cannabis/marijuana. More specifically, the THC found within cannabis is an agonist for the CB1 receptor, which is responsible for the majority of the drug's effects. In addition to exogenous ligands like THC, there are endogenous ligands for CB receptors found naturally in your brain, including anandamide and 2-AG.

CB1 receptors help regulate signaling in the brain. In the traditional model of synaptic transmission, the presynaptic neuron releases a neurotransmitter, which binds to a receptor in the postsynaptic neuron. Messages are sent from cell to cell, allowing for the operation of the complex network that is your nervous system. Endocannabinoids play a somewhat unusual role in this process by generating a retrograde signal -- sent from the postsynaptic cell back to the presynaptic cell. Neurotransmission causes the postsynaptic cell to produce endocannabinoids, which are released back into the synapse and bind to CB1 receptors on the presynaptic cell. CB1 activation then attenuates subsequent neurotransmitter release by the presynaptic cell (or by other cells that just happen to be in the neighborhood, if they express CB1 receptors), which decreases the strength of the synapse. This feedback balances other forms of synaptic plasticity like short-term facilitation and long-term potentiation. The endocannabinoid mechanism is also important for long-term depression (LTD), a form of synaptic plasticity that can play a role in the extinction of old memories. Some believe that this explains anecdotal accounts of short-term memory disruption after cannabis use, as overactivation of CB1 receptors by the agonist THC could detrimentally dampen synaptic strength.

Endocannabinoids

The figure above shows a simplified version of the endocannabinoid system, in which glutamate neurotransmission from a presynaptic cell (top) leads to endocannabinoid synthesis by the postsynaptic cell (bottom), release of endocannabinoids into the synapse, and subsequent inhibition of further glutamate release by the presynaptic cell. Figure stolen from Prof. Randy Hall, who used it in his lecture yesterday.

Of course, LTD isn't the only mechanism of action for cannabinoids. THC is a popular recreational drug because it induces many other effects, including euphoria, relief of pain and nausea, and reduction of anxiety. It also, as any liberal arts graduate can attest, gives people the munchies. For this reason, the endocannabinoid system is a potential target for many avenues of drug development[1], but for now we'll focus on appetite suppressants.

Hunger and feeding behavior are controlled by a variety of molecules produced peripherally (for example, insulin made by the pancreas and leptin made by fat cells) and centrally (such as neuropeptide Y). Most biological functions related to feeding are centrally controlled by the hypothalamus, the brain's main neuroendocrine center. Hypothalamic cells are capable of sensing both circulating hormones and neuropeptides, allowing them to balance signals from the brain and the periphery. The endocannabinoid system plays a role in controlling hunger and feeding behavior via the hypothalamus, as described in this review by Di Marzo & Matias[2]:

[T]he brain endocannabinoid system controls food intake at two levels. First, it tonically reinforces the motivation to find and consume foods with a high incentive value, possibly by interacting with the mesolimbic pathways involved in reward mechanisms. Second, it is activated 'on demand' in the hypothalamus after short-term food deprivation and then transiently regulates the levels and/or action of other orexigenic and anorectic mediators to induce appetite.

In other words, stimulation of CB1 receptors causes animals to eat more food, and to seek out more rewarding foots (sweet or fatty) than they otherwise word. Inhibiting the action of endocannabinoids removes the preference for rewarding foods and can prevent an animal from eating, even if it has been deprived of food for some time. Other research indicates that the hormone ghrelin, which induces feeding behavior, increases endocannabinoids in the hypothalamus, and that CB1 receptor knockout mice don't have a normal appetitive response after receiving a dose of ghrelin[3].

Because of the crucial role that endocannabinoids play in hunger and eating, they're a potential target for appetite suppressant drugs. Rimonabant, which was commercially marketed as Acomplia, acts as a CB1 antagonist. This straightforward mechanism decreases appetite by interfering with endocannabinoids and their hypothalamic effects. In other words, this drug gives people the anti-munchies. But, given the broad spectrum of endocannabinoid-mediated effects in the brain, does a CB1 antagonist have other, less desirable effects? This is why we do experiments before making a new drug publicly available.

