There is a lot of discussion surrounding not only the different forms of ketamine (intranasal, intravenous, intramuscular, versus oral), but also the number of infusions a person should receive to gain relief from treatment resistant depression (TRD). If you do a Google search and check out various ketamine clinic websites, you’ll typically find a recommendation of an initial series of six ketamine infusions. Why is that and do you really need multiple infusions and boosters? In this post we set out to explain what’s going on here.
Are Multiple Ketamine Infusions Necessary?
Research supports multiple ketamine infusions are needed to minimize depression symptoms and maintain antidepressant effects. We recommend pursuing the 6 series infusion to start, followed by boosters as needed.
A single ketamine infusion can be effective within hours of the infusion to reduce depression symptoms for up to 80% of patients. However, these effects can last only up to a few days to a week. Multiple infusions in the form of a series of six infusions can prolong the antidepressant effects for up to several weeks (and for some people months).
In the setting of chronic, high-dose ketamine use in abusers, studies demonstrate unfavorable changes in the brain, and neurotoxicity in the rodent model. Fortunately, one study of clinical ketamine use at Yale Psychiatric Hospital looking at patients who received ketamine infusions on a long-term basis showed no evidence of cognitive decline, delusions, or cystitis in their sample of patients.
To understand what could be best for you, you’ll need to explore where the recommended protocol comes from and what can happen with too much for too long, and more. It’s a lot but no worries we’re here to walk you through it!
Why Clinics Offer a Series of 6 Infusions: A Short History on Ketamine for Depression
The initial study which put ketamine on the map was Dr. Berman’s placebo-controlled, double-blind study. The results demonstrated a significant reduction in depression symptoms within 72 hours following a single ketamine infusion. Like in medicine and science, other researches with studies of similar design would further support and validate these findings. Despite the robust antidepressant response, relapse would eventually happen within several days to a week after, causing researchers to look to see if multiple infusions could prolong the antidepressant effect.
Then a study found that 6 infusions over a 12-day period in 10 patients with treatment resistant depression (TRD) was well tolerated and safe. This study demonstrated a delayed relapse to 19 days after the 6th infusion (a range of 6-45 days) for 8 of 9 patients. One patient had minimal depressive symptoms and antidepressant medication free for more than 3 months!
Another study demonstrated similar findings. Here 14 participants were enrolled of which 12 completed 6 infusions. Of these 12, eleven (91.6%) had an antidepressant effect. With the increasing number of infusions, this study demonstrated a more robust antidepressant effect, while maintaining safety and efficacy of this treatment. Thus, supporting the current standard of practice of offering 6 ketamine infusions.
With research supporting not only the rapidly effective treatment with a single infusion and the maintained effect with a series of treatments, doctors were ready to revolutionize the treatment of depression, and clinics began offering the recommended 6 infusion series. Depression, especially treatment-resistant depression, is not as simple as taking a pill. Honestly, it would be naive to believe just one treatment of any drug or therapy would be the key to improving symptoms.
If you want to learn more about ketamine’s colorful history going from battlefield anesthetic to club drug to mental health treatment, check out our blog, “A Brief History Of Ketamine.”
How Can I Tell If Infusions Are Going To Be Effective For Me?
The real question here is, should I sign-up for the 6 infusions at first, or should I just try one and see how it goes? A study by Dr. Murrough and colleagues set out to determine how effective durable multiple infusions could be. In this study, they took 24 participants - 21 of which received all 6 of the planned scheduled ketamine infusions. They found those who had an antidepressant response at 4 hours from the initial infusion was 94% sensitive and 71% specific in predicting response to subsequent infusions. Conversely, lack of a rapid response indicated a poor likelihood of response to additional infusions. At the end of the 6 infusion series, they found the median time to relapse was 18 days (however with an intersubject variability from 4 to more than 83 days). The findings of this study suggests multiple infusions result in a more prolonged and robust decrease in depression symptoms compared to a single infusion, even once the infusions have been completed.
