Modulation of anxiety through blockade of anandamide hydrolysis

[frizzantik]

The psychoactive constituent of cannabis, Delta9-tetrahydrocannabinol, produces in humans subjective responses mediated by CB1 cannabinoid receptors, indicating that endogenous cannabinoids may contribute to the control of emotion. But the variable effects of Delta9-tetrahydrocannabinol obscure the interpretation of these results and limit the therapeutic potential of direct cannabinoid agonists. An alternative approach may be to develop drugs that amplify the effects of endogenous cannabinoids by preventing their inactivation. Here we describe a class of potent, selective and systemically active inhibitors of fatty acid amide hydrolase, the enzyme responsible for the degradation of the endogenous cannabinoid anandamide. Like clinically used anti-anxiety drugs, in rats the inhibitors exhibit benzodiazepine-like properties in the elevated zero-maze test and suppress isolation-induced vocalizations. These effects are accompanied by augmented brain levels of anandamide and are prevented by CB1 receptor blockade. Our results indicate that anandamide participates in the modulation of emotional states and point to fatty acid amide hydrolase inhibition as an innovative approach to anti-anxiety therapy.

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Very interesting.. it seems they're developing drugs which prevent the breakdown of cannabinoids. It'd be nice for pot to get some potentiators like other drugs

 

[frizzantik]

Thus, at doses that almost abolished FAAH activity and substantially raised brain anandamide levels, URB597 and its analog URB532 did not evoke catalepsy, reduce body temperature or stimulate feeding, three key symptoms of cannabinoid intoxication in the rodent11.

Nevertheless, the compounds did elicit marked anxiolytic-like responses, which paralleled their ability to inactivate FAAH and were prevented by the CB1 receptor antagonist rimonabant. We interpret these findings to indicate that URB597 and URB532 may selectively modulate anxiety-like behaviors by enhancing the tonic actions of anandamide on a subset of CB1 receptors which may normally be engaged in controlling emotions.

also, the chemicals they used decreased anxiety and pain (not mentioned in the quote above but in the article it is) without inducing a catonic state or increasing hunger.. it sounds like they've isolated the best parts of the high

 

[BilZ0r]

It'll be a long long time before drugs like that enter the clinic, but they will undoubtable be more succesful than straight CB1 agonists, because I'm sure their tolerability will be much higher.

 

[fishman]

i was considering going on to graduate school to get involved in endocannabinoid-related psychopharmacology, but it quickly became clear to me that any real, clinical applications are years, if not decades away, at least in the US. while i truly believe that if the pharmaceutical industry were to fully exploit this particular signalling system they could have another SSRI-like-scene on their hands, i think that the social stigma will be really hard to get around any time soon. plus, they have yet to tap the SSRI/SNRI pool... only recently have they started handing out SSRIs for premature ejaculation! if you're into endocannabinoid research and haven't read any of daniele piomelli's work out of uc-irvine, check him out. he's a badass.

 

[fungus44]

if you're into endocannabinoid research and haven't read any of daniele piomelli's work out of uc-irvine, check him out. he's a badass.

Is there a suggested link?

Are SCRIs on the agenda as antidepressants or hypnotics?

 

[fishman]

in my opinion, reuptake inhibition is just the tip of the iceberg. anxiolytics, antidepressants, sedative-hypnotics, mood stabilizers, who knows? i believe that if the social stigma wasn't so pronounced that we'd already be seeing these things being as commonplace as SSRIs/SNRIs. maybe in 20 years we'll get there. or, i could be totally wrong. it's just a gut feeling i have...

 

[C6H6]

while i truly believe that if the pharmaceutical industry were to fully exploit this particular signalling system they could have another SSRI-like-scene on their hands

The cannabinoid system has been very thoroughly explored by the pharmaceutical industry. Non-selective cannabinoid agonists didn't make it far in spite of the great efforts, because it wasn't possible to separate the welcome effect from the psychotropic side effetcs. More recently developed selective CB2 agonists have better chances. They act only peripherally, mainly on the immune system, and have no psychotropic effect. The first blockbuster comming from cannabinoid research will be the antagonist rimonabant for weight-loss and smoking cessation. It antagonizes the endocannabinoids and inhibits feeding. Rimonabant is in the final stages of testing and should hit the market in 2006. It will be big like the SSRI. So many overweight people who can and will want to use it!

 

[BilZ0r]

^ We'll see... I'm just curious to see what effect they will have... seizures? Or memory effects? If blocking central cannabinoid receptors doesn't effect something massively I'm gonna be so shocked... I mean, how dense are those receptors expressed? 3rd most dense after GABA-A and AMPA?