Systematic Reviews of Ketamine Therapy for Depression: What the Evidence Shows (2020–2024)

This page summarizes systematic reviews and meta-analyses published between January 2020 and December 2024 on the use of ketamine-based treatments for depression. The evidence is organized into six categories:

1. IV and Injection Ketamine – Research on intravenous and intramuscular administration, the most studied forms.
2. Esketamine (Spravato Nasal Spray) – Findings on the FDA-approved intranasal formulation.
3. Oral Ketamine– Systematic reviews of ketamine in lozenge, capsule, or sublingual forms.
4. Ketamine vs. Esketamine – Head-to-head comparisons in clinical trials and pooled analyses.
5. Ketamine + Psychotherapy – Studies examining whether pairing ketamine with talk therapy leads to better outcomes.

Only studies focused on depression were included. Reviews involving other conditions (e.g. PTSD, chronic pain, anxiety, addiction) were excluded. Each section draws only from systematic reviews and meta-analyses, which represent the highest level of evidence.

Frequently Asked Questions About Ketamine Therapy 

Which is more effective for treating depression: IV ketamine or the esketamine nasal spray Spravato?

Twenty-five systematic reviews and meta-analyses—such as those published in EClinicalMedicine (2023), Journal of Affective Disorders (2024), and Expert Opinion on Drug Safety (2022)—consistently show that IV ketamine is substantially more effective than Spravato (esketamine nasal spray) for treating depression.

In pooled studies, IV ketamine tripled the likelihood of achieving symptom response compared to placebo (RR = 3.01), while esketamine showed only a modest improvement (RR = 1.38). Remission rates were also dramatically higher: patients receiving IV ketamine were 2.5 to 4 times more likely to achieve remission than those on placebo, whereas esketamine increased remission odds by just 28%–47%.

Effect sizes tell a similar story—IV ketamine scored a Cohen’s d of -0.75 (a large effect), while esketamine averaged -0.38, only slightly above what’s seen with SSRIs (≈0.30). These differences are not subtle. In fact, the antidepressant impact of IV ketamine is among the strongest seen in modern psychiatry. While esketamine acts quickly, its effects often fade within weeks unless continued, and dropout rates in trials were up to 80% higher than for IV ketamine.

Does oral ketamine work for depression?

Systematic reviews suggest that oral ketamine may reduce depression symptoms, but the results are slower, weaker, and less reliable than other forms like IV ketamine. Across four meta-analyses published since 2020, oral ketamine consistently took 2 to 6 weeks to show effects—about the same timeline as SSRIs (Journal of Clinical Psychiatry, 2019; Psychopharmacology Bulletin, 2020). That’s a major difference from IV ketamine, which often begins working within 24 hours (Journal of Affective Disorders, 2020).

While one review reported a large effect size (SMD = -0.75) (Psychopharmacology Bulletin, 2020), this didn’t always translate into meaningful remission or lasting recovery. In fact, none of the systematic reviews provided strong evidence that oral ketamine can end depression the way IV ketamine sometimes does (World Journal of Biological Psychiatry, 2023; Journal of Affective Disorders, 2020). Response and remission rates hovered around RR = 2.6–2.8, but these were only marginally statistically significant (p ≈ 0.06–0.07), raising questions about how dependable they really are (Psychopharmacology Bulletin, 2020).

The quality of evidence is also a concern. Reviews consistently flagged problems with small sample sizes, short follow-up periods, and inconsistent reporting of side effects (World Journal of Biological Psychiatry, 2023; Journal of Clinical Psychiatry, 2019). As a result, the long-term safety and effectiveness of oral ketamine remain unclear (Journal of Affective Disorders, 2020).

Bottom line: Oral ketamine shows early promise, but the research doesn’t yet support it as a fast-acting or dependable treatment for depression—especially in treatment-resistant cases. It’s not useless, but it’s not ready for primetime either.

How effective is oral ketamine compared to other administration methods?

Oral ketamine appears significantly less effective than IV ketamine and shows weaker, slower results than esketamine nasal spray. In four systematic reviews published between 2020 and 2024, oral ketamine showed moderate antidepressant effects—but unlike IV ketamine, which often works within 24 hours, oral forms typically take 2 to 6 weeks to show any meaningful improvement (Journal of Clinical Psychiatry, 2019; Psychopharmacology Bulletin, 2020). That’s on par with SSRIs, not psychedelics.