Now we are not saying if you don’t feel better within four hours of your infusion, cancel your other infusions! You need to remember that all these studies had small sample sizes (aka not many study participants). Plus, they didn’t look into other factors which could affect treatment such as dosage or non-medical factors such as coupling infusions with therapy, coaching, exercise, meditation, sleep hygiene, and other healthy habits. What we’ve found in our patients, is that sometimes it can take up to 4-5 infusions for some to feel the effect.
Does the Amount of Ketamine Given Effect The Number of Infusions I Should Get?
Something to take into consideration about the initial ketamine studies is that they did not look into how the number of ketamine infusions a patient would need if the amount of ketamine was increased over the course of the infusion series. Interestingly, there was a study performed to look at various ketamine doses for antidepressant effects in those with TRD. The results revealed that participants who received intravenous ketamine treatments had significant improvement compared to those who received the active placebo (midazolam). However, after controlling for multiple comparisons, only the standard dose (0.5 mg/kg) and high dose (1 mg/kg) of ketamine were superior to active placebo. Conversely, the low dose (0.1 mg/kg) was significant only before adjustment, and the 0.2 mg/kg dose did not show any significant effects compared to active placebo. This suggests clinical evidence for antidepressant effectiveness from the 0.5 mg/kg and 1.0 mg/kg dose range of ketamine.
At Reset Ketamine, we use gradually ascending doses of ketamine to achieve the maximal effects for our patients. Usually, we start at 0.5 mg/kg and then titrate upwards, depending upon patient effect and safe vital sign assessments. We believe higher doses will lead to non-ordinary states of consciousness, which may lead to a more potent, profound, and prolonged effect.
Read more about what a ketamine infusion feels like here.
Concerns About Too Much Ketamine: Looking At Research With Rats & Chronic Ketamine Abuse
There are studies in the rodent model (aka rats) showing repeated high doses of NMDA receptor antagonists (ketamine included) can be toxic to neurons. Furthermore, studies involving individuals with a long history of ketamine abuse, showed adverse changes to the brain on neuro-imaging. But what needs to be kept in mind here is that the amount of ketamine given or consumed to the subject (rat or human) is not to the same degree as that given in the infusion clinic setting. The amount of ketamine used recreationally or in the abuse setting is much higher, and is likely used more frequently and for a much longer period of time.
As we mentioned earlier, there was a recently published long-term study looking at intravenous ketamine use at Yale Psychiatric Hospital. Fortunately, the study showed no long-term adverse effects, like cognitive decline, delusions, or ketamine-induced cystitis in their sample of patients.
Overall, our goal for ketamine infusions is to catalyze healing and create paradigm shifts, which over time translates to less frequent usage, and for some, hopefully no more need of ketamine in the future.
Related Questions
Of The Six Infusions, Do You Need To Do It In A 2 Or 3 Week Time Frame?
According to Dr. Singh & colleagues, they found that receiving ketamine infusions in a twice a week protocol over 4 weeks, was equally as effective as a three times a week protocol over 4 weeks for depression. What is exciting about this study is that is shows flexibility in treatment without necessarily sacrificing effect.
Want to learn more? Check out our blog post, “Ketamine Infusion Protocol: Twice A Week Or Three Times A Week?”
What Other Factors Contribute To Ketamine Infusions’ Effectiveness?
Depression is multifactorial, meaning using a drug to solely address the biochemical aspect of the disease may not be effective. This is one of the limitations of these ketamine studies, which looked at only the dosage of ketamine or only looked at ketamine’s effect on depression symptoms. Factors such as having a healthy mind-set prior to the infusions and the setting of the infusion, along with support and integration (AKA putting what you learned during the infusion into everyday life practice) after the infusions is the key to making you feel better and creating prolonged transformational change in your life.
We go into more detail on this topic on our blog post, “How To Prepare For And Integrate From A Ketamine Infusion”
How Do You Know It’s Time For a Booster?
