By Edmund Murphy

Last updated: 19 March 2024 & medically reviewed by Dr. Kimberly Langdon

In recent years, ketamine has become increasingly popular as an alternative to conventional antidepressant medications. For those who are suffering from severe depression and have been unresponsive to standard medication, ketamine has proven to be a successful alternative that is helping save lives across America and the world. But how does ketamine work as a treatment for depression?

Key takeaways:

  • Ketamine treatment for depression is only used for adults who have had no success with traditional antidepressants like SSRIs or SARIs, have a severe depressive disorder, or are suicidal.

  • Patients who are resistant to depression treatment will be administered esketamine twice a week for up to four weeks then once a week for up to nine weeks.

  • While the benefits of ketamine infusions as a treatment for depression have proven positive, there are side effects that may occur from taking the drug that can have negative consequences.

Ketamine as a treatment for depression

Since 2019, ketamine has also been available as a treatment-resistant alternative for those suffering from depression, in the form of the S(+) enantiomer of ketamine (esketamine) nasal spray version (Spravato®).[1] Pharmacies have to be enrolled in a special program called REMS (Risk Evaluation and Mitigation Strategy) in order to dispense this medication. 

This form of treatment for depression is only used for adults who have had no success with traditional antidepressants like SSRIs or SARIs, have a severe depressive disorder, or are suicidal.[2] Most patients will need to continue taking their course of antidepressants and will need to attend REMS monitored clinic or office to take the medication. 

Doctors will administer the nasal spray and monitor the patient for two hours afterward to check for any side effects. Patients who are resistant to depression treatment will be administered esketamine twice a week for up to four weeks then once a week for up to nine weeks. After nine weeks, patients will normally only receive the medication once every week or fortnight.

As there is still the potential for abuse and dependence on esketamine, the FDA has put a black box warning on the packaging. This warning also lists the risk of sedation, lack of attention, and risk of suicidal ideation and behaviors.[2]

How does ketamine work to treat depression?

As ketamine use for treating depression is still relatively new in the field of medicated therapy science, how the drug works and why it is effective in treating depressive disorders is not entirely known. It is also not clear why those who have previously found conventional antidepressant medications unsuccessful see better results with ketamine. 

The most commonly accepted theory is that ketamine binds to N-methyl-D-aspartate (NMDA) receptors in the brain. Ketamine appears to increase the number of glutamate neurotransmitters between NMDA neurons and creates connections to other receptors known as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA).[3] The blockade of NMDA and activation of AMPA receptors through glutamate production is believed to release separate molecules that help neurons communicate with each other through new neural pathways. This process, known as synaptogenesis, is believed to affect thought patterns, cognition, and mood.[3]

What are the possible side effects of ketamine infusions for depression treatment?

While the benefits of ketamine infusions as a treatment for depression have proven positive, there are side effects that may occur from taking the drug that can have negative consequences. However, these side effects may not outweigh those of ongoing or long-term depression.

  • Possible side effects of ketamine infusion include:

  • Nausea/vomiting

  • Increased blood pressure

  • Dissociation (out-of-body-experience)

  • Perceptual disturbances (increased awareness/stimulation of noises, colors, textures, the passage of time)

For most people receiving ketamine infusions, these side effects (notably those involving dissociation and perception) are often felt more during the first infusion and end very soon after. These effects can also often be felt with the esketamine nasal spray, though the timing and intensity of these effects may be a little different. Read here to learn more about the effects of ketamine and how long it stays in your system. 

While esketamine treatment for depression is legal, there are other methods of ketamine administration that are not approved by the FDA but are still used in a medical setting. These include IV infusions and shots which are administered at a doctor's office and lozenges that are given to be taken at home between treatments.[2] 

While these forms of administration are less widely used than nasal spray treatments they are still legal in most states and safe to use. However, these forms of treatment come with the risk of abuse and dependence if use isn’t monitored closely. 

Some people who take ketamine to treat their depression may become dependent on the substance and begin to seek the substance outside of medical channels and use it to self-medicate. Some will occasionally microdose the substance, taking small amounts sporadically to keep a state of calm without fully experiencing the high felt from the drug when taken in large amounts.

Even the practice of microdosing, while not as dangerous as full abuse, is still illegal and can be dangerous when trying to treat depression or other mental health conditions. People who suffer from mental health conditions should always take extra caution when abusing hallucinogens as the warped sense of reality can become emotionally upsetting.

You can learn more about the legal status of ketamine in our ketamine controlled substance guide.