When response and remission rates were reported, they hovered around 2.6 to 2.8 times higher than placebo—but these findings barely cleared the bar for statistical significance and came from small, high-bias studies (Psychopharmacology Bulletin, 2020; World Journal of Biological Psychiatry, 2023). By contrast, IV ketamine tripled the chance of symptom response (RR = 3.01) and nearly quadrupled remission (RR = 3.78) in much larger and more rigorous reviews (EClinical Medicine, 2023; Expert Opinion on Drug Safety, 2022). Esketamine’s performance was more modest than IV but still more consistent than oral: effect sizes ranged from 0.15 to 0.38, with a response rate of 1.38 over placebo (American Journal of Psychiatry, 2024).

So while oral ketamine might help some people, the current evidence shows it’s slower, less powerful, and far more uncertain than either IV or nasal administration. It doesn’t yet offer the reliability or rapid relief that define ketamine’s clinical reputation.

How quickly does ketamine therapy work to reduce or eliminate depression symptoms or suicidal ideation?

Ketamine therapy can begin reducing depression symptoms or suicidal thoughts in as little as 40 minutes, with peak antidepressant effects typically emerging within 24 hours of a single infusion. This finding, backed by multiple systematic reviews and meta-analyses, makes ketamine one of the fastest-acting depression treatments in psychiatry (Current Neuropharmacology, 2014; Molecular Psychiatry, 2022; Frontiers in Psychiatry, 2024).

In clinical trials of IV ketamine, response rates (meaning a ≥50% reduction in symptoms) were seen in 45% to 65% of patients within 24 hours—compared to just 5%–20% for placebo (Therapeutic Advances in Psychopharmacology, 2023; Brain Sciences, 2023). Remission (few or no symptoms) occurred in up to 30% of patients after one infusion, and repeated infusions increased the odds to 40% or more (Brain Sciences, 2023; Current Neuropharmacology, 2014).

Suicidal ideation often drops even faster. Some reviews found that suicidal thoughts diminished within 40 minutes, though this wasn’t consistent across all studies (Current Neuropharmacology, 2014; Therapeutic Advances in Psychopharmacology, 2023). One large meta-analysis reported that patients receiving ketamine were 10 times more likely to show improvement in suicidal ideation by Day 1 compared to placebo (Translational Psychiatry, 2024). Repeated infusions further extended this benefit, helping keep suicidal thoughts lower for days or even weeks in some cases (Translational Psychiatry, 2024).

The speed of action is one of ketamine’s most defining strengths. No other approved antidepressant—including SSRIs or esketamine nasal spray—matches the rapid onset consistently observed with IV ketamine.

What percent of people who undergo ketamine therapy report at least a 50% reduction in symptoms?

According to twelve systematic reviews and meta-analyses published between 2020 and 2024, between 30% and 76% of patients who undergo ketamine therapy for depression report at least a 50% reduction in symptoms—a benchmark known as clinical response (Therapeutic Advances in Psychopharmacology, 2023; Brain Sciences, 2023; Molecular Psychiatry, 2022; Current Neuropharmacology, 2014).

The median response rate across these reviews was 55%, meaning that over half of patients experienced a major drop in depressive symptoms, often after just one or two infusions (Frontiers in Psychiatry, 2024). In randomized controlled trials of IV ketamine, the results were even stronger, with response rates reaching 63%, compared to 5%–20% for placebo (Therapeutic Advances in Psychopharmacology, 2023; Brain Sciences, 2023). By contrast, real-world studies found slightly lower rates, around 30%—a pattern commonly observed in psychiatric research when trial controls are removed (Therapeutic Advances in Psychopharmacology, 2023).

These numbers place IV ketamine among the most effective depression treatments ever studied—especially for people who haven’t responded to SSRIs, psychotherapy, or other standard options.

What percent of people who undergo ketamine therapy report going into remission (little or no symptoms)?

Across five major systematic reviews and meta-analyses published between 2020 and 2024, between 27% and 43% of patients who received ketamine therapy for depression reported going into remission—meaning their symptoms became minimal or disappeared altogether (Brain Sciences, 2023; Molecular Psychiatry, 2022; Current Neuropharmacology, 2014; Frontiers in Psychiatry, 2024; Therapeutic Advances in Psychopharmacology, 2023).

The median remission rate was 29%, typically measured after just one or two IV ketamine infusions. Some studies reported even higher remission rates (up to 40%) with “serial” infusions, though the exact number of treatments varied and wasn’t always clearly defined (Brain Sciences, 2023).

