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My Response to the 'Trial of Ketamine Masked by Surgical Anesthesia in Depressed Patients'

Last month, Stanford researchers preprinted (ie, published but not yet peer reviewed) the results of a thought-provoking study which looked into the antidepressant effects of ketamine. While I found the study’s methods creative and conclusion interesting, I was dismayed—but not surprised—by how the internet reacted.

Along with other psychedelics like MDMA and psilocybin, ketamine is going through a resurgence in novel and exciting scientific research. Unfortunately, many websites paraphrase these studies with controversial sounding language in order to get higher search engine results page rankings, website visits, URL clicks, and dollars. For example (my emphasis added):

  • Ketamine May Not Be a Remedy for Depression from HealthNews1
  • Ketamine Fails to Beat Active Placebo for Depression from Mad in America Foundation2
  • Ketamine no better than placebo at alleviating depression, unusual trial finds from American Association for the Advancement of Science3
  • Hyped as a Depression Treatment, Ketamine Is a Mystery from Bloomberg Opinion4 and republished by Anchorage Daily News5

Today, I will offer a second opinion on this popular study. I will review its design and propose ways in which future research may improve our understanding of ketamine’s role in treating depression. I will also highlight firsthand examples on why I believe ketamine is a safe and effective treatment for people suffering from Treatment Resistant Depression (TRD) and Major Depressive Disorder (MDD).

The Study

First, I encourage you to read the study on PubMed Central.6

This appeared to be a small but well-controlled study with a creative twist to address a common question in this type of research: Is it possible to run a blind study with psychedelics?

Let me explain. Since by definition, psychedelics produce obvious and unmistakable changes in perception and mood, participants will realize who received the placebo. This knowledge may distort the study’s outcome measures in a concept known as subject-expectancy bias.7

In other words, if you believe that you received the placebo, you may expect nothing to happen and vice-versa. Further, researchers and care providers involved with the study may also subconsciously treat the participants differently if they know who received the placebo. The typical remedy is to mask not just the participants, but everyone involved in a process called blinding. However, blinding may not be possible when the substance being studied (in this case ketamine) will visibly alter a participant’s conscious state.

This study attempted to overcome this issue by selecting participants who would be sedated by other surgical anesthetics such as propofol before the administration of ketamine or placebo. If participants would not be able to guess whether they received ketamine or placebo better than chance, then the blinding would be successful.

Study Facts:

  • There were 40 adult participants who were diagnosed with Major Depressive Disorder (MDD) as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS).8
  • All participants were recruited from preoperative clinics and were preparing to undergo elective surgery that did not involve the heart or brain.
  • Participants were randomly assigned into one of two groups: a study (ketamine) and control (placebo).
  • Participants were effectively blind because they were unable to guess whether they received ketamine or placebo better than chance would predict.
  • Participants in the study group received a single subanesthetic dose of ketamine (0.5mg per kg of bodyweight) that was diluted into 40mg of normal saline.
  • Participants in the control group received a single 40mg dose of normal saline.
  • The study allowed participants to receive psychotherapy and antidepressant therapy before, during, and after the study as long as they had been regularly receiving the therapy for four or more weeks before screening.
  • The primary outcome measured was the difference in MADRS scores at 1, 2, and 3 days after the infusion. A secondary outcome compared the MADRS scores before and after the infusion.


The researchers concluded that while both reduced depression, ketamine was not more or less effective than placebo. In other words, they suggested that ketamine did not alleviate symptoms of MDD any better than placebo and that ketamine may be ineffective for short-term treatment of MDD. Based on my experience with treating patients at Innerbloom Ketamine Therapy, I found these conclusions interesting but potentially flawed.

Improvement Opportunities

While I applaud its novel approach, this study is not without limitations. I believe the following ideas may help inform future research which builds upon this notable study.

Opportunity #1: Adjust the protocol.

One major limitation of the study is the use of a single ketamine infusion rather than multiple. The standard way to treat MDD with ketamine involves a series of infusions, usually 6-8, over 3 to 4 weeks. This protocol acknowledges that it may take more time for some patients to respond to ketamine therapy than others. It also recognizes that many patients will not have an immediate and/or robust response from a single infusion.

In my experience treating patients at Innerbloom Ketamine Therapy, symptoms of MDD do not always decrease significantly after a single infusion. While some patients show improvements after 1-2 infusions, it is not uncommon for others to experience noticeable and positive improvements only after subsequent infusions. Unfortunately, there is no reliable method to determine who will need 1-2 vs the full series before starting treatment. We have encountered a meaningful percentage of patients who require 4+ infusions before noticing significant relief of depressive symptoms. Furthermore, all study participants received a dose of 0.5mg ketamine per kg of bodyweight. This dosage is an appropriate starting place, and some patients may need higher doses to achieve meaningful results.

