John Krystal of Yale U. in an article in Proceedings of the National Academy of Sci. (2023) gave new information about the anatomical and physiological effects of ketamine and about how to extend its effects. Ketamine in animals acutely (in a matter of hours) increases spines, synapses, and dendrites and physiological connectivity in neurons in the prefrontal cortex. Data now support these findings in humans with depression, but AD effects of ketamine tend to dissipate over a period of 3 to 5 days and require repeated infusions to maintain the improvement. Synaptic density can be measured with SV2A and this can be enhanced with a Navitor Pharmaceuticals drug acting on mTORC1. Surprisingly low doses of rapamycin, an inhibitor of mTOR1, extends the duration of AD effects of ketamine, increasing the response rate at 2 weeks from 13% to 41%. Ketamine restores only the spines that have been reduced in depression and rapamycin is thought to extend the duration of the restored spines. It may do this by increasing the neurotropic effects of microglia. The tripartite synapse of pre and post synaptic neurons and astrocytes, may now be better described as the tetrapartite synapse with the inclusion of microglial.

Adding psychotherapy to the effects of ketamine in PTSD increases and extends efficacy.

AD effects of ketamine can be extended with cognitive behavioral therapy. Thus, ketamine increases synaptic efficacy, synaptic density, glutamate homeostasis, and experience-dependent neuroplasticity. Extending the persistence of these effects by various chemical and psychotherapeutic mechanisms may give new ways of enhancing and prolonging the therapeutic effects of this rapidly acting agent.

Interestingly, Kaye at Yale U. reports that in contrast to transient effects of ketamine, the AD effects of therapy-assisted psilocybin appear to be very long lasting and the associated increases in spines persist for longer than 37 days. Another psychedelic MDMA that is effective in PTSD causes large increases in spines, although they are less persistent and are gone by 34 days.

Editor's Note: As we have previously highlighted in the BNN, these data on ketamine and other psychedelics reversing the anatomical and physiological deficits in prefrontal neurons of depressed animals and humans (spines, dendrites, synapses and intercellular communication), give a new view of the real, reliable, and replicable neurological defects accompanying depression. The rapid correction of these neural abnormalities in conjunction with the rapid induction of antidepressant effects are not only paradigm shifting from a treatment perspective, but have major implications for the assertion that there is a neurobiological basis of depression and its treatment.

As such, these data should do much to counter the continuing stigma too often accompanying the term “mental” illness that it is somehow not as real as other medical and neurological conditions, and as it is often asserted that “it is just all in one’s head.”  This picks up on the unfortunate associations and definitions of “mental” as imaginary, all in the mind, and evanescent and that mental illness can readily be countered with effort and will power such as “pulling oneself up by the bootstraps,” (the latter of which is in itself a logical impossibility.)

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