While these results are impressive for such a short course of treatment, long-term remission data is scarce. Most studies tracked patients for only a week or two. So while ketamine shows striking short-term potential to bring depression into remission—faster than any traditional antidepressant—we still don’t know how often that remission lasts without continued treatment.

Does combining ketamine with psychotherapy improve outcomes?

Early evidence suggests it might—but the science is still catching up. Across four systematic reviews published between 2020 and 2024, combining ketamine with psychotherapy showed signs of improving outcomes, especially for people who initially responded well to ketamine. In several studies, patients who received therapy after ketamine experienced longer-lasting antidepressant effects and lower relapse rates compared to those who didn’t (Journal of Pain Research, 2022; British Journal of Psychiatry, 2023). One trial found that 44% of patients reached remission when ketamine was paired with cognitive behavioral therapy—an encouraging signal, even if based on small sample sizes (British Journal of Psychiatry, 2023).

But in the only randomized trial focused on depression, combining psychotherapy with ketamine showed no significant benefit over ketamine alone (Journal of Affective Disorders, 2022). And most of the strongest results came from PTSD studies, not depression. The meta-analyses noted that therapy might help extend ketamine’s effects, but the data were too limited to explain why—or to say which therapeutic approach works best, or when to deliver it (Journal of Clinical Psychiatry, 2023).

The likeliest explanation? Ketamine may open a temporary “therapeutic window”—a period of heightened neuroplasticity and emotional openness—when therapy hits harder and sticks longer. That window could be the key. But for now, ketamine-assisted psychotherapy remains promising but unproven, and larger, better-controlled trials are still needed to turn that promise into certainty.

IV Ketamine Therapy: Systematic Review Findings

Based on Five Systematic Reviews & Meta-Analyses Published in The Last 5 Years (2020-2024)

Key Findings 

– IV ketamine consistently produced rapid antidepressant effects, often within 24 hours of a single infusion.
– Response rates in clinical trials ranged from 45% to 65%, compared to placebo rates between 5% and 20%.
– Remission occurred in up to 30% of patients after just one infusion—a striking result given the brevity and intensity of the treatment.
– Serial infusions led to remission rates of up to 40%, though the term “serial” was not always clearly defined (most likely 2 infusions)
– Some studies reported significant reductions in suicidal ideation within 40 minutes, though these effects were not universally found to be statistically significant.
– Antidepressant effects were sustained in many patients for up to 7 days, and in some cases, longer—especially with repeated infusions.
– Real-world response rates (~30%) were lower than those in controlled clinical trials (~63%), a pattern commonly observed in psychiatric research.
– These outcomes were observed across five large-scale systematic reviews and meta-analyses published between 2014 and 2024.

What This Research Suggests About IV Ketamine

Across five systematic reviews and meta-analyses, IV ketamine consistently demonstrated rapid antidepressant effects, often within 24 hours of a single infusion. Response rates in clinical trials ranged from 45% to 65%, and remission rates of 30% after a single treatment were not uncommon—a striking outcome for such a brief intervention. Some studies also reported reductions in suicidal ideation within 40 minutes, though these effects were not universally found to be statistically significant.

While “serial infusions” were often associated with even higher remission rates (up to 40%), most reviews did not specify how many infusions these protocols included. Based on the source studies referenced in these reviews, it appears that the vast majority involved just one or two infusions, making it difficult to draw conclusions about longer treatment courses. Overall, the evidence strongly supports IV ketamine as a fast-acting and clinically meaningful option for treatment-resistant depression, while also highlighting the need for greater clarity and consistency in how treatment protocols are defined and reported.

Systematic Reviews Cited

Therapeutic Advances in Psychopharmacology (2023) 

Title: Ketamine For Bipolar Depression: An Updated Systematic Review

– 48% of IV ketamine patients achieved ≥50% symptom reduction; placebo group: 5%

– Controlled trial response rate: 63%; real-world studies: 30%

– Some reductions in suicidal ideation were observed, though findings varied

Brain Sciences (2023) 

Title: An Update on the Efficacy of Single and Serial Intravenous Ketamine Infusions and Esketamine for Bipolar Depression

– MADRS scores dropped by 11–12 points within 2 days

– Response rates: 54% (single), 55% (serial); remission: 30% (single), 40% (serial)

– Esketamine data was limited but showed similar MADRS reductions

Note: a reduction of 11 to 12 points represents a substantial improvement and can be characterized as a high or very high change in the context of clinical depression treatments. This kind of improvement can make a noticeable difference in a patient’s daily functioning and overall quality of life, particularly in acute settings where rapid relief from symptoms is critical.