Opportunity #2: Control for other medications.

The researchers noted that opioids may interfere with the antidepressant effects of ketamine. Therefore, the study attempted to control for opioids and saw no differences among the participant groups. Importantly, the researchers did not mention other perioperative management techniques. For example, oftentimes patients may receive benzodiazepines before or after a surgical procedure to lessen anxiety. Medicines like midazolam, diazepam, and lorazepam, among other psychoactive medications, also have the potential to decrease the efficacy of ketamine. Additionally, the researchers did not include details on the types of concurrent antidepressant therapy some participants received. Some antidepressants like lamotrigine (Lamictal) may interfere with ketamine.

As part of our comprehensive medical evaluation before starting ketamine therapy, we always ask about medications. This is to identify and manage potential interactions that may adversely affect our patient’s health or the effectiveness of ketamine’s ability to heal. In cases where patients are taking benzodiazepines, we may temporarily adjust their medication to promote safety and efficacy.

Opportunity #3: Incorporate Ketamine-Assisted Psychotherapy and a healthy lifestyle.

Since all participants showed symptoms of depression, it is likely that some were receiving psychotherapy before, during, and after the study. However, the researchers did not describe how many participants received psychotherapy nor the type of psychotherapy.

Earlier this year, we began collaboration with Cindy Nelson, LMFT, who is a local licensed therapist with experience with Ketamine-Assisted Psychotherapy or KAP. We introduced KAP because we believe that positive results require more than ketamine alone. We have found that patients who incorporate psychotherapy (which involves preparation for ketamine therapy, intention setting, and integrating their ketamine experience into their everyday lives) often have better outcomes with regards to alleviation of depressive symptoms.

We also see that patients who are successful at developing healthy lifestyle habits (eg, sound sleep, better food choices, regular exercise, meditation, mindfulness) in conjunction with ketamine therapy fare better more often than patients who do not.

Opportunity #4: Instead of masking, incorporate psychoactive effects.

No doubt, the debate will continue on how to design studies involving psychedelics, given their increasing acceptance for healing potential. And while researchers may devise more creative ways to mask psychoactive effects, maybe the answer is to blind participants another way.

Artistic watercolor painting of a woman
Credit: Kateryna Kovarzh via Adobe Stock

Barring the creation of a new form of ketamine which lacks psychoactive effects (if that’s even possible), researchers should contemplate producing psychoactive effects in control groups. In fact, some studies have already attempted this by comparing groups who receive different doses of the same psychedelic. However, what if there were a way to compare the antidepressant effects of ketamine with the antidepressant effects of psilocybin? Or some other psychoactive medicine? Of course, such a study would need participants with no prior experience or knowledge of any psychedelics.

While conclusive findings are elusive, I believe that ketamine’s psychoactive effects are integral to the healing process. All patients who have successfully completed a series of infusions at Innerbloom Ketamine Therapy have experienced the psychoactive effects of ketamine. And many show strong positive responses based on PHQ-9 assessment and depression scoring after treatment.


I find recent studies like these encouraging because it shows that more attention and resources are being spent on promising new medicines like ketamine. However, with increased interest, there is commensurate risk that findings will be overstated or misrepresented, especially by those trying to steal our precious attention. In fact, based on the study’s objective title and careful design, it appears that the researchers were well aware of how their work might be mischaracterized by others. Only with careful review of the research behind the sensational headlines and misleading articles will we be able to truly advance the science of treating the challenging symptoms of depression.


  1. https://healthnews.com/news/ketamine-may-not-be-a-remedy-for-depression/
  2. https://www.madinamerica.com/2023/05/ketamine-fails-to-beat-active-placebo-for-depression/
  3. https://www.science.org/content/article/ketamine-no-better-placebo-alleviating-depression-unusual-trial-finds
  4. https://www.bloomberg.com/opinion/articles/2023-06-02/can-ketamine-treat-depression-why-researchers-struggle-to-answer#xj4y7vzkg
  5. https://www.adn.com/opinions/national-opinions/2023/06/05/opinion-hyped-as-a-depression-treatment-ketamine-is-a-mystery/
  6. Lii TR, Smith AE, Flohr JR, Okada RL, Nyongesa CA, Cianfichi LJ, Hack LM, Schatzberg AF, Heifets BD. Trial of Ketamine Masked by Surgical Anesthesia in Depressed Patients. medRxiv [Preprint]. 2023 May 1:2023.04.28.23289210. doi: 10.1101/2023.04.28.23289210. PMID: 37205558; PMCID: PMC10187335.
  7. https://en.wikipedia.org/wiki/Subject-expectancy_effect
  8. https://www.mdcalc.com/calc/4058/montgomery-asberg-depression-rating-scale-madrs

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