Pan PAM at Trk-type receptors: TrkB (BDNF), TrkA (NGF, ~60% activation plateau), and TrkC (Önnestam et al., 2023). Doesn’t directly activate; amplifies endogenous neurotrophin signaling contextually. The allosteric bias is the advantage: enhancement follows actual BDNF release rather than forcing constant activation, same design principle that makes TAK-653 outperform agonist AMPA PAMs. ACD-856 also increases BDNF expression in a feed-forward loop (Önnestam et al., 2023).
Wider significance: most antidepressants and psychedelics are now understood to be direct TrkB PAMs, including ketamine (via 2R,6R-HNK), psilocin, LSD, fluoxetine, and imipramine. BDNF itself has antidepressant effects when infused directly into hippocampus (Shirayama et al., 2002), and the pharmacological convergence on TrkB explains why so many structurally unrelated compounds share mood and cognitive effects. The AMPA-NMDA-BDNF-TrkB cascade that TAK-653 engages upstream converges on TrkB. These two hit adjacent nodes in the same pathway, which is why the combination is so clean.
Half-life: 20 hours (Önnestam et al., 2023). Phase 0 and Phase 1 complete with no adverse effects (Önnestam et al., 2023). Predecessor ACD-855 had a 68-day half-life; pharmacokinetic improvement is large. Currently in Alzheimer’s development. Everychem first vendor.
TrkA partial agonism plateaus at 60%, avoiding full excitotoxic potential. May contribute anti-inflammatory effects. Still, growth factor potentiation promoting cell survival is a theoretical cancer risk. Monitor.
Subjectively builds over 3-4 weeks. Restores awe and emotional richness: things become more beautiful, experiences richer, empathy sharper. Not euphoric. A genuine baseline shift. Initial sleepiness faded completely.
Dose: 15mg nightly Cycling: Ongoing, no tolerance to core effect Stacks: TAK-653 (upstream AMPA PAM + downstream TrkB PAM, adjacent nodes, best synergy), Usmarapride (drives hippocampal BDNF release, ACD-856 amplifies it at TrkB), N-Acetylsemax (upregulates TrkB expression, ACD-856 potentiates the sensitized receptor) Notes: Phase 0 + Phase 1 complete (Önnestam et al., 2023). 3-4 weeks to full effect. TrkA cancer risk theoretical but real enough to track. Everychem first vendor.
Bibliography
- Önnestam, K., Nilsson, B., Rother, M., Rein-Hedin, E., Bylund, J., Anderer, P., Kemethofer, M., Halldin, M. M., Sandin, J., & Segerdahl, M. (2023). Safety, Tolerability, Pharmacokinetics and Quantitative Electroencephalography Assessment of ACD856, a Novel Positive Allosteric Modulator of Trk-Receptors Following Multiple Doses in Healthy Subjects. The Journal of Prevention of Alzheimer’s Disease, 10(4), 778–789. https://doi.org/10.14283/jpad.2023.89
- Shirayama, Y., Chen, A. C.-H., Nakagawa, S., Russell, D. S., & Duman, R. S. (2002). Brain-Derived Neurotrophic Factor Produces Antidepressant Effects in Behavioral Models of Depression. Journal of Neuroscience, 22(8), 3251–3261. https://doi.org/10.1523/JNEUROSCI.22-08-03251.2002