Serotonergic Psychedelics and Neuroplasticity

[Rainbow]

I'd be curious to know if anyone has thoughts on the following paper: https://doi.org/10.1016/j.celrep.2018.05.022

Highlights and Summary (copied from paper)

• Serotonergic psychedelics increase neuritogenesis, spinogenesis, and synaptogenesis
• Psychedelics promote plasticity via an evolutionarily conserved mechanism
• TrkB, mTOR, and 5-HT2A signaling underlie psychedelic-induced plasticity
• Noribogaine, but not ibogaine, is capable of promoting structural neural plasticity

"Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders."

Musings

The research is presented more in the context of depression and mood disorders, but could have implications for general neurological health.

I'm also wondering if anyone has further thoughts on ketamine, especially for E4s. I've been reading that anesthetics may not be a good idea for E4s, so was wondering if this would apply to ketamine as well.

By the way, I do have the full text if anyone is interested.

[Fiver]

My understanding of the biology is that these drugs can induce neurogenesis, in part through an increase in BDNF. This is believed to be one of - maybe the primary - ways that SSRIs work. Different SSRIs raise BDNF to different degrees - in one study Zoloft was superior to other commonly-prescribed SSRIs (in this one way) by about 10X. I believe ketamine has a similar impact. Low BDNF is one way that many degenerative diseases are related. Raising BDNF is generally considered to be helpful is preventing / delaying / maybe treating AD, depression, PD, MS, etc. Levels that are too high seem to be associated with seizures, at least in some studies, however. We often talk about exercise to raise BDNF. Novelty does this. Some plant phenolics can do this also. One caveat is that raising BDNF levels is not as helpful for those with the BDNF variant that is less functional. I believe there is a type of insulin growth factor that acts on the same receptors as BDNF, so it may be possible for folks with the less effective version of BDNF to activate these pathways using other signals.

I don't know about these other compounds. But we seem to be moving towards ketamine as an antidepressant for resistant cases. So maybe it will be studied for AD.

It's all very interesting. I think this subject is one of the important ones that will get lots of attention going forward.

[Rainbow]

My understanding of the biology is that these drugs can induce neurogenesis, in part through an increase in BDNF. This is believed to be one of - maybe the primary - ways that SSRIs work. Different SSRIs raise BDNF to different degrees - in one study Zoloft was superior to other commonly-prescribed SSRIs (in this one way) by about 10X. I believe ketamine has a similar impact. Low BDNF is one way that many degenerative diseases are related. Raising BDNF is generally considered to be helpful is preventing / delaying / maybe treating AD, depression, PD, MS, etc. Levels that are too high seem to be associated with seizures, at least in some studies, however. We often talk about exercise to raise BDNF. Novelty does this. Some plant phenolics can do this also. One caveat is that raising BDNF levels is not as helpful for those with the BDNF variant that is less functional. I believe there is a type of insulin growth factor that acts on the same receptors as BDNF, so it may be possible for folks with the less effective version of BDNF to activate these pathways using other signals.

Thanks for giving some context. Interesting indeed! Good to know about the BDNF caveat you mentioned (I believe I have that variant, actually).