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This article is off the Bulletproof blog:

  • Ketamine, which gained notoriety as a club drug in the ‘90s, is gaining momentum as a wonder drug for the treatment of depression
  • Ketamine, which works directly on brain receptors, can offer relief from depression symptoms in as little as 24 hours — as opposed to traditional antidepressants, which work on shifting hormonal balances in the brain and can take up to 8 weeks to become effective
  • Ketamine infusion therapy can be an effective way to manage depression symptoms — but only under the supervision of a medical doctor


There’s a new treatment that’s gaining traction as a wonder drug for depression — and that’s ketamine. According to its advocates, medically administered ketamine infusions have the potential to revolutionize the way doctors treat depression — and give people struggling with depression unprecedented relief from their symptoms.

On a recent Bulletproof Radio podcast episode (iTunes), Dave spoke with neuropsychiatrist Dr. David Feifel, one of the first people to use ketamine to treat depression. “I had patients who it’s basically taken them from being suicidal to living a very full and complete life,” said Feifel. “[Some] return on a periodic basis and some of them have just stopped coming in [because they’ve been cured].”

For people struggling with depression, treatment is crucial. Unfortunately, traditional treatments don’t work for everyone; about 30% of people with depression don’t respond to traditional pharmaceutical treatment, and even for people who do respond, antidepressants can take up to eight weeks to take effect — which, when you’re struggling with depression, can feel like a lifetime.

According to the Anxiety and Depression Association of America, more than 16 million American adults struggle with major depressive disorder. And, for many, depression can be debilitating; depression is the leading cause of disability for Americans between the ages of 15 and 44, costing the US economy a whopping $210 billion per year in lost productivity and missed days of work.

Disclaimer: This article and video feature a medical procedure performed by a medical professional. Do not try this at home. All information, content, and material is for informational purposes only and is not intended to serve as a substitute for the consultation, diagnosis, and/or medical treatment of a qualified physician or healthcare provider. 

Related: How to Fight Depression Without Medication

What is ketamine?

what is ketamineBefore we jump into how ketamine works — and why it’s such an effective treatment for depression — let’s talk about what, exactly, ketamine is.

Ketamine is classified as a dissociative anesthetic, along with drugs like PCP and nitrous oxide. It’s currently a class III scheduled drug (meaning it’s approved for use in hospital or medical settings). At high doses, ketamine is an ideal anesthetic, since it causes sedation and amnesia without suppressing respiratory function or lowering blood pressure.

In lower doses, ketamine can cause hypnotic states, altered perception of sight and sound, pain relief, and dissociative states. These dissociated states can make you feel detached from your body or from your surrounding environment (similar to an out of body experience).

Because of the dissociative effects and visual and auditory effects it can produce, ketamine gained popularity in the club scene as a hallucinogenic (most commonly known as Special K). But while the drug definitely has potential to be abused recreationally, when used under medical supervision, studies show ketamine infusions have the potential to be a complete game-changer for people struggling with severe, treatment-resistant depression.

“When traditional treatments don’t work, [ketamine] is the least harsh, safest, and fastest-working option that provides long-term relief,” says Dr. Francisco Cruz, a board-certified psychiatrist at Ketamine Health Centers, a ketamine infusion center in Miami, Florida.

How do ketamine infusions work on depression?

ketamine infusion therapy depressionResearch into ketamine as a treatment for depression is new, so doctors aren’t entirely sure why ketamine is so effective, particularly for patients who haven’t responded to more traditional treatments — but most doctors believe it’s thanks to the way ketamine interacts with the brain.

While traditional antidepressants shift the balance of hormones called neurotransmitters in the brain, ketamine works directly on receptors. Ketamine blocks NMDA (also known as glutamate) receptors, which are widely believed to play a major part in depression — and as it blocks that receptor, it changes the way brain cells communicate, directly impacting other receptors in the brain, including the opiate receptors, which affect depression and pain responses.

“Ketamine is a dissociative agent that works on the neurotransmitter glutamate,” says Cruz. “By antagonizing the glutamate receptor, it has downfield effects on other neurotransmitters in the brain such as serotonin and the opiate system.”

Because ketamine works on receptors — and not on shifting hormone balances — the effects are dramatically faster. While traditional antidepressants can take anywhere from 4 to 8 weeks to start taking effect, ketamine starts to work almost immediately — sometimes within minutes.  During a study of ketamine’s effect on people with treatment-resistant bipolar depression,[1] participants experienced a reversal of a significant symptom — loss of interest in pleasurable activities — within 40 minutes of their first ketamine infusion.

Related: Lower Your Glutamate Levels Naturally With KetoPrime

The fact that ketamine infusions provide near-immediate relief from depression symptoms can be a literal lifesaver — particularly for people struggling with suicidal ideation. A study from the American Journal of Psychiatry[2] found that ketamine was able to significantly reduce suicidal thoughts in participants with major depressive disorder in just 24 hours — and without any of the lasting negative side effects typical of other depression treatments.