Most ketamine infusion clinics will have you complete depression tests / scores or have some other way to measure your symptoms before and after infusions. Seeing how your scores are returning in relation to your pre-infusion levels is one way of knowing it’s time for a booster. We contact our patients to see how they are doing and check-in if they may need a booster infusion. Also, you can reflect on how you are doing and feeling. Some people can feel when negative thoughts or habits that no longer serve them return or if they are feeling less active, they know it’s time for a booster.
Who Shouldn’t Get Ketamine Infusions?
Individuals with uncontrolled hypertension, cardiac disease, uncontrolled thyroid disease, active substance abuse, active manic phase of bipolar disorder, active delusions and hallucinations symptoms such as schizophrenia, and those who have had a bad experience with ketamine in the past.
Check out more details on this topic on our blog post, “The 7 Types Of People Who Should Not Get Ketamine.”
Learning something new in our blog post? We hope this was helpful. Please share this post if you enjoyed and were educated by it! If you have any questions or comments please leave them below.
References:
Berman, Robert M, et al. “Antidepressant Effects of Ketamine in Depressed Patients.” Biological Psychiatry, vol. 47, no. 4, 2000, pp. 351–354., doi:10.1016/s0006-3223(99)00230-9.
Fava, Maurizio et al. “Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD).” Molecular psychiatry, 10.1038/s41380-018-0256-5. 3 Oct. 2018, doi:10.1038/s41380-018-0256-5
Liao Y, Tang J, Corlett PR, Wang X, Yang M, Chen H, et al. Reduced dorsal prefrontal gray matter after chronic ketamine use. Biol Psychiatry. 2011;69:42–48.
Liao Y, Tang J, Ma M, Wu Z, Yang M, Wang X, et al. Frontal white matter abnormalities following chronic ketamine use: a diffusion tensor imaging study. Brain. 2010;133:2115–2122.
Murrough, James W., et al. “Rapid and Longer-Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression.” Biological Psychiatry, vol. 74, no. 4, 2013, pp. 250–256., doi:10.1016/j.biopsych.2012.06.022.
Olney JW, Labruyere J, Price MT. Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science. 1989;244:1360–1362.
Olney JW, Labruyere J, Wang G, Wozniak DF, Price MT, Sesma MA. NMDA antagonist neurotoxicity: mechanism and prevention. Science. 1991;254:1515–1518
Rot, Marije Aan Het, et al. “Safety and Efficacy of Repeated-Dose Intravenous Ketamine for Treatment-Resistant Depression.” Biological Psychiatry, vol. 67, no. 2, 2010, pp. 139–145., doi:10.1016/j.biopsych.2009.08.038.
Singh, Jaskaran B., et al. “A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression.” American Journal of Psychiatry, vol. 173, no. 8, 2016, pp. 816–826., doi:10.1176/appi.ajp.2016.16010037.
Shiroma, Paulo R., et al. “Augmentation of Response and Remission to Serial Intravenous Subanesthetic Ketamine in Treatment Resistant Depression.” Journal of Affective Disorders, vol. 155, 2014, pp. 123–129., doi:10.1016/j.jad.2013.10.036.
Wilkinson, Samuel T., et al. “Acute and Longer-Term Outcomes Using Ketamine as a Clinical Treatment at the Yale Psychiatric Hospital.” The Journal of Clinical Psychiatry, vol. 79, no. 4, 2018, doi:10.4088/jcp.17m11731
Research supports multiple ketamine infusions are needed to minimize depression symptoms and maintain antidepressant effects. We recommend pursuing the 6 series infusion to start, followed by boosters as needed.
To understand what could be best for you, you’ll need to explore where the recommended protocol comes from and what can happen with too much for too long, and more. It’s a lot but no worries we’re here to walk you through it!
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Learn what to expect during ketamine therapy, including key preparation steps, emotional responses, and tools to navigate your ketamine infusion experience.