10 Best Supplements to Take During Ketamine Therapy for Depression and Anxiety

Ketamine therapy has become a widely accepted and increasingly common treatment for mental health conditions such as depression and anxiety. It is available in several forms — intravenous (IV) ketamine and nasal Spravato® (esketamine) in clinical settings, or oral formulations that can sometimes be taken at home. 

Ketamine is particularly promising for individuals with treatment-resistant depression and chronic anxiety, providing rapid relief where traditional methods like oral antidepressants and psychotherapy often fall short. Endorsed by psychiatrists and approved by the FDA, ketamine and Spravato® are recognized as safe and effective options for those seeking long-lasting relief from depression and anxiety.

While ketamine itself can provide meaningful results, its benefits may be further optimized — and potential side effects minimized — with the right supplements. The supplements you choose during ketamine therapy for depression and anxiety can make a significant difference.

In this post, we’ll examine a carefully chosen selection of supplements that may enhance ketamine’s therapeutic effects, safeguard brain and liver health, and support overall mental well-being. These include ingredients found in mental wellness formulas like Newy, along with other well-researched supplements.

1. Agmatine Sulfate

Agmatine sulfate is a naturally occurring compound derived from the amino acid L-arginine. In the brain, it acts as both a neurotransmitter and a neuromodulator, affecting several key systems involved in mood, pain, and cognition.

What makes agmatine especially interesting in the context of ketamine therapy is its capacity to interact with the same NMDA receptors that ketamine targets. By modulating NMDA activity, agmatine may help regulate glutamate signaling — the key pathway thought to drive ketamine’s rapid antidepressant effects. This indicates that supplementing with agmatine could potentially improve mood regulation, prolong the benefits of ketamine therapy, and bolster resilience against depressive symptoms.

Beyond mood, agmatine has also shown potential for managing chronic pain. It affects multiple receptor systems involved in pain perception and inflammation, providing a complementary mechanism to ketamine’s own analgesic effects.

By regulating nitric oxide (NO) pathways, agmatine promotes vascular health, blood flow, and neuroprotection. These effects can be especially beneficial during ketamine therapy, as improved circulation and decreased neuroinflammation help optimize brain plasticity and healing.

Potential Benefits of Agmatine During Ketamine Therapy:

• May enhance and prolong ketamine’s antidepressant effects
• Supports mood regulation through NMDA receptor modulation
• Offers pain-relieving properties that complement ketamine
• Promotes vascular health and neuroprotection
• Contributes to stress resilience and cognitive support

For patients undergoing ketamine therapy, agmatine sulfate is a versatile supplement that not only supports brain health but may also work synergistically with ketamine’s unique mechanisms to enhance both mood and its antidepressant effects. 

2. Omega-3 Fatty Acids

Omega-3 polyunsaturated fatty acids (PUFAs), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are essential fats found in fish oil and marine algae. These fatty acids are vital for brain health, cell membrane integrity, and inflammation regulation — all factors highly relevant to depression and anxiety.

Research has shown that omega-3 supplementation can decrease depressive symptoms, especially in individuals with treatment-resistant depression. Their antidepressant effects seem to be partly due to their anti-inflammatory properties. Chronic inflammation is increasingly seen as a significant factor in mood disorders, pain syndromes, and even immune-related conditions.

Formulation matters. Studies suggest that supplements with a higher proportion of EPA (more than 50% EPA compared to DHA) are more effective in reducing depressive symptoms. 

Potential Benefits of Omega-3s During Ketamine Therapy:

• Help reduce neuroinflammation, supporting ketamine’s neuroplastic effects
• Improve depressive symptoms and mood regulation
• Support cardiovascular and metabolic health

By reducing inflammation and enhancing brain function, omega-3 fatty acids can effectively complement ketamine therapy, helping patients attain more stable and enduring improvements in mood and mental health.

3. Alpha-lipoic acid (ALA)

Alpha-lipoic acid is a naturally occurring compound produced in the body and found in certain foods. Known for its potent antioxidant and detoxification properties, ALA has been extensively researched for its role in brain health, energy production, and protection against age-related cognitive decline. Its ability to reduce oxidative stress, regulate inflammation, and regenerate other key antioxidants like glutathione makes it a notable supplement to include on this list. 