Any effective weight loss drug is a potential goldmine, and drug makers know this. Acomplia was developed by the pharmaceutical company Sanofi-Aventis and sold on the European market. During that time, Acomplia was also undergoing clinical trials in the US in an attempt to achieve FDA approval. It seems that despite some potential drawbacks to the drug, it was promoted heavily by academic physicans, many of whom did not disclose the fact that they were being paid by Sanofi-Aventis (indeed, some flat-out denied any conflict of interest when prompted) or the fact that articles being ascribed to them were probably ghostwritten by the pharmaceutical company. Dr. McPartland notes these facts in his study[4] of literature published on Acomplia during the pre-approval period.

A MEDLINE search was performed for rimonabant review articles, limited to articles authored by USA physicians who served as consultants for the company that manufactures rimonabant. Extracted articles were examined for industry-friendly bias ... Eight review articles were identified, but only three disclosed authors' financial conflicts of interest, despite easily accessible information to the contrary. The Takhar CME bias instrument demonstrated statistically significant bias in all the review articles. Biased statements that were nearly identical reappeared in the articles, including disease mongering, exaggerating rimonabant's efficacy and safety, lack of criticisms regarding rimonabant clinical trials, and speculations about surrogate markers stated as facts. Distinctive and identical misrepresentations regarding the endocannabinoid system also reappeared in articles by different authors.

To see Dr. McPartland really lay the smack down on the biased reviewers, please read his article. It goes into plenty of detail about "publication bias, which arises when pharmaceutical corporations choose not to publish unfavorable studies. ... [T]he use of unvalidated or disputed surrogate endpoints, favorable claims not supported by trial data, overstated treatment efficacy, downplayed adverse effects, lack of internal validity and external validity or generalizability, and failure to disclose financially-conflicted interests" in the Sanofi-Aventis-funded studies of Acomplia. Perhaps most damning: "[Evidence-based medicine] relies upon meta-analyses of [randomized clinical trials]. A meta-analysis of the [trials] concluded that rimonabant was safe and effective. The meta-analysis was funded by Sanofi-Aventis. ... four independent meta-analyses of the trials have questioned rimonabant's efficacy and potential for adverse effects."

Since Dr. McPartland completed his analysis of Acomplia studies, Acomplia has been taken off the European market, and the FDA rejected the drug "after data submitted by Sanofi-Aventis revealed adverse effects in RIO trials that went unreported in RIO publications, including one death in a rimonabant-treated subject (ruled a suicide by the FDA) that did not appear in the pertinent publication." It seems that chronic CB1 inhibition is not a good thing, which makes a kind of intuitive sense -- if CB1 agonists like THC make you "high," it's likely that CB1 antagonists could make you "low" (even suicidally so, if you believe the FDA's ruling). Anecdotal reports from Acomplia users in Europe suggest that while the drug effectively suppresses appetite, it also noticeably increases feelings of anxiety and unease.

Despite taking Sanofi-Aventis to task rather brutally for misrepresenting data in an attempt to sell their skinny pills, Dr. McPartland suggests that CB1 antagonists may be useful for acute conditions mediated by the endocannabinoid system, even if they are not appropriate for chronic administration. He also makes sure to declare his own potential conflict of interest: "The author previously received research and/or salary support from the Cannabinoid Research Institute, a research division of GW Pharmaceuticals."

References

1. Pacher, P.; Bátkai, S.; Kunos, G. (2006) The Endocannabinoid System as an Emerging Target of Pharmacotherapy. Pharmacological Reviews 58:389-462. DOI: 10.1124/pr.58.3.2

2. Di Marzo, V.; Matias, I. (2005) Endocannabinoid Control of Food Intake and Energy Balance. Nature Neuroscience 8:585 - 589. DOI: 10.1038/nn1457

3. Kola, B.; Farkas, I.; Christ-Crain, M.; Wittmann, G.; Lolli, F.; Amin, F.; Harvey-White, J.; Liposits, Z.; Kunos, G.; Grossman, A.B.; Fekete, C.; Korbonits, M. (2008) The Orexigenic Effect of Ghrelin Is Mediated through Central Activation of the Endogenous Cannabinoid System. PLoS ONE 3(3). DOI: 10.1371/journal.pone.0001797

4. McPartland, J. (2009) Obesity, the Endocannabinoid System, and Bias Arising from Pharmaceutical Sponsorship. PLoS ONE 4(3) DOI: 10.1371/journal.pone.0005092

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