Rapamycin and Ketamine: Better Results?

IV Ketamine can rapidly improve depression and suicidality symptoms. The duration of benefit is variable, however. In 2020, a group of researchers at Yale tried something counter-intuitive: they combined ketamine with a dose of rapamycin—an mTORC-1 inhibitor that should have blocked ketamine’s plasticity signal. Surprisingly, adding rapamycin doubled the antidepressant effect of ketamine. What is rapamycin and how might some patients benefit from combining rapamycin with ketamine for longer relief from depression?

What is Rapamycin?

Rapamycin is a fascinating molecule derived from bacteria on Easter Island that became FDA approved as an immunosuppressant. Interestingly, there is a dose-dependent effect of rapamycin on inflammation: at high, continuous doses it is an immunosuppressant, but at lower or intermittent doses it modulates the immune system. It has been shown to lower pro-inflammatory cytokines, improve vaccine responses (Everolimus), and increase lifespan in many animal models.

Does Rapamycin Boost Ketamine Response?

Yale's findings created a paradigm shift in how mTORC1 may affect neuroplasticity and symptoms of depression. Individuals who use rapamycin for longevity self-report improved mood compared to controls (though this could be confounded by other variables). Follow up studies have shown that rapamycin is safe to combine with ketamine, though the effects on non-depression symptoms remain unclear.

Ketamine is also used in patients for chronic pain, including CRPS (complex regional pain syndrome). Interestingly, a recent study found the addition of rapamycin to ketamine significantly improved the pain response to ketamine.

How Might Rapamycin Augment Ketamine?

We believe there are several ways rapamycin improves the antidepressant effects of IV Ketamine:

• Anti-inflammatory: rapamycin dampens inflammation and may stabilize synaptic density - this appears important in ketamine's antidepressant response
• Autophagy: mTORC1 plays an important role in cellular "clean up" and neuroplasticity by degrading and recycling toxic or dysfunctional cellular components that worsen depression
• Microglial reset: Rapamycin appears to modulate microglial activation to prevent aberrant nerve signaling after nerve injury.

Rapamycin appears to act less as a blunt mTOR “off-switch” and more as a timed modulator that conditions the immune and intracellular environment so ketamine’s plasticity signal can mature instead of dissipate.

Should you Discuss Rapamycin with your Doctor?

Promising early studies demonstrate the potential for rapamycin to extend ketamine’s antidepressant window—doubling two-week remission in the best study to date. This may be more important in patients with inflammation driving their depressive symptoms. While there are risks with any medication, rapamycin has been shown to be safe over decades of use. Speak with a doctor at Clarus Health today so learn if rapamycin may augment your IV Ketamine and experience for longer lasting results.