In the context of ketamine therapy, ALA’s benefits are especially relevant. Depression and anxiety are closely linked to oxidative stress and neuroinflammation, both of which can impair brain function. By neutralizing harmful free radicals and protecting brain cells from oxidative damage, ALA may help create a more supportive environment for ketamine’s neuroplastic effects to develop.

ALA also plays a vital role in mitochondrial function — the process of converting glucose and fatty acids into cellular energy (ATP). Supporting mitochondrial efficiency not only enhances energy and vitality but also reduces the buildup of harmful metabolic byproducts that can worsen inflammation and oxidative stress. 

Potential Benefits of ALA During Ketamine Therapy:

• Provides strong antioxidant protection, reducing oxidative stress linked to mood disorders
• Supports neuroprotection and cognitive function
• Enhances mitochondrial energy production, helping combat fatigue
• Aids in detoxification by binding to and clearing heavy metals
• May improve insulin sensitivity and support stable blood sugar, indirectly benefiting mood stability

By reducing oxidative stress, boosting energy production, and supporting brain health, alpha-lipoic acid offers a powerful complement to ketamine therapy. 

4. Vitamin D

Vitamin D is a vital nutrient that plays a crucial role in maintaining bone health, supporting immune function, and various other physiological processes throughout the body. In addition to its well-known role in calcium metabolism, vitamin D is now understood to be important for brain health and mood regulation. Vitamin deficiency is widespread — affecting over 40% of the U.S. population — with higher rates among Black Americans, women, young adults, and during the darker winter months when sun exposure is limited.

Low vitamin D levels have been associated with several major health issues, including depression, cardiovascular disease, and even cancer. In fact, deficiency is viewed as a significant risk factor for both physical and mental health problems. 

Research indicates that vitamin D supplementation can alleviate depressive symptoms, especially in people with major depressive disorder and women experiencing postpartum depression. 

Vitamin D3 is the preferred form of supplementation because it mimics the type produced naturally in the skin when exposed to sunlight and is more effective than vitamin D2 at increasing serum vitamin D levels. D3 can be obtained from foods such as fatty fish, eggs, cheese, and mushrooms, though diet alone is rarely enough to fix a deficiency.

Potential Benefits of Vitamin D During Ketamine Therapy:

• Supports mood regulation and may help reduce depressive symptoms
• Addresses widespread deficiency that often worsens mental health outcomes
• Enhances immune function and overall resilience during treatment
• Works synergistically with ketamine by strengthening underlying brain and body health

Vitamin D deficiency is one of the most common — yet treatable — factors affecting mental health. By maintaining proper levels, patients undergoing ketamine therapy can create a stronger foundation for mood improvement, making vitamin D a simple and highly effective supplement to add.

5. Milk Thistle

Milk thistle is a flowering herb that has been used for centuries to promote health, most notably liver health. Its primary bioactive compound, silymarin, is a potent antioxidant and anti-inflammatory agent that protects the liver from damage, enhances detoxification, and promotes cellular repair. 

In the context of ketamine therapy, liver health is especially important. Oral formulations of ketamine must pass through the liver before reaching the bloodstream, a process known as first-pass metabolism. This not only determines how effectively ketamine is metabolized but also places added stress on the liver. By protecting against oxidative stress and inflammation, milk thistle may help safeguard the liver from potential hepatotoxicity and ensure that ketamine is processed efficiently, supporting both safety and effectiveness.

Even for patients receiving IV ketamine or Spravato®, maintaining optimal liver function is crucial, since the liver plays a central role in metabolizing medications, regulating hormones, and influencing neurotransmitters like dopamine and serotonin that are deeply tied to mood.

Potential Benefits of Milk Thistle During Ketamine Therapy:

• Supports liver function during oral ketamine treatment by protecting against first-pass metabolic stress
• Enhances detoxification and promotes glutathione regeneration, boosting the body’s antioxidant defenses
• Reduces systemic inflammation, supporting overall mood and brain health
• Provides neuroprotective effects
• May positively influence neurotransmitter balance, offering indirect antidepressant effects

By protecting one of the body’s most vital organs, milk thistle offers crucial support during ketamine therapy. This is especially important for patients using ketamine, where keeping the liver healthy helps prevent damage and ensures the drug is metabolized efficiently.

6. Magnesium

Magnesium is an essential mineral involved in hundreds of enzymatic reactions throughout the body, supporting everything from cardiovascular and immune health to muscle function and bone strength. Magnesium deficiency is common due to poor diet, stress, and the depleting effects of coffee and alcohol. This widespread deficiency has been linked to chronic conditions such as diabetes, cardiovascular disease, and chronic pain.