Current Neuropharmacology (2014) 

Title: The Role of Ketamine in Treatment-Resistant Depression: A Systematic Review

– 65% response rate within 24 hours of a single infusion

– Suicidal ideation dropped within 40 minutes and remained lower for hours

– Some patients maintained remission for up to 3 months

– Repeated infusions prolonged antidepressant effects

Frontiers in Psychiatry (2024)

Title: Efficacy And Safety Of Ketamine And Esketamine For Unipolar And Bipolar Depression: An Overview Of Systematic Reviews With Meta-Analysis

– Ketamine increased short-term response and remission rates vs. placebo

– Strongest effects were in unipolar depression; bipolar results were mixed

– For bipolar depression, most studies found no significant difference between ketamine and placebo after 1–2 weeks

Molecular Psychiatry (2022) 

Title: International Pooled Patient-Level Meta-Analysis Of Ketamine Infusion For Depression: In Search Of Clinical Moderators

– 24-hour response: 45.5% for ketamine vs. 20.5% for placebo (NNT = 4)

– 7-day response: 37.7% vs. 18.3% (NNT = 5.2)

– Remission: 27% at 24 hours vs. 13% placebo; 25% at 7 days vs. 12%

Key Takeaways

RESPONSE RATES (50%+ reduction in symptoms)

Range: 30% – 76%

(read as “between 30% and 76% of patients saw depressive symptoms reduced by half or more.”)

Median: 55%*

(read as “the median response rate for a 50% or greater reduction in depression symptoms was 55%, meaning that half of the reported study response rates were below this value and half were above.”)

Notes:

• Out of 12 systematic reviews, there were 9 published Response Rates

• Many of the studies simply concluded that IV ketamine was “effective or highly effective” without mentioning numbers.

REMISSION RATES (few or no symptoms–basically ending the depression)

Range: 27% – 43%

The median Remission Rate (few or no symptoms): 29%*

Out of 12 systematic reviews, there were only 5 published Remission Rates

* These numbers are very misleading

Most systematic reviews and meta-analyses on IV ketamine measure response and remission rates after just one or two infusions, typically within a few days. That tells us one thing: ketamine works fast. But it tells us almost nothing about what really matters to patients—what are the chances that a full protocol of IV ketamine can end or nearly end their depression?

Long-term data on IV or injection ketamine therapy simply doesn’t exist in the published literature. The studies we do have are limited, typically capping out at six infusions.

For instance, this open-label study found a 79% remission rate after a 9-month follow-up, but it lacks the controlled rigor of a randomized trial.

Another study showed that six infusions over four weeks led to 69% of patients with suicidal ideation achieving full remission—but frustratingly, it doesn’t report remission rates for depression itself. 

And while this study here followed patients for a full 12 months, it was based on just six infusions. The remission rate was 46%.

These studies were not included in my analysis because I focused strictly on systematic reviews and meta-analyses—the highest level of evidence. Individual studies lack the broader synthesis and methodological rigor that systematic reviews provide in assessing long-term efficacy and safety.

Which Is More Effective at Achieving Full Remission: IV Ketamine or Esketamine Nasal Spray?

An analysis of 12 systematic reviews and meta-analyses suggests that IV racemic ketamine is significantly more effective than intranasal esketamine (Spravato) at leading to full remission from depression. However, as with response rates and symptom reduction, it is important to clarify that no head-to-head trials directly compared ketamine and esketamine. Instead, all findings come from separate placebo-controlled studies. Across multiple analyses, IV ketamine consistently produced much higher remission rates than esketamine.

1. IV Ketamine Was More Likely to Lead to Full Remission in Placebo-Controlled Studies

While both IV ketamine and esketamine helped some patients reach full remission (complete resolution of depression symptoms), IV ketamine showed a much stronger effect when each was tested separately against a placebo:

• One meta-analysis found that patients receiving IV ketamine were nearly four times more likely to achieve full remission compared to placebo (RR = 3.78, 95% CI: 2.44–5.78), whereas patients on esketamine were only 1.28 times more likely to reach remission compared to placebo (RR = 1.28, 95% CI: 1.11–1.47).
• Another review found that the remission rate for IV ketamine was 2.52 times higher than for esketamine (RR = 3.70 vs. 1.47).

These findings suggest that patients receiving IV ketamine are significantly more likely to experience a full resolution of depression symptoms than those taking esketamine, based on separate placebo-controlled studies.

