How Does Ketamine Work Compared to “Classical” Psychedelics?

Have you ever wondered exactly how it works in the brain? Let’s unravel this mystery together – we’ll explore how it actually works. Think of it as Therapeutic-Use Ketamine 101. No pop quizzes, though.

Ketamine’s Mechanism in the Brain, Simplified

Unlike classic psychedelics that primarily target serotonin receptors (we’ll get to that comparison below), ketamine acts on the NMDA (N-methyl-D-aspartate) receptors, which are part of the glutamatergic system, the primary excitatory neurotransmitter system in the brain. 

Explain like I’m 5: ketamine blocks an inhibitory neuron from, well, inhibiting. 

The process:

  • Ketamine blocks the NMDA receptor on GABA neurons.
  • GABA are inhibitory neurons.
  • Because the inhibitory neurons are blocked, a glutamate surge is created.
  • This surge triggers increased neural connectivity, potentially improving mood and cognition.

Want to dive deeper? Read The Mechanisms Behind Rapid Antidepressant Effects of Ketamine: A Systematic Review with a Focus on Molecular Neuroplasticity (Frontiers) or Nushama’s post, The Neuroscience of Ketamine.


The Key to Therapeutic Use: Subanesthetic Dosing

The “psychedelic” experience of ketamine is dependent on the dose used, occurring at both what’s considered subanesthetic as well as anesthetic doses, although still significantly lower than what is used for general anesthesia in surgery. 

  • Subanesthetic dosing (via IV): typically ranges from 0.5mg/kg to 1mg/kg (Nushama’s protocol usually starts at .8mg/kg)
  • Anesthetic dosing (via IV): typically ranges from 1mg/kg to 4.5mg/kg


Anesthetic or Psychedelic?

Ketamine’s use at a subanesthetic dose occupies a unique place in the field of psychoactive substances. Unlike “classic” psychedelics (such as LSD and psilocybin), its pharmacological profile and effects on the mind and body set it apart in significant ways. Here are a few:

  • Mechanism of Action
    • Classic Psychedelics: mainly exert their effects by activating the serotonin 5-HT2A receptors in the brain. 
    • Ketamine: primarily an NMDA receptor blocker that modulates glutamate.


  • Chemical Structure
    • Classic Psychedelics: most classic psychedelics are structurally similar to serotonin, which is why they can effectively bind to and activate serotonin receptors.
    • Ketamine: its chemical structure is not similar to serotonin and does not interact with serotonin receptors in the same way as traditional psychedelics, but instead acts on the glutamate system.


  • Psychoactive Effects
    • Classic Psychedelics: typically produce alterations in sensory perception, visual hallucinations, synesthesia (blending of sensory experiences), and deep introspective states that can lead to spiritual or mystical experiences.
    • Ketamine: the dissociative experience with ketamine is often described as an “out-of-body” experience—while visual and auditory hallucinations often occur with sub-anesthetic IV doses used at Nushama, they differ from classic psychedelics. 

Routes of Administration and Their Differences

Ketamine is most commonly administered intramuscularly, intravenously, nasally, and orally. The choice of administration depends on various factors, including the clinical setting, the person’s condition, and the desired onset and duration of effects. 

Here’s a breakdown of the common differences: 

  • Intravenous (IV) Ketamine
    • Onset and Duration: rapid onset of effects, typically within minutes—the duration of effects is usually short, often less than an hour when the drip is stopped
    • Dosage Control: allows for precise dosage control
    • Bioavailability: near 100% bioavailability
    • Experience: often associated with stronger experiences due to the rapid onset from the IV


  • Intramuscular (IM) Ketamine
    • Onset and Duration: slower onset than IV, usually within 5 to 15 minutes. Duration of effects can last slightly longer.
    • Dosage Control: dosage is fixed once administered, offering less flexibility than  IV
    • Bioavailability: high bioavailability (approximately 93%), though slightly lower than IV
    • Experience: slightly more gradual onset than IV (but faster than oral)


  • Nasal Ketamine
    • Onset and Duration: rapid onset, similar to IV, usually within minutes. Duration of effects varies but is generally shorter than IM.
    • Bioavailability: lower than IV and IM due to potential variability in absorption through nasal mucosa.
    • Experience: intensity of effects can vary


  • Oral Ketamine
    • Onset and Duration: slowest onset, typically taking 30 minutes to an hour but effects can last several hours.
    • Bioavailability: significantly lower due to the first-pass metabolism in the liver
    • Experience: gradual onset and prolonged duration can be more manageable but may result in less pronounced therapeutic effects

For more information,
read our blog post about IV ketamine and alternative routes.



Move Beyond Symptom Relief with Ketamine

Ketamine’s potential for mental health is profound. Studies have shown significant reductions in symptoms of depression, anxiety, and PTSD, often within hours of administration. This rapid onset of action is a stark contrast to traditional antidepressants, which may take weeks to show effects. Of course, to sustain relief from mood disorder symptoms with ketamine therapy, integration therapy is critical.

Curious about ketamine? Contact us today.


Discover What Psychedelic Medicine Can Do for You

To transcend depression, anxiety, alcohol use disorders, and trauma-induced mood disorders, Nushama offers IV ketamine for an ego-dissolving psychedelic experience. A holistic path of mindful intention setting, ketamine journeys, and thoughtful integration in safe, healing-focused settings empower members to reset and reconnect.

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