DOI is a psychedelic drug commonly used in research as a 5HT-2A agonist, but is known to bind to all 3 isoforms of the 5HT-2 receptor (A, B, and C). 5HT-2A receptors are present in the CNS as well as the periphery, but little was known about its role in inflammatory processes. To investigate the effects on proinflammatory markers, rat aortic muscle was isolated, and grown in a petri dish. The cells were then pretreated with DOI or other 5HT-2A agonists such as LSD, 2C-BCB, and LA-SS-Az (an analogue of LSD). After 24 hours, TNF-a was added, and the expression of inflammatory mediators was measured. These inflammatory processes measured were ICAM-1, VCAM-1, IL-6, NO synthase, and NF-kB.
DOI was found to inhibit ICAM-1, VCAM-1, and IL-6 with an EC50 (effective concentration to inhibit 50% of the activity induced by TNF-a) of 10-20 pM; some 300-fold more potent than currently used anti-inflammatory drugs. DOI was also found to inhibit NOS activity and NF-kB translocation to the nucleus. This effect was found to be 5HT-2A dependent by using specific inhibitors for each of the 5HT-2 receptor subtypes. And while LSD, 2C-BCB, and LA-SS-Az were also found to inhibit TNF-a mediated increases in inflammatory molecules, none were nearly as potent as DOI.
When DOI was added at the same time as TNF-a, it was still found to completely block proinflammatory markers. Even when DOI was added 4 hours after TNF-a addition, it blocked 50% of the increase in inflammatory molecules. To investigate this mechanism further, the researchers looked at PKC, which is known to activate ICAM-1 expression. They found that an inhibitor of PKC inhibited TNF-a stimulation of all the proinflammatory markers tested.
This discovery represents a novel way to treat inflammation. While the drugs tested in this experiment are all psychoactive, there may be development of 5HT-2A agonists that are not psychoactive, or cannot cross the BBB.
Full paper here:
http://www.ncbi.nlm.nih.gov/pubmed/18708586
SBrookshire; PSIO495K
I am surprised that this study was conducted in the United States. Currently lysergic acid diethylamide (LSD) is listed as a schedule I controlled substance under the controlled substance act. This means that the federal government considers LSD to have "no accepted medical usage in treatment in the United States." These researchers must have been given an exception to this rule.
ReplyDeleteI find it hard to believe that in the future patients will be receiving derivatives of psychoactive drugs in order to treat their inflammation. I would expect research and development costs to always be higher when illegal substances are used.
I agree that it seem like something that has psychoactive effects, especially LSD, would be not very applicable to medical practices. However, I have recently read and posted about a derivative of cannabis that was shown to reduce inflammation but DID NOT cause any psychoactive effects and suggest that it may a useful area of study. Now perhaps this may not have a similar component but if one were to be found with such potency for anti-inflammmation it would be interesting to see how effective it would be as treatment for diseases.
ReplyDeleteI am just about to begin an experimental treatment for psoriasis with doses of LSD.
ReplyDeleteThe doses will begin way below the recreational treshold for the drug.
The experiment will be done in the most scientific way possible. Expect a report in a few months