Low magnesium levels have been consistently linked to symptoms of depression and anxiety. Interestingly, even individuals without a deficiency seem to benefit from magnesium supplements. One proposed mechanism is its effect on brain-derived neurotrophic factor (BDNF), a growth factor that encourages neuroplasticity. BDNF is believed to be a key mediator of ketamine’s rapid antidepressant effects, raising the exciting possibility that magnesium could enhance or extend ketamine’s impact on the brain. While this synergy is still being studied, the connection highlights why magnesium may be especially valuable during ketamine therapy.

Potential Benefits of Magnesium During Ketamine Therapy:

• Supports mood regulation and reduces symptoms of depression and anxiety
• Enhances sleep quality and relaxation, promoting recovery after sessions
• Increases BDNF production, potentially reinforcing ketamine’s neuroplastic effects
• Supports cardiovascular, metabolic, and bone health

By reducing stress, supporting neuroplasticity, and enhancing mood stability, magnesium provides a natural foundation that can complement ketamine therapy. Whether in glycinate or threonate form, this mineral may help patients achieve more balanced, long-lasting improvements after ketamine treatment.

7. L-theanine

L-theanine is an amino acid naturally present in green tea leaves, valued for its calming yet non-sedating effects. It helps reduce stress and promotes relaxation while keeping alertness. One of its main functions is to boost alpha brain wave activity, which is linked to a calm and focused state of mind.

L-theanine works by modulating neurotransmitters like GABA, serotonin, and dopamine, all of which are key in regulating mood. By increasing these “feel-good” chemicals, L-theanine helps reduce stress, improve sleep, and support resilience against anxiety and depression. It also helps buffer caffeine's stimulating effects, which explains why green tea usually offers smoother energy and focus compared to coffee.

In the context of ketamine therapy, L-theanine’s stress-reducing and neuroprotective properties can offer important complementary benefits. Ketamine works by enhancing glutamate signaling. L-theanine has been shown to modulate glutamate activity and protect neurons from excitotoxicity (excessive stimulation), which may help support ketamine’s therapeutic effects while reducing overstimulation. Its role in improving sleep and relaxation can also be especially valuable between ketamine sessions, when integration and recovery are crucial.

Potential Benefits of L-theanine During Ketamine Therapy:

• Promotes relaxation and reduces stress without sedation
• Enhances mood and emotional balance by supporting dopamine, serotonin, and GABA activity
• Improves sleep quality, which is vital for integration after sessions
• Protects brain cells by reducing excess excitatory activity
• Provides calm, focused energy that can support day-to-day functioning during treatment

Whether through tea, matcha, or supplements, L-theanine provides a gentle yet effective way to boost relaxation, focus, and mood stability — making it a valuable complement to ketamine therapy for depression and anxiety.

8. Ginger 

Rich in bioactive compounds like gingerols and shogaols, ginger is well known for its ability to reduce nausea, ease digestive discomfort, and provide anti-inflammatory and antioxidant support.

For individuals undergoing ketamine therapy, ginger may be especially valuable. Nausea is one of the most common side effects of ketamine, often occurring during or shortly after treatment. Ginger’s natural anti-nausea properties have been demonstrated in clinical studies to be effective for motion sickness, pregnancy-related nausea, and post-operative nausea, making it a safe and supportive option to help manage this potential side effect.

Beyond reducing nausea, ginger’s anti-inflammatory properties may also help lower systemic inflammation, which is increasingly recognized as a factor in mood disorders like depression and anxiety. Its antioxidant effects further support brain health by shielding neurons from oxidative stress. Additionally, ginger may promote digestion and gut health — an important factor since the gut-brain axis plays a vital role in regulating mood.

Potential Benefits of Ginger During Ketamine Therapy:

• Provides natural relief from nausea, a common side effect of ketamine
• Reduces inflammation, which may help stabilize mood 
• Offers antioxidant protection to support brain health
• Promotes digestive function and gut-brain balance

Ginger is readily available in many forms — fresh, dried, teas, capsules, or standardized extracts — and is generally safe when used in moderation. Its long history of safe use makes it a trusted natural supplement for those undergoing ketamine therapy.

