19 May 2021

Ketamine Side Effects on Males Versus Females

CDR (Dr.) Kennett Radford presented his research findings during TSNRP Virtual Nursing Grand Rounds on 12 May 2021.

Ketamine is a potent analgesic, available to a broad patient age range, and has a wide safety profile which makes it the preferred medication for various conditions such as acute pain and treatment-resistant depression. It is widely used in operating rooms, emergency medicine settings, in ketamine clinics, and during psychiatric treatment. However, the sex-related differences of its effects are not yet well understood.

Principal Investigator Navy CDR Kennett Radford, PhD, CRNA, Program Director and Assistant Professor at the Graduate School of Nursing, Nurse Anesthesia Program at the Uniformed Services University – in partnership with Kwang Choi, PhD, presented their research findings during the TriService Nursing Research Program (TSNRP) Virtual Nursing Grand Rounds on 12 May 2021. TSNRP’s Nursing Grand Rounds promote the integration of research and evidence-based practice into everyday nursing practice.

CDR Ken Radford, PhD, CRNA
CDR Ken Radford, PhD, CRNA

Using a clinically relevant model, CDR (Dr.) Radford and Dr. Choi’s lab is one of the first to publish on intravenous ketamine in rodent models. CDR Radford’s Geneva-managed study is titled “Role of IV Ketamine on Fear Memory and Brain Activation” and his lab has published several manuscripts in Translational Psychiatry;  International Journal of Molecular Science; and Pharmacology, Biochemistry, and Behavior describing their research findings. His findings recommend that future preclinical studies utilize a clinically relevant route of administration and account for biological sex differences to improve translation between preclinical and clinical investigations.

Ketamine is a preferred analgesic in the military

Ketamine received approval from the U.S. Food & Drug Administration (FDA) as an anesthesia medicine in 1970. It was used on the battlefields of the Vietnam War and was used as the principal analgesic during the war in Afghanistan. Today, ketamine is becoming increasingly popular in the treatment of pain following traumatic injury, as well as treatment-resistant major depressive disorders. The Committee on Tactical Combat Casualty Care recommends ketamine as part of the triple optional analgesia for severe pain with the intravenous (IV) route of administration as the most common.

“Ketamine is without a doubt the preferred analgesic on the battlefield,” said CDR (Dr.) Radford during the TSNRP presentation. “It preserves respiratory status, treats severe pain, has a large safety window for dosing, is hemodynamically stable, and is now safe for traumatic brain injury (TBI).”

More women in combat roles prompted the need for more research

The ban on women in combat was lifted in 2013 and the percentage of women in the services is on the rise. The effects of ketamine on women and stress-related disorders is becoming a more relevant topic because the impacts of medications are different between men and women.

CDR (Dr.) Radford is interested in understanding the gap in the literature – stating there is limited evidence describing differences between men and women with regards to ketamine and impacts on stress-related disorders and there is limited information on ketamine and stress disorders for men and women.

In his research, Radford found that sexual dimorphisms exist between males and females and discovered different ketamine responses in his research. The study had three research aims: to compare dissociative behavior between male and female rats after ketamine, to examine the effects on rodent fear memory, and to examine regional brain activity.

Next Steps: Timing and Dose Matters

“Overall, there does appear to be differences that could impact dosing strategies moving forward,” said CDR (Dr.) Radford. “Timing and doses matter.”

His research found short-term fear memory effects that resemble acute stress disorder but no longer-term effects. They found sex-related behavioral and analgesic differences, enhanced fear memory in females, and evidence of sex-related brain region activations which, he stated, requires further investigation.

A paradox, stated Radford, is that ketamine administered at the time of injury in a traumatic experience seems to enhance memory, however, ketamine administered at later time points is used to treat PTSD and reduce fearful memories. His research team is finalizing metabolism data in males and females, measuring effects on inflammation and TBI, ketamine treatment for post-traumatic headache, treatments for TBI and effects of memory-related tasks, and interaction with opioids to prevent opioid dependence.

“Ketamine is a fantastic choice for opioid-free analgesia and for those experiencing chronic pain to help relieve pain,” said CDR (Dr.) Radford. “I am not disputing the great benefits of ketamine but we have also found that ketamine administered at the time of traumatic injury may have unintended consequences that deserve further research”

“It is important for clinicians to consider the downstream effects of medications during traumatic experiences and evaluate risk versus benefits for any medication that you’re administering,” concluded Radford.


Disclaimer: The views expressed do not reflect the official policy of the Army, the Department of Defense, or the U.S. Government.