Blocking serotonin (5-HT) may treat alcoholism
-
After decades of animal research implicating the serotonin system in the development of all sorts of “addictions”, it looks like a human trial is finally under way. More specifically, a trial with the serotonin receptor 5-HT3 antagonist called ondansetron (named AD04 in the trial), taken orally. Ondansetron is not a new drug and I have been posting about it for years and Ray has been mentioning for even longer. Its typical dosing regimen (for nausea) is 4mg-8mg every 6-12 hours. However, at such doses it can cause severe constipation and even bowel obstruction, and even a serious side effects known as “QT-interval prolongation”, which can increase the risk of sudden cardiac arrest. Curiously, most of the animal studies demonstrating anti-depressant, anxiolytic, anti-Parkinson, anti-cancer and anti-addiction effects used much lower doses, in the human-equivalent dose range of 0.5mg-1mg, which most doctors consider too low to be of any effectiveness. It just so happens that the clinical trial below uses precisely such low-doses – i.e. 0.33mg twice daily. So, it looks like somebody is reading the scientific literature…or Ray’s articles:-)
While this trial is certainly good news, it of course immediately draw attention to the flip side of that coin. Namely, if serotonin is a cause of alcoholism (considered currently incurable) and likely other addictions as well, how can serotonin still be officially promoted by medicine as the “happiness hormone”? Just as importantly, how can SSRI drugs be prescribed like candy, even to toddlers, if their effects are very likely addiction-forming? Considering the ever-growing epidemic of substance abuse (including alcohol) in Western countries, how much of that epidemic is iatrogenic (caused by SSRI drugs) and/or from stress (which raises serotonin)? There is a serious disconnect here and I hope the reformed FDA (that we hear about is in the works) will address this obvious paradox, and not in favor of serotonin/SSRI.
“…Adial Pharmaceuticals today announced that it has completed a pharmacokinetics (PK) study of AD04, an investigational genetically targeted, serotonin-3 receptor antagonist, and therapeutic agent for the treatment of alcohol use disorder (AUD) in patients with heavy drinking. This data will help guide the study design for the upcoming phase 3 clinical trial of AD04.1 “Completion of this study achieves our goal to obtain the data we needed to design a more precise and informed phase 3 trial protocol, including evaluating the optimal dosing regimen to maximize the efficacy and safety of AD04 in patients with AUD. Its completion is in accord with previous guidance provided by the FDA and is intended to enhance the likelihood of success in our upcoming phase 3 trial,” said Cary Claiborne, president and chief executive officer of Adial. In this single-center, relative bioavailability, open label study, investigators enrolled a total of 30 healthy adult volunteers in 2 cohorts. Heavy drinking was defined as less than 10 drinks/drinking day. Cohort 1 (n=6) was a randomized, open-label, 2-sequence, 2-period crossover study to evaluate the PK variability of ondansetron from AD04 0.33 and 0.99 mg. Cohort 2 (n=24) was a randomized, open-label, 6-sequence, 4-period crossover study to evaluate the relative bioavailability of the AD04 0.33 mg tablet to a marketed ondansetron 4 mg tablet, dose proportionality of ondansetron PK between AD04 0.33 and 0.99 mg, and the effect of food on the bioavailability of ondansetron administered as the AD04 0.33 mg tablet. Results showed that, because of the lower dose, AD04 0.33 mg delivered lower ondansetron PK exposure than the marketed reference standard ondansetron 4 mg tablet. Furthermore, ondansetron PK exposure increased in proportion to dose across a 3-fold AD04 dose range. Lastly, AD04 can be taken in fed or fasted states.”
“…AD04 (0.33mg ondansetron taken orally twice daily) acts upon the 5HT3 pathway and is thought to reduce alcohol craving. This mode of action is distinct from, but complimentary to, the currently approved therapies for AUD.”
-
