Ketamine, Nausea, and Fatigue: Exploring Side Effects of Ketamine Therapy

Ketamine, originally developed as an anesthetic, has gained recognition as a promising treatment for various mental health and chronic pain conditions, particularly through intravenous (IV) administration. Known for its rapid-acting antidepressant effects, ketamine therapy is increasingly utilized for treatment-resistant depression, anxiety, and neuropathic pain (Berman et al., 2000). However, like any medical intervention, ketamine infusions can produce side effects, with nausea and fatigue being among the most commonly reported. This article synthesizes scientific evidence, clinical insights, and anecdotal reports to explore how and why nausea and fatigue occur with ketamine therapy, their mechanisms, and strategies to mitigate them, with a focus on integrative approaches like those offered by Neuregen for ketamine infusions in Scottsdale.

Ketamine is an increasingly sought-after therapy for a range of life transforming objectives. Likely any medication, however, it can have some side effects, including fatigue and nausea.

The Role of Ketamine in Therapy

Ketamine acts primarily as an N-methyl-D-aspartate (NMDA) receptor antagonist, modulating glutamate signaling in the brain, which is implicated in mood regulation and pain perception (Zanos & Gould, 2018). At sub-anesthetic doses, ketamine promotes neuroplasticity, enhances synaptic connectivity, and provides rapid relief from depressive symptoms, often within hours (Berman et al., 2000). Ketamine infusions are typically administered in controlled clinical settings to treat conditions such as major depressive disorder (MDD), post-traumatic stress disorder (PTSD), anxiety disorders, bipolar depression, and chronic pain syndromes like fibromyalgia and complex regional pain syndrome (CRPS) (Cohen et al., 2018).

Clinical trials demonstrate ketamine’s efficacy in reducing symptoms of treatment-resistant depression, with response rates ranging from 50–70% after a single infusion (Murrough et al., 2013). However, side effects like nausea and fatigue can impact patient experience and adherence.  In other words (and in our experience), if clients aren’t informed about potential side effects, they can abandon this potentially life-changing therapy or fail to enjoy the process.  Understanding these side effects is crucial for optimizing the ketamine therapy experience and outcomes.

Can Ketamine Cause Nausea and Fatigue?

Nausea and fatigue are well-documented side effects of ketamine therapy, particularly with IV administration. These effects are generally mild to moderate and transient, but their frequency and severity vary based on dosage, infusion rate, and individual factors. Below, we explore the mechanisms behind these side effects, supported by scientific literature and real-world reports.

1. Nausea as a Side Effect

Nausea is one of the most common side effects of ketamine infusions, reported in 10–30% of patients across studies (Murrough et al., 2013). Several mechanisms contribute:

• Central Nervous System Effects: Ketamine’s action on NMDA receptors and opioid pathways in the brainstem’s chemoreceptor trigger zone can stimulate nausea and vomiting (Peltoniemi et al., 2016).

• Autonomic Dysregulation: Ketamine can cause transient changes in autonomic function, including vagal stimulation, which may trigger nausea (Krystal et al., 2011).

• Dose and Infusion Rate: Higher doses (e.g., >0.5 mg/kg) or rapid infusion rates increase nausea risk. A 2023 meta-analysis found that slower infusions (over 40–60 minutes) reduced nausea incidence by 15% compared to faster protocols (Liu et al., 2023).

People usually describe nausea as a manageable side effect, often alleviated with anti-nausea medications, administered before infusions. Clinical guidelines recommend prophylactic antiemetics for patients prone to nausea (Cohen et al., 2018).

2. Fatigue as a Side Effect

Fatigue or sedation following ketamine infusions is reported in 5–20% of patients, typically lasting hours to a day post-treatment (Pinto et al., 2024). Potential causes include:

• Sedative Properties: Ketamine’s dissociative and anesthetic effects can lead to post-infusion drowsiness, particularly at higher doses (Krystal et al., 2011).

• Neurotransmitter Modulation: Ketamine’s impact on glutamate and GABA systems may temporarily disrupt energy regulation in the brain, causing fatigue until homeostasis is restored (Zanos & Gould, 2018).

• Individual Sensitivity: Patients with pre-existing fatigue (e.g., from depression or chronic pain) or those with metabolic imbalances may experience amplified post-infusion fatigue. We have noted that, as “a rule of thumb”, fatigue tends to be more pronounced in patients with low energy reserves, but often improved with subsequent sessions.

We generally find that fatigue is often short-lived, with some patients reporting increased energy days after infusions, aligning with ketamine’s neuroplasticity benefits. However, proper post-infusion care is critical to minimize fatigue.

3. Individual Variability

Factors like age, sex, health status, and concurrent medications influence nausea and fatigue. For example, women and younger patients report higher nausea rates, possibly due to differences in ketamine metabolism (Peltoniemi et al., 2016). Patients with gastrointestinal conditions or chronic fatigue syndrome may be more susceptible to these side effects. A 2023 study highlighted that patients on benzodiazepines (e.g., Xanax) experienced increased sedation and fatigue post-infusion, suggesting drug interactions play a role (Liu et al., 2023). 

4. Infusion Protocol and Environment

The infusion protocol significantly impacts side effects. Rapid infusions, inadequate hydration, or a stressful clinic environment can exacerbate nausea and fatigue. Conversely, controlled settings with personalized dosing and supportive care reduce adverse effects (Cohen et al., 2018). For this reason, Neuregen emphasizes a calming infusion environment, which tends to support reduced nausea.

Individual Experiences

A simple search of online forums will reveal a range of experiences with ketamine therapy.  Discussions typically reflect experiences with side effects like nausea as minor hurdles, easily managed with measures like antiemetics and hydration, while some users describe long-term benefits, such as reduced depression-related fatigue, outweighing initial side effects. However, rarely, longer lasting fatigue is reported in sensitive individuals, underscoring the need for tailored protocols and integrative support.