9. Creatine Monohydrate

Creatine is primarily recognized as a sports supplement that enhances strength, speeds recovery, and helps prevent injuries. However, its benefits go far beyond the gym. As a vital component in the body’s energy metabolism, creatine supports maintaining healthy levels of ATP — the energy source for both muscles and the brain. By restoring phosphocreatine stores, creatine provides a consistent energy supply during periods of high demand, whether from physical activity, emotional stress, or mental effort.

This energy-stabilizing effect is especially important for mental health. Periods of depression, anxiety, or “brain fog” often happen when energy levels in the brain are low. Research indicates that creatine supplements may help. Clinical studies with patients who have major depressive disorder show that creatine has antidepressant effects, likely by boosting energy use in brain circuits that control mood. Other research from neurological conditions like Parkinson’s disease also highlights its potential to improve both mood and thinking skills.

A new 2024 German study adds to this growing evidence, showing that creatine supplementation can enhance cognitive performance during sleep deprivation. Participants who took creatine showed better resilience in memory and executive function tasks compared to those without supplementation. Since sleep quality can sometimes be disrupted during ketamine therapy — either temporarily after sessions or as part of underlying mood disorders — creatine may provide protective support.

Potential Benefits of Creatine During Ketamine Therapy:

• Enhances brain energy metabolism to decrease fatigue and brain fog
• Supports mood regulation and may complement ketamine’s antidepressant effects
• Improves memory and cognitive resilience, even during stress or sleep deprivation
  

By boosting cellular energy where it’s needed most, creatine functions as more than just an athletic aid — it’s a versatile supplement that may improve brain health, mood, and cognitive performance during ketamine therapy.

10. N-acetylcysteine (NAC)

N-acetylcysteine is a supplement derived from the amino acid cysteine and best known as a precursor to glutathione, one of the body’s most powerful antioxidants. By increasing glutathione levels, NAC helps the body defend against oxidative stress, reduce inflammation, and support detoxification processes. 

Beyond its antioxidant role, NAC also affects glutamate, the brain’s most abundant excitatory neurotransmitter. Dysregulation of glutamate has been linked to mood disorders, addictive behaviors, and compulsive tendencies. NAC’s ability to help normalize glutamate activity suggests it may work together with ketamine, providing extra support in stabilizing mood, decreasing cravings, and enhancing stress resilience.

NAC has been researched across various psychiatric and neurological conditions, including depression, bipolar disorder, schizophrenia, OCD, and substance use disorders. Clinical trials indicate that NAC supplementation can decrease depressive symptoms. For patients receiving ketamine therapy, this makes NAC an especially promising supplement for supporting long-term recovery and lowering the risk of relapse.

Potential Benefits of NAC During Ketamine Therapy:

• Increases glutathione to reduce oxidative stress 
• Modulates glutamate activity, enhancing ketamine’s mechanism of action
• May decrease depressive symptoms and support mood regulation.
• Aids recovery in conditions involving cravings, compulsions, or addiction

Although available over-the-counter in the US, NAC is regulated as a pharmaceutical medication for specific medical uses and requires a prescription in some countries, highlighting its potent effects. 

Supplements and Safety

Before starting any new supplements, especially during medical treatments like ketamine therapy, consult your doctor or psychiatrist. Some supplements can interact with medications, affect how your body processes ketamine, or may not be suitable for your health condition.

Supplements can't replace the need for prescription medications in some situations. However, when used carefully, they can significantly improve the safety, effectiveness, and long-term results of ketamine — especially for conditions like depression and anxiety.

Whether you're using a pre-made stack like Newy or developing your own routine, the goal is to listen to your body, monitor what works, and stay in contact with your care provider.

 

About the Author:

Dr. Ray Rivas is a medical doctor, former trauma surgeon, and the founder of Innerbloom Ketamine Therapy, a clinic dedicated to advancing mental health care through innovative treatments. With a deep passion for holistic wellness, he also leads Newy, a nootropic supplement company designed to support brain health. Drawing on decades of clinical expertise, a career focused on mental health, and personal experiences with growth and healing, Dr. Rivas is devoted to empowering individuals with the tools they need to achieve lasting mental and physical health.

Disclaimer:

The content provided on this blog and website is for educational and informational purposes only and should not be considered medical advice. Newy supplements are not intended to diagnose, treat, cure, or prevent any disease. Always consult a qualified healthcare professional before starting any new supplement, especially if you are pregnant, nursing, have a medical condition, or are taking other medications.

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