2. IV Ketamine Had a Much Greater Impact on Remission Rates

Several systematic reviews found that IV ketamine consistently outperformed esketamine in terms of how many patients achieved full remission:

• One analysis found that racemic ketamine had a remission rate that was 152% higher than esketamine’s.
• Another study confirmed that IV ketamine was 2.52 times more effective at ending depression than esketamine.

These results reinforce the idea that while esketamine provides some benefit, it does not appear to drive remission as effectively as IV ketamine.

3. Ketamine Had a Substantially Larger Effect Than Esketamine in Placebo-Controlled Studies

• One review found that racemic ketamine nearly quadrupled the chance of achieving full remission compared to placebo (RR = 3.70), whereas esketamine increased remission rates by only 1.47 times compared to placebo.

This means that for every patient who reached full remission on esketamine, a much larger percentage achieved remission on IV ketamine, based on separate placebo-controlled trials.

Final Thoughts

Findings from these systematic reviews and meta-analyses suggest that IV ketamine is much more effective than esketamine at achieving full remission from depression. However, it’s important to be clear:

• There were no head-to-head comparisons between IV ketamine and esketamine. All findings are based on separate placebo-controlled studies.
• One review found that IV ketamine was nearly four times more likely to lead to full remission than placebo, while esketamine was only 1.5 times more likely.
• Another analysis found that IV ketamine had a remission rate 2.52 times higher than esketamine.
• IV ketamine’s overall remission rate was 152% higher than esketamine’s in one meta-analysis.

While esketamine can help some patients achieve remission, IV ketamine appears to be a far stronger option for completely eliminating depression symptoms.

Key Findings from 4 Systematic Reviews and Meta-Analyses On Oral Ketamine (2020–2024)

– Oral ketamine appears to offer a moderate antidepressant effect, but the evidence base remains small, methodologically limited, and inconsistent in clinical impact.
– Unlike IV ketamine or esketamine nasal spray—which often show symptom relief within hours or days—oral ketamine consistently takes 2 to 6 weeks to produce measurable improvement, a timeline that mirrors traditional antidepressants.
– While some meta-analyses reported statistically significant reductions in depression severity (e.g., SMD = -0.75), the reviews raised doubts about whether this improvement translates into meaningful clinical benefit for most patients.
– Remission and response rates (RR ≈ 2.6–2.8) were only marginally statistically significant (p-values near 0.06–0.07), leaving it unclear whether these effects are robust or replicable.
– Importantly, no systematic review provided convincing data that oral ketamine achieves the full remission or rapid response observed with IV formulations—especially in treatment-resistant cases.
– Across the reviews, methodological issues were common: high risk of bias, small sample sizes, brief follow-up periods, and inconsistent tracking of adverse events. These limitations make it difficult to draw confident conclusions about safety or long-term benefit.
– Overall, while early results suggest oral ketamine has potential as an antidepressant, the current evidence lacks the clarity, strength, and consistency needed to support its widespread use. The treatment may be promising, but much stronger studies are required to determine whether it is truly effective, for whom, and under what conditions.

What This Research Suggests About Oral Ketamine

The collective evidence from four systematic reviews suggests that oral ketamine may offer moderate antidepressant effects, but its clinical value remains uncertain. Unlike intravenous ketamine or esketamine nasal spray—both known for their rapid onset of action—oral ketamine consistently demonstrated a delayed therapeutic effect, with improvements typically emerging between 2 and 6 weeks. This timeline mirrors traditional antidepressants, raising questions about whether oral ketamine offers any distinct advantage in urgent or treatment-resistant cases.

Although some pooled analyses showed statistically significant reductions in depression symptoms, the data on response and remission rates were marginally significant at best, with wide confidence intervals and p-values hovering just above conventional thresholds for reliability. More importantly, none of the reviews provided compelling evidence that oral ketamine achieves the high remission rates seen with IV formulations.

Methodological limitations were a consistent concern across reviews. Most of the included studies were small, short in duration, and carried a high risk of bias—particularly in how they monitored adverse effects. The lack of rigorous, long-term trials means the durability of oral ketamine’s antidepressant effects—and its safety profile—are still largely unknown.

In short, oral ketamine shows early promise but lacks the evidentiary strength needed to support confident clinical use. For patients and clinicians hoping for a fast-acting, game-changing alternative, the current data are underwhelming. Until larger, higher-quality trials are conducted, oral ketamine should be considered an experimental option—one that may help some, but cannot yet be relied on as a robust treatment for depression.