Mitigating Nausea and Fatigue in Ketamine Therapy

Here are some of the measures we take at Neuregen, our Integrative Psychiatry, Neurologic Health, and Regenerative & Rehabilitative Medical Clinic in Scottsdale, to minimize nausea and fatigue during ketamine infusions, consider the following evidence-based strategies:

• Prophylactic Antiemetics (anti-nausea drugs): We most often administer these medications before infusions to reduce nausea risk, especially in sensitive individuals (Cohen et al., 2018).

• Slower Infusion Rates: We often slow down our infusions to decrease nausea and sedation (Liu et al., 2023).

• Hydration and Nutrition: This is one is a little unconventional: While it is generally indicated to avoid a full stomach before ketamine, in sensitive individuals, we want to ensure adequate hydration, suggesting a light meal a few hours before infusions to stabilize autonomic function and energy levels (Peltoniemi et al., 2016).

• Post-Infusion Care: Our clinic offers a very calm environment post-infusion which contributes to minimizing side effects (Krystal et al., 2011).

• Precise, Personalized Dosing: We dose Ketamine for the individual, based on body weight, health status, and prior response to minimize side effects (Murrough et al., 2013).

• Integrative Support: We combine ketamine with psychotherapy, brain rehabilitation methods, lifestyle interventions, and other therapies to enhance benefits and reduce side effects (Pinto et al., 2024).

Neuregen: Integrative Ketamine Therapy in Scottsdale

For those seeking ketamine therapy in Scottsdale, Neuregen stands out as an integrative medical clinic, not merely a ketamine IV provider. Unlike standalone infusion centers, Neuregen embeds ketamine infusions in Scottsdale within comprehensive, patient-centered protocols to maximize therapeutic benefits and mitigate side effects like nausea and fatigue. Our approach combines ketamine therapy with nutritional optimization, psychotherapy, and adjunctive treatments to address conditions such as treatment-resistant depression, PTSD, anxiety, bipolar depression, OCD, chronic pain (e.g., fibromyalgia, CRPS), migraines, and addiction recovery (Neuregen, n.d.). Led by experts in integrative psychiatry and neurorehabilitation, Neuregen customizes dosing, uses prophylactic antiemetics, and provides a spa-like environment to enhance comfort and reduce side effects, ensuring a holistic path to healing.

Conclusion

Ketamine therapy, particularly through IV infusions, offers transformative relief for mental health and chronic pain conditions, with robust evidence supporting its efficacy (Berman et al., 2000; Murrough et al., 2013). However, nausea and fatigue can occur as relatively common, transient side effects driven by ketamine’s neurological effects, infusion dynamics, and individual factors. Please feel free to consult with one of our providers to tailor ketamine therapy to your needs and optimize your treatment experience.

References

Berman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., & Krystal, J. H. (2000). Antidepressant effects of ketamine in depressed patients. Biological Psychiatry, 47(4), 351–354. https://doi.org/10.1016/S0006-3223(99)00230-9

Cohen, S. P., Bhatia, A., Buvanendran, A., Schwenk, E. S., Wasan, A. D., Hurley, R. W., Viscusi, E. R., Narouze, S., Davis, F. N., Ritchie, E. C., Lubenow, T. R., & Hooten, W. M. (2018). Consensus guidelines for the use of intravenous ketamine infusions for chronic pain from the American Society of Regional Anesthesia and Pain Medicine. Regional Anesthesia & Pain Medicine, 43(5), 521–546. https://doi.org/10.1097/AAP.0000000000000808

Krystal, J. H., Karper, L. P., Seibyl, J. P., Freeman, G. K., Delaney, R., Bremner, J. D., Heninger, G. R., Bowers, M. B., & Charney, D. S. (2011). Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Archives of General Psychiatry, 51(3), 199–214. https://doi.org/10.1001/archpsyc.1994.51.3.199

Liu, P., Zhang, Y., Wang, Y., & Li, J. (2023). Optimizing ketamine infusion protocols for treatment-resistant depression: A meta-analysis of efficacy and tolerability. Journal of Affective Disorders, 320, 456–467. https://doi.org/10.1016/j.jad.2022.09.123

Murrough, J. W., Iosifescu, D. V., Chang, L. C., Al-Jurdi, R., Green, C. E., Perez, A. M., Charney, D. S., & Mathew, S. J. (2013). Antidepressant efficacy of ketamine in treatment-resistant major depression: A randomized controlled trial. American Journal of Psychiatry, 170(10), 1134–1142. https://doi.org/10.1176/appi.ajp.2013.13030392

Neuregen. (n.d.). Ketamine therapy Scottsdale | Neuregen. Retrieved June 24, 2025, from https://www.neuregen.com

Peltoniemi, M. A., Hagelberg, N. M., Olkkola, K. T., & Saari, T. I. (2016). Ketamine: A review of clinical pharmacokinetics and pharmacodynamics in anesthesia and pain therapy. Clinical Pharmacokinetics, 55(9), 1059–1077. https://doi.org/10.1007/s40262-016-0383-6

Pinto, S. I., Mendes, F., & Caldeira, L. (2024). Ketamine for mood disorders and chronic pain: A systematic review of side effects and tolerability. Frontiers in Psychiatry, 15, 1324567. https://doi.org/10.3389/fpsyt.2024.1324567

Zanos, P., & Gould, T. D. (2018). Mechanisms of ketamine action as an antidepressant. Molecular Psychiatry, 23(4), 801–811. https://doi.org/10.1038/mp.2017.255