I have several posts on my blog of studies demonstrating that 5-HT antagonists have demonstrated pr-eclinical activity in treating PD, which strongly implicates 5-HT as a key driver of this pathology. This experimental observation is further strengthened by the known signs of PD, which include tremors (a known sign of excess 5-HT) as well as mood and cognitive disturbances. Several doctors emailed me to say that this hypothesis is premature since there are other conditions such as essential tremor (ET) that has overlapping symptoms with PD and there is no evidence that excess 5-HT drives that condition. Well, the study below may finally provide some clarity to this issue. Namely, while dopamine rises and 5-HT falls in people with ET under various daily situations, in people with PD dopamine levels largely stay the same, while 5-HT levels either also stay the same or rise. In other words, in non-PD people, the DA/5-HT ratio varies – i.e. it rises in most positive situations while falling in negative ones. In PD patients the DA/5-HT ratio is virtually constant and low most of the time (due to the low baseline DA). Be that as it may, the study corroborates the use of serotonin antagonists as treatment for PD and suggests that combining them with a DA agonist may have synergistic (curative?) effects. About a decade ago, I suggested to several PD patients who emailed me that they ask their doctors about such a combo treatment, and the ones that emailed me back after having tried the combo all said that their disease progression has been arrested. My suggestion at the time was based purely on intuition, given the known negative effects of 5-HT on the entire brain due to its role as a master “negative” metabolic regulator. In other words, PD is yet another condition driven by low metabolism. The study below and the others I discovered in recent years suggest that my intuition was on the right track. Ray was right about this – truth always comes first through intuition, which is based on experience, and not through analytical/abstract thinking.
Oh, one last thing that I found interesting. Apparently, 5-HT rises robustly when there is an expectation of punishment/adversity. No wonder depression and PD rates are skyrocketing. Most of the Western population lives in chronic anxiety and fear of punishment from just about anybody around them.
https://www.nature.com/articles/s41467-025-63079-w
“…In looking at the response of DA, we found there was a difference between positive and negative NPE trials, with DA release on average being higher on positive NPE trials (N-M4: main effect of NPE F(1, 558.31) = 4.01, p = 0.046), and while DA patterns were not present in PD patients (e.g., Fig. 2f), patient group differences in DA were not statistically robust (p > 0.05). Notably, the differences in 5HT responses appeared more robust, and the overall reduction in 5HT on positive NPEs observed in ETs was absent in PDs (N-M5: NPE × Patient Group interaction for 5HT; F(1, 545.01) = 4.46, p = 0.035; 5HT response on positive NPE, ET vs. PD t(81.3) = −2.281, Bonferroni corrected p = 0.025).”
“…The importance of DA-5HT opponency during reward-related processing has previously been proposed62,63; with fast changes in DA release generally linked to the prediction of rewards and increases in 5HT release associated with an expectation of punishment64,65. ”
“…But when they looked closely—using refined tools and a model of how people formed expectations—it was not dopamine that best distinguished Parkinson’s from essential tremor. Instead, it was serotonin, a different neurotransmitter that has not been as prominent in theories of Parkinson’s disease, opening a new view and potentially powerful scientific and clinical insight into this disease. “What surprised us was how much serotonin stood out,” Howe says. “It wasn’t just that dopamine was disrupted, which was expected. It was that the normal back-and-forth between dopamine and serotonin was gone. There’s neither the serotonin dip nor the dopamine rise. It’s not just one system being disrupted—it’s the lack of that dynamic interaction that turned out to be the clearest difference between Parkinson’s and essential tremor.”
