What are the Chemical Effects of Ketamine and Lithium for Bipolar Disorder?

About the Author Dr. Steven P. Levine is a board-certified psychiatrist internationally recognized for his contributions to advancements in mental health care. Though he is a psychiatrist who places great emphasis on the importance of psychotherapy, medication is often a necessary component of treatment, and he was dissatisfied with the relatively ineffective available options with burdensome side effects. Dr. Levine pioneered a protocol for the clinical use of ketamine infusions, has directly supervised many thousands of infusions and has helped establish similar programs across the country and around the world.

Bipolar Disorder, Lithium, and Ketamine: What You Need to Know

You may have seen the press on using Ketamine to treat Major Depressive Disorder, but did you know that studies have shown Ketamine can alleviate depressive symptoms caused by bipolar depression as well?  Ketamine is a medication that was originally developed in the 1960s as a general anesthetic, however, in the last decade, Ketamine, in low doses, has been used to help people suffering from major depression, bipolar depression, postpartum depression, generalized anxiety, OCD, PTSD, and even acutely suicidal thoughts in a matter of hours as opposed to months.1 In 2014, Thomas Insel, Director of the National Institute of Mental Health, stated that “recent data suggest that Ketamine, given intravenously, might be the most important breakthrough in antidepressant treatment in decades.”

Lithium is a medication that has been around since the early 1800s.  It was originally found to be useful in dissolving uric acid crystals and subsequently in the later 1800s was utilized to treat bipolar disorder (mania and depression).  John Cade, an Australian psychiatrist, published a study in 1949 in which he treated guinea pigs with lithium and noticed that they appeared to calm down. Lithium was FDA approved for the acute treatment of bipolar disorder (mania) in 1970 and subsequently for maintenance therapy.  Lithium is believed to also have some antidepressant properties and is often used by psychiatrists for patients who suffer from major depressive disorder in order to help their antidepressant medications work more effectively. Lithium is also important in that it is only one of two oral medications on the market today that have anti-suicidal properties.  The third medication with anti-suicidal properties is Ketamine (given intravenously).

Lithium is a medication for which blood levels must be monitored closely due to the fact that it has a narrow therapeutic window of effectiveness.  If this is not monitored closely, patients can become toxic from the drug and have serious adverse outcomes. In addition to blood levels, one must also monitor thyroid function and kidney function as it has been known at times to affect these organs.

One question that often can arise is whether lithium and Ketamine can be taken at the same time.  The answer to this is yes and it is safe to do. One who is already on lithium could continue to take it as usual and Ketamine will not affect the overall drug levels in the bloodstream.  In fact, there is actually some overlap in cell signaling pathways between lithium and Ketamine and due to this reason, there have been some theories that this combination may increase the effectiveness of response to Ketamine.  One study by Chiu, CT et al in the International Journal of Neuropsychopharmacology from 2014 found that pretreating mice with 600 mg of lithium helped to potentiate the antidepressant effects of a 2.5 mg/kg dose of Ketamine.2 Most other studies, albeit limited to date, have not shown this to be the case and these results have not been demonstrated in human studies.  Because the theoretical combinative effects of Ketamine and lithium are so appealing, research on this combination is still ongoing.

In summary, if a patient with bipolar disorder feels fairly stable on lithium overall but still has depressive episodes, one might consider Ketamine as a valid choice to help treat the depressive episodes.  Ketamine may be an option for several reasons including its quick onset of action and lower overall side effect profile at sub-anesthetic doses than other standard psychiatric treatment choices. Most side effects of Ketamine are transient and dissipate within a few hours, at most, after treatment.  For manic patients, lithium is still the gold standard treatment and there are other good options such as Depakote and Tegretol. Often, medications such as Latuda and Seroquel are also used in bipolar patients, but these carry a higher risk of side effects. Ketamine is certainly not a substitute for lithium in the treatment of mania, but Ketamine will usually dramatically improve symptoms in those with bipolar depression by providing a safe, low-risk option with high reward potential.


  1. Mercer, SJ. et al. ‘The Drug of War’–a historical review of the use of Ketamine in military conflicts. ‘The Drug of War’–a historical review of the use of Ketamine in military conflicts. J R Nav Med Serv. 2009;95(3):145-50.
  2. Krupitsky E, Burakov A, Romanova T, Dunaevsky I, Strassman R, Grinenko A. Ketamine psychotherapy for heroin addiction: immediate effects and two-year follow-up. J Subst Abuse Treat. 2002;23(4):273-283.1. Ruscio AM, Stein DJ, Chiu WT, Kessler RC. The epidemiology of obsessive-compulsive disorder in the National Comorbidity Survey Replication. Mol Psychiatry. 2010;15(1):53-63. doi:10.1038/mp.2008.94.