Systematic Reviews Cited

Journal of Clinical Psychiatry 2019

Title: Oral Ketamine for Depression: A Systematic Review

– Oral ketamine did not produce immediate effects; statistically significant improvements in depression symptoms typically appeared after 2 to 6 weeks of treatment.

– This delayed onset mirrors the timeline of traditional antidepressants, contrasting sharply with the rapid effects of IV ketamine.

– The improvement was statistically significant (p < .05), suggesting the results were unlikely due to chance—but the reviews did not confirm whether this translated into meaningful clinical benefit for patients.

– Systematic reviews emphasized the slower onset of oral ketamine’s antidepressant effects compared to IV formulations, raising questions about its usefulness for patients needing rapid relief.

Psychopharmacology Bulletin 2020

Title: An Update on the Efficacy and Tolerability of Oral Ketamine for Major Depression: A Systematic Review and Meta-Analysis

– Oral ketamine produced a moderate reduction in depressive symptoms compared to placebo (SMD = -0.75; 95% CI: -1.08 to -0.43; p < 0.0001).

– Significant benefits were observed by the second week of treatment (SMD = -0.71; 95% CI: -1.08 to -0.35; p = 0.001; I² = 0%), suggesting a quicker onset than traditional antidepressants.

– Patients were about 2.6 to 2.8 times more likely to achieve response or remission compared to placebo, but these findings were only marginally statistically significant (RR = 2.58 for response; RR = 2.77 for remission; p ≈ 0.06–0.07).

– While oral ketamine appears safe and moderately effective, its ability to deliver full remission remains uncertain and requires confirmation from larger studies.

World Journal of Biological Psychiatry 2023

Title: Oral ketamine for depression: An updated systematic review

– All included studies reported significant improvements in depressive symptoms following oral ketamine treatment.

– The randomized controlled trials were marked by a high risk of bias, largely due to flawed analysis methods and inadequate monitoring of adverse events.

– Early evidence supports oral ketamine’s antidepressant potential, but larger studies with longer follow-up periods are needed to confirm its antisuicidal effects and effectiveness in treatment-resistant depression.

Journal of Affective Disorders 2020

Title: The effect of intravenous, intranasal, and oral ketamine in mood disorders: A meta-analysis

– Both intravenous and intranasal ketamine formulations show strong short-term effectiveness in reducing symptoms of treatment-resistant depression, while oral ketamine demonstrates a more gradual but still meaningful benefit.

– Intranasal ketamine or esketamine reduced depressive symptoms within 24 hours, with a large and statistically significant effect size (Hedges’ g = 1.247; 95% CI: 0.591–1.903; p < 0.01).

– Intravenous ketamine or esketamine showed a large effect size at 2–6 days (g = 0.949), but results were not statistically significant (95% CI: -0.308–2.206; p = 0.139), limiting confidence in the finding.

– Intranasal ketamine sustained a large and statistically significant effect between 7–20 days post-treatment (g = 1.018; 95% CI: 0.499–1.538; p < 0.01).

– Oral ketamine showed a moderate but statistically significant effect by days 21–28 (g = 0.633; 95% CI: 0.368–0.898; p < 0.01), indicating delayed but meaningful symptom improvement.

What Can We Say About Oral Ketamine with Some Degree of Certainty?

An analysis of four systematic reviews suggests that oral ketamine may have some antidepressant effects, but the data is extremely limited, and its clinical usefulness remains unclear. Unlike IV ketamine and the esketamine nasal spray, which have been studied extensively for their rapid-acting antidepressant properties, oral ketamine has primarily been investigated in smaller studies with shorter follow-ups and methodological limitations. The findings suggest that oral ketamine may reduce depression symptoms over time, but whether it is effective enough to be a reliable treatment remains unknown.

1. Oral Ketamine Takes Weeks to Show an Effect, Unlike IV Ketamine and Esketamine

Unlike IV ketamine and the esketamine nasal spray, which can produce rapid antidepressant effects within hours or days, oral ketamine takes much longer to show meaningful improvements.

• One systematic review found that significant symptom improvement began around the second week of treatment, with a standardized mean difference (SMD) of -0.71 (95% CI: -1.08 to -0.35; p = 0.001).
• Another review noted that oral ketamine did not produce statistically significant antidepressant effects until after 2 to 6 weeks of treatment, a time course similar to traditional antidepressants.

This suggests that oral ketamine does not offer the same rapid relief as IV ketamine and esketamine, and its delayed onset makes it difficult to determine how it compares to other antidepressant options.

