Ketamine
Ketamine HCl · Ketalar
Ketamine is a dissociative anesthetic first synthesized in 1962 and FDA-approved since 1970 for anesthesia and analgesia. It acts primarily as an NMDA receptor antagonist and has emerged as a breakthrough treatment for depression, particularly treatment-resistant depression (TRD). The S-enantiomer (esketamine, marketed as Spravato) received FDA approval in 2019 for TRD in conjunction with an oral antidepressant.
Starting dose. 0.5mg/kg — IV over 40 min (clinical standard for depression)
Clinical setting with monitoring. No driving for 24 hours post-treatment. Empty stomach preferred to reduce nausea.
Start here. Every protocol below is ordered lowest-first. Begin at the smallest effective dose, hold about a week to assess tolerance, and step up only if needed.
How it works
Ketamine is a non-competitive NMDA (N-methyl-D-aspartate) receptor antagonist that blocks the ion channel at the PCP binding site. At sub-anesthetic doses used for depression, it preferentially blocks NMDA receptors on GABAergic interneurons, disinhibiting glutamatergic pyramidal neurons. This produces a transient surge of glutamate in the prefrontal cortex and hippocampus.
The glutamate surge activates AMPA receptors, which triggers downstream signaling through BDNF (brain-derived neurotrophic factor) and the mTOR pathway. This cascade promotes rapid dendritic spine growth and synaptogenesis - literally creating new synaptic connections - within hours. This synaptic plasticity mechanism explains both the rapid onset and the transient nature of ketamine's antidepressant effect.
Additional mechanisms include opioid receptor modulation (mu and kappa), HCN1 channel blockade, and anti-inflammatory effects via inhibition of microglial activation and reduction of pro-inflammatory cytokines. The S-enantiomer (esketamine) has approximately 4x higher NMDA affinity than racemic ketamine.
What to expect
Hours 2-24: Rapid antidepressant onset. Dissociative effects resolve within 2 hours. Mood improvement often noted same day.
Evidence
References for this compound are being re-checked against their source records. We are not showing them until each one is confirmed to support the claim it sits under.
Interactions & stacking
Two different questions: what is documented about running these together, and what is documented about drawing them into the same syringe. A good pharmacological partner can still have to be pinned separately.
Documented together
Keep separate
Check any specific pair in the Stack & Interaction Checker, which answers both questions separately. Absence of a documented conflict is not evidence of safety.
Pharmacokinetics
(ketamine), ~5 hours (norketamine active metabolite)
IV, ~5-15 min IM, ~20-30 min sublingual, ~20-40 min intranasal
Including active metabolites
IV, ~93% IM, ~25-30% sublingual, ~45-50% intranasal, ~17-20% oral
Dissociative effects: 45-90 min IV, 1-2 hr IM, 1-3 hr sublingual. Antidepressant effects: 1-3 weeks per treatment.
Hepatic (CYP3A4 and CYP2B6 N-demethylation to norketamine). Renal excretion of hydroxylated metabolites and conjugates.
Storage. Store vials at controlled room temperature (20-25C). Protect from light. Sublingual troches should be refrigerated for extended storage. Esketamine (Spravato) nasal spray devices stored at room temperature in original packaging.
Regulatory status
Schedule III controlled substance (DEA). FDA-approved for anesthesia (1970) and esketamine (Spravato) approved for treatment-resistant depression (2019) under REMS program. Racemic ketamine used off-label for depression via IV, IM, sublingual, and intranasal routes. Spravato must be administered in certified healthcare settings with post-dose monitoring.
Put it to work
Calculate, log & track
Open Ketamine straight into OnePin with your vial and dose pre-filled, then let it handle the syringe math and remind you before the vial runs out.
Open Ketamine in the app →Go deeper
The guide & community
The complete Ketamine walkthrough, real protocol discussion and coaching live inside the BlessUp community on Skool.
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