Ketamine belongs to a group of drugs known as dissociative anesthetics. Other drugs in this class include phencyclidine (PCP), dextromethorphan (DXM), and nitrous oxide. These drugs have medicinal use; they also have a potential for abuse. Due to this, Ketamine is classified as a schedule 3 drug.

IV ketamine has been in use for decades as an anesthetic (OR) drug. It is the anesthetic of choice for children because it has a wide safety margin (it does not cause respiratory depression). IV ketamine can also be used to manage treatment-resistant depression (TRD). However, it can only be used off-label since the FDA has not approved it for this purpose.

In March 2019, nasal ketamine was approved by the FDA for the management of treatment-resistant depression (TRD). However, nasal ketamine has to be administered together with an oral antidepressant. It should only be offered to patients who have tried and failed to benefit from two different classes of antidepressants.

What is the Difference Between Ketamine and Esketamine?

Nasal ketamine is a form of ketamine that is offered via the intranasal route. Nasal ketamine is usually offered as S-ketamine or Esketamine, a molecule taken from the ketamine molecule. It is also called an altered form, enantiomer, or mirror image of ketamine. A combination of enantiomers is referred to as a racemic mixture. IV ketamine is the racemic mixture of ketamine.

Ketamine and esketamine can be administered through the intravenous, intramuscular, or intranasal routes. The intravenous route increases the absorption and efficacy of the drug. However, the FDA has only approved nasal esketamine for the treatment of depression.

Esketamine Patent

Esketamine was patented by Jansenn (a branch of Johnson & Johnson) for the management of TRD in 2013 under the trade name Spravato.

In the following sections, nasal ketamine will be referred to as Esketamine, while I.V Ketamine will be referred to as Ketamine.

Esketamine vs. Ketamine: Mechanism of Action

Esketamine and Ketamine have a similar mechanism of action because they are more or less mirror images of each other.

Esketamine works by modulating the glutamatergic system and through this pathway it creates new synapses in the brain. It is believed that depression causes the loss of neural connections and synapses in brain cells. Esketamine helps to renew these connections and hence recreate cell communication.

Ketamine works in about ten different pathways; one that is very significant is the NMDA receptor pathway. This pathway plays a massive role in central sensitization, which involves anxiety, chronic pain, CRPS, opioid-induced hyperalgesia, and depression.

While the mild dissociative effects of Ketamine dissipate soon after Ketamine has been administered, the antidepressant effects are often sustained for about a week. This suggests that the antidepressant effects of the drug are sustained long after the drug has been metabolized.

Further research will help to elucidate the exact mechanisms of Esketamine and Ketamine in addressing TRD.

Esketamine vs. Ketamine: Administration

How is Esketamine Administered?

Esketamine is only offered at FDA-approved healthcare facilities called Ketamine clinics. These clinics provide ketamine therapy for the treatment of mental health conditions. Patients are typically started on the standard dose (56mg or 84mg) twice a week for the first four weeks. It is then offered once a week for the next four weeks. Depending on the patient’s response, it can then be provided weekly or bi-weekly. Once the patient receives the medication, they are monitored at the clinic for at least two hours before they are allowed to leave. The patient is not allowed to leave the clinic with the nasal ketamine.

How Is Ketamine Administered?

Racemic Ketamine is mainly administered as a slow IV infusion. Patients are first started on a very low dose of IV Ketamine administered at a controlled rate for about 70 minutes. The exact dose is calculated based on the patient’s weight and tolerance levels.

The dose given for depression is significantly less than what is administered for anesthesia (about a tenth). The patient should receive 6-8 infusions for 3-4 weeks. The treatment can then be adjusted based on the patient’s response. Most patients will achieve remission within the first four weeks and may not need ketamine boosters after 3-4 months.

Esketamine vs. Ketamine: Costs in the U.S

The Johnson & Johnson cost of Spravato is $590 for the 56 mg dose and $885 for the 84mg dose. This means that a patient can spend up to $4,720 to $6,785 in the first month without adding facility fees. It is not yet clear if insurance will cover the cost of Spravato.

The cost of IV ketamine is $500-$700 per dose retail price. In 8 weeks, the patient will have spent $3,500 and $4,900 (assuming average response to therapy).

Both nasal and IV ketamine are not covered by insurance.

Esketamine vs. Ketamine: Uses

Nasal Ketamine, aka Spravato, is used with an oral antidepressant for treatment-resistant depression (TRD). It can also be used to treat PTSD, anxiety, and chronic pain conditions.

IV ketamine is used to induce anesthesia. It can also be used to manage depression and chronic pain conditions.

Nasal Spray vs. Infusion Ketamine: Which is More Effective?

A 2020 study carried out by Queen’s University in Canada and the National Institute of Mental Health in the US was recently published in the Journal of Affective Disorders. The study compared racemic Ketamine to Esketamine and found IV ketamine to be more effective than nasal Ketamine in the management of unipolar and bipolar depression. It is important to note that the FDA has not approved racemic (IV) ketamine to manage depression and is therefore used off-label.

Sample and Methods

This was a review that compared randomized controlled trials that involved nasal or intravenous Ketamine in the management of depression. They included studies where Ketamine was used as a solo agent or used in combination with other antidepressants.

The study cited by Psychology Today included 24 randomized controlled trials with 1877 participants ranging from 36 to 70 years. 98% of the participants had major depression, while 2% had bipolar depression. In most of the included studies, Ketamine has been used in conjunction with other antidepressants. 75% of the participants were suffering from treatment-resistant depression (a lack of positive response to two or more antidepressants).

Nasal Spray vs. Infusion Ketamine: Safety

Nasal spray and infusion ketamine are considered relatively safe in medical settings because they do not affect breathing or circulation as other anesthetic medications do.

In low doses, patients may feel “floaty” after receiving these medications. Most clinicians will offer other drugs to mitigate the expected side effect- such as midazolam and clonidine. Patients should also be psychologically prepared so that they know what to expect. Most of these adverse effects are transient and will not last beyond a few hours.

However, some patients with the following conditions should not receive Ketamine for medical purposes:

  • Brain swelling, lesion, or tumor
  • Hypertension

Nasal Spray vs. Infusion Ketamine: Adverse Effects

Patients have reported the following adverse effects after using Esketamine and Ketamine:

  • Hallucinations
  • Delirium
  • Nausea
  • Slurred speech
  • Dissociation from reality
  • Increased pressure in the eyes and brain

Both medications are relatively safe because they do not depress breathing. Also, remember that the dosages of Esketamine and Ketamine for depression are significantly lower than those given for anesthesia.

In higher doses, these medications may cause increased blood pressure and intracranial pressure in the brain. This may cause brain edema, glaucoma, and brain lesions following prolonged use.

These adverse effects may be more pronounced in people aged over 65 years.

Nasal Spray vs. Infusion Ketamine: Addiction

Prolonged use of Esketamine or Ketamine can cause dependence, tolerance, and withdrawal symptoms. Long-term use may cause toxic buildup and overdose; the complications of long-term use can be fatal.


Ketamine can be offered either as an infusion or spray to treat chronic depression. From the studies mentioned above, it appears that infusion ketamine is more effective in relieving symptoms of depression. However, the FDA has only approved nasal ketamine for this indication. Thus, further research is urgently needed to compare the risks versus benefits of nasal and infusion ketamine that will provide future directions on the use of Ketamine to manage depression.

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