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A lactone opioid is a chemical with opiate like effects that is structurally a lactone. A lactone is a heterocyclic ring system where there is an oxygen atom double bonded to a carbon atom that is itself bonded to an oxygen atom in a ring.

          /   \\
       O=C     C  
          \   /

This might seem like a less than breathtaking matter, but that chemicals with a lactone structure could have an effect on opiate receptors was quite surprising. It was especially surprising given the first substance found that fit this description, which was Salvinorin. Salvia Divinorum had gained some reputation as a potent and unpredictable psychedelic drug that often caused strange amnesiac episodes followed by long-lasting changes in attitudes and perceptions of self and the world. And while that might seem strange, to neurochemists it was just as surprising when it was revealed, in 2007 that Salvinorin acted on the kappa opiate receptor. Previously, all known drugs that worked on the opiate receptor were alkaloids, drugs that contain a heterocyclic ring containing a nitrogen atom. While this might seem like a small technical difference, it was very surprising to see a chemical with such a structure having such a powerful effect. A somewhat likely comparison would be to see a minivan enter the Indianapolis 500, and win.

However, there is at least one other chemical with a lactone structure that is known to be active at the kappa receptor: Nepetalactone and its derivatives, which is found in the Nepeta, or catnip, genus. There have been two studies that show that Nepeta and Nepetalactones are active at the kappa opiate receptor. However, they are not pharmacologically significantly so in humans, and their effect in cats is supposedly due to olfactory stimulation, and not central nervous system action. In addition, menthol, which is not a lactone but is structurally similar, has been shown to have a weak effect on the kappa opiate receptor.

Since there does seem to be some evidence for thinking that lactones are active at the kappa opiate receptor, it might be possible that two other families of chemicals with lactones that are purported to have psychoactive effects might fit in this category: these are kava kava, which has a family of lactones and has a long history of use as a sedative, and valerian, which along with other chemicals, was discovered in 2011 to have some lactones of a rather complicated nature. Valerian has also traditionally been used as sedative.

Another important point of interest is that if these chemicals work at the kappa opiate receptor, which unlike the mu opiate receptor, which is where morphine and its derivatives work, does not produce euphoria or addiction. While the kappa opiate receptor does produce pain relief and intoxication, its effect also includes dysphoria and disassociation that many people find less than pleasant. Individual's response to drugs that are active at this receptor also tends to be highly idiosyncratic and inconsistent, which also fits mental response to these substances: some people get knocked out by kava and valerian, while others feel nothing. Salvia is also famous for people's wildly different responses and reactions to it.

What is most interesting to me is even with the gigantic worldwide investment in pharmaceutical research, how long the structure and mechanism of these drugs was either ignored or looked over. Both from a scientific and commercial standpoint, the assumption was that opiates would have a basic structure, based on a morphinan skeleton. While many small adjustments have been made to this basic structure to produce opiates that maximize analgesia while minimizing side effects, it could very well be that the major pain-killer of the 21st century is hiding in a rare subspecies of valerian.


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