2. The Antidepressant Effect Is Statistically Significant but May Not Be Clinically Meaningful

Some of the reviews reported statistically significant reductions in depression symptoms, but statistical significance does not necessarily mean the improvement was large enough to be meaningful for patients.

• A pooled analysis in one review found an SMD of -0.75 (95% CI: -1.08 to -0.43; p < 0.0001), indicating a moderate reduction in depressive symptoms compared to placebo.
• Another study confirmed statistically significant antidepressant effects (p < 0.05) but cautioned that this does not necessarily translate into a strong clinical benefit for most patients.

Because oral ketamine was not compared directly to standard antidepressants, it remains unclear whether these effects are unique or whether oral ketamine simply works in the same way as existing medications but with different side effects.

3. Response and Remission Rates Are Uncertain and Likely Unreliable

Unlike IV ketamine and esketamine, where response and remission rates are well-documented in placebo-controlled trials, the evidence for oral ketamine’s ability to produce full remission is weak.

• One review found that oral ketamine increased remission rates by 2.77 times compared to placebo (95% CI: 0.96 to 8.00; p = 0.06) and response rates by 2.58 times (95% CI: 0.94 to 7.08; p = 0.07).
• However, these findings were only marginally statistically significant, meaning they could be due to chance rather than a real effect.

Moreover, the absolute response and remission rates were not reported in these systematic reviews, making it impossible to determine how many patients actually benefited from the treatment. Without clear data on how many people experienced meaningful improvements, the clinical value of oral ketamine remains questionable.

4. The Studies Had Significant Limitations

All four systematic reviews found some improvement in depressive symptoms with oral ketamine, but they also highlighted major limitations in the research.

• One review noted that the randomized controlled trials had a high risk of bias due to poor analysis methods and inadequate adverse event monitoring.
• Another emphasized that the studies were too small and too short to determine whether oral ketamine has meaningful long-term effects, particularly for treatment-resistant depression.
• None of the reviews provided strong evidence that oral ketamine prevents suicide, a key benefit associated with IV ketamine and esketamine.

Final Thoughts

Based on these four systematic reviews, the evidence for oral ketamine remains weak.

• Unlike IV ketamine and esketamine, which work quickly, oral ketamine takes weeks to show any effect, making it difficult to compare its usefulness as a rapid-acting antidepressant.
• While some studies reported statistically significant antidepressant effects, the actual clinical benefit remains unclear, and remission rates are inconsistent.
• The overall quality of the evidence is low, with small sample sizes, high risk of bias, and no clear data on long-term effectiveness.

Without larger, well-controlled studies, it is impossible to say whether oral ketamine is a reliable antidepressant treatment. The findings suggest potential, but the lack of consistent clinical benefit and weak remission data make it unclear whether oral ketamine is an effective alternative to existing treatments.

Research Comparing Ketamine Alone vs. Ketamine Combined with Psychotherapy 

Based on 4 Systematic Reviews & Meta-Analyses Published in The Last 5 Years (2020-2024)

Key Insights 

– Combining ketamine with psychotherapy appears to extend antidepressant effects and reduce relapse, especially in patients who initially respond to ketamine.

– Studies in PTSD show large symptom reductions, but evidence in depression is more mixed.

– Research quality is still low, and better trials are needed to confirm how and when psychotherapy adds value.

– Early findings suggest ketamine may create a “therapeutic window” in which talk therapy is more effective.

What This Research Suggests About Ketamine Combined with Psychotherapy

Across four systematic reviews published between 2020 and 2024, early findings suggest that combining ketamine with psychotherapy may help prolong the antidepressant effects of ketamine, reduce relapse, and produce greater symptom improvement than ketamine alone. This is especially true in studies of posttraumatic stress disorder (PTSD), where combined treatment led to large reductions in symptom severity—including a pooled effect size (SMD) of –7.26 for clinician-assessed outcomes.

In depression, the results were more mixed and preliminary, with only one randomized trial reporting no additional benefit of ketamine-assisted psychotherapy (KAP) over standard care. Still, other reviews observed that patients who received psychotherapy after ketamine showed more sustained improvements than those who didn’t—suggesting that therapy may help extend remission and possibly prevent relapse in those who initially respond to ketamine.

While these findings are promising, the evidence base is still limited. Most studies used small sample sizes, employed varying psychotherapeutic techniques, and differed in ketamine dosing and timing. Few trials were randomized, and the overall quality of evidence was considered low to moderate. Additionally, none of the studies directly tested the mechanisms behind why or how psychotherapy might amplify or prolong ketamine’s effects.

Taken together, the research suggests that ketamine may create a temporary therapeutic window—through mechanisms like enhanced neuroplasticity, altered perspective, or increased emotional openness—during which psychotherapy could be more effective. But for now, the combined use of ketamine and psychotherapy should be seen as experimental but promising, with a clear need for larger, well-controlled studies to determine when, how, and for whom this combination works best.

Systematic Reviews Cited

J Affect Disord (2022)

Time: Active mechanisms of ketamine-assisted psychotherapy: A systematic review

– Ketamine-assisted psychotherapy (KAP) may help reduce symptoms of substance use disorders, but evidence is still limited and results are mixed.

– In the only randomized trial focused on treatment-resistant depression, KAP did not show a benefit over standard care.

– None of the studies directly tested how KAP works, but researchers believe ketamine’s short-term effects on brain chemistry—like blocking NMDA receptors and boosting neuroplasticity—may support psychotherapy.

– The review also suggests that ketamine’s impact on mindset—such as enhancing insight, shifting perspective, or evoking spiritual experiences—might make therapy more effective.

– Overall, the science behind KAP is still emerging. The review highlights a need for larger, high-quality trials to understand when and how this treatment works.

Journal of Clinical Psychiatry (2023)

Time: Combining Ketamine and Psychotherapy for the Treatment of Posttraumatic Stress Disorder: A Systematic Review and Meta-Analysis

– Combining ketamine with psychotherapy significantly reduced PTSD symptoms across all studies included in the review.

– The pooled symptom reduction was substantial, with a standardized mean difference (SMD) of –7.26 for clinician-assessed symptoms and –5.17 for patient-reported symptoms—both statistically significant.

– All four studies involved different combinations of ketamine administration and psychotherapeutic techniques, but each reported meaningful improvements in PTSD symptoms.

– While the results are promising, the sample size was small (only 34 patients), and two of the four studies were rated as low quality.

– Because of the limited data and methodological weaknesses, the overall quality of the evidence is low, but early findings suggest that ketamine-assisted psychotherapy may offer a powerful new option for treating PTSD.

Journal of Pain Research 2022

Time: Ketamine Assisted Psychotherapy: A Systematic Narrative Review of the Literature

– Among those who initially responded to ketamine, patients who received psychotherapy afterward experienced more sustained improvements in depression scores over 14 weeks. (Exact numbers were not reported.)

– Adding psychotherapy to ketamine treatment appears to prolong remission and reduce the risk of relapse.

– Evidence suggests that psychotherapy may help extend ketamine’s antidepressant effects, but most studies had small sample sizes and limited methodological rigor.

– While early findings are promising, larger and more robust randomized controlled trials are needed to confirm these outcomes.

 British Journal of Psychiatry 2023

Time: Ketamine and psychotherapy for the treatment of psychiatric disorders: systematic review

– When psychotherapy was added to ketamine treatment for depression, patients experienced greater and more sustained improvement compared to those receiving ketamine alone.

– One study combining cognitive behavioral therapy (CBT) with ketamine for treatment-resistant depression found that 50% of patients showed significant improvement, and nearly 44% achieved remission.

– These results suggest that therapy may help maintain the antidepressant effects of ketamine, potentially reducing relapse.

– However, due to differences in therapy types, ketamine dosing, treatment schedules, and small sample sizes, researchers caution that current findings are preliminary. Larger, standardized studies are needed to confirm how best to combine ketamine and psychotherapy.

Early Evidence Suggests Therapy May Prolong Ketamine’s Benefits

Several studies indicate that patients who receive therapy after ketamine treatment experience more sustained improvements in depression scores compared to those who do not. This suggests that psychotherapy could help extend ketamine’s antidepressant effects and lower relapse rates, though the strength of this conclusion is limited by the available data.

Encouraging but Preliminary Findings

One study found that when cognitive behavioral therapy (CBT) was combined with ketamine for treatment-resistant depression, 50% of patients showed significant improvement, and nearly 44% achieved remission. While these numbers are encouraging, they come from a small sample, and variations in study designs make it difficult to draw firm conclusions.

More Research Is Needed to Confirm the Connection

Despite promising trends, the evidence remains inconclusive due to small sample sizes, inconsistent methodologies, and a lack of large randomized controlled trials. Differences in therapy types, ketamine dosing strategies, and treatment schedules further complicate the picture. More high-quality research is necessary to determine the best ways to integrate psychotherapy with ketamine treatment for long-term depression relief.