“Studies have shown ketamine infusion therapy relieves suicidal ideation within 24 hours without harsh side effects like memory loss, which often happens with treatments like electroshock,” says Cruz. “On the contrary, patients reported minimal side effects with ketamine infusion therapy.”

What to expect during a ketamine treatment

ketamine infusion therapy depression

Dave Asprey and Bulletproof Radio Executive Producer Selina talk through the ketamine procedure with Dr. Matt Cook

If you’re struggling with depression, have had little success with more traditional treatments, and want to explore ketamine infusion as a potential treatment, the first step is to speak with your doctor. While your primary care physician likely won’t be able to provide ketamine infusion therapy at their office, they can refer you to a reputable center that specializes in using ketamine as a treatment for major depressive disorder.

Once you’re referred to a ketamine infusion center, you can expect to do an initial assessment with a doctor to determine whether ketamine therapy is right for you. During this assessment, you’ll go over both your medical and mental health history. You’ll also want to let your doctor know of any medications you’re taking; there are a few medications that may interact with ketamine (like Lamictal and certain benzodiazepines) and you may need to adjust your dosage or when you take your medication.

Ketamine and substance abuse

This is also the time to come clean about any past or current struggles with substance abuse. It’s important for your doctor to know if you have a history of addiction before you start ketamine therapy — but addiction struggles won’t necessarily disqualify you from receiving treatment. In fact, ketamine treatment may provide an added benefit when it comes to dealing with your addiction issues.

“We do a drug test during our initial assessment even before considering scheduling an infusion session. However, a previous history of addiction is not a contraindication to treatment,” says Cruz. “Actually, there are research studies going on now using ketamine to treat addiction…  [Ketamine is] also a good, non-addictive alternative to opioids when it comes to treating chronic pain — which is essential in a time when opioid-abuse is plaguing our community.”

You should also let your doctor know of any additional conditions you’re struggling with, as ketamine might be able to provide relief in other areas. “Ketamine can also be used to treat a slew of conditions like PTSD, OCD and fibromyalgia,” says Cruz.

In the video above, Bulletproof Radio Executive Producer, Selina, tries a ketamine infusion to treat phobic anxiety.

Ketamine dosage and side effects

Once you’ve gotten the green light to move forward with ketamine for depression, you can schedule your first infusion. Ketamine is administered through an IV and sessions typically last 45 minutes. You’ll want to bring someone with you to your ketamine infusion sessions, since you definitely won’t be able to drive home.

“Short term side effects include a dissociative state, mild sedation, and possible dizziness/nausea,” says Cruz. Luckily, those effects should wear off in a few hours. “There are no significant long-term side effects that have been reported.”

When it comes to how much ketamine you need to take, there’s no “magic dosage” — the amount of ketamine needed during infusions will vary from person to person. Your doctor will start with a low dosage and continue to adjust until the dosage that effectively treats your symptoms.

“We dose in weight, and the typical anesthetic dose is probably four to eight milligrams per kilogram. The dose that we use starts anywhere from a quarter of a milligram, .25 milligrams per kilogram, up to two, sometimes two and a half, three milligrams per kilogram,” explains Feifel.

Interestingly, you have to be awake during the treatment in order for it to treat your depression, says Feifel. When used at higher doses, as a tranquilizer, patients don’t wake up with the same antidepressant effect.

As for the number of treatments your doctor will recommend — how many infusions you’ll need will all depend on where you are, what you’re struggling with, and how your body responds to the ketamine treatments (at Ketamine Health Centers, a total of six infusions over three weeks is recommended to maximize the effects of the ketamine — but the number of treatments following that initial course will depend on each individual).

Feifel says ketamine is like dialysis for the mind. “The treatment for depression requires repeated administration. It’s not just a one time thing,” he says. While some people require periodic treatments, others no longer need it.

What not to do with ketamine treatment

ketamine infusion therapy depressionClearly, ketamine infusion therapy is an incredible tool if you’re struggling with major depressive disorder — but that doesn’t mean you should try to take treatment into your own hands.

Using ketamine as a treatment for depression under the supervision of a medical professional and hitting the club and scoring some Special K are two completely separate things — and while getting ketamine infusion therapy from a specialized doctor can be life-changing, attempting to administer your own ketamine treatment can be extremely dangerous.

The dissociative state caused by ketamine can, under the wrong circumstances, put you in danger (which is why it’s historically been used as a date rape drug). Compounding the danger factor, if you don’t get your ketamine infusions from a doctor, you also have no way of knowing the dosage or what’s actually in the drug — which can put you at serious risk.

Bottom line: ketamine should only be used under the supervision of a doctor. Doctors will not prescribe ketamine for patients to take home, and there’s a reason for that — the dangers far outweigh the risks.

Should you take ketamine for depression?

Ketamine has the potential to completely revolutionize the way doctors are able to treat major depressive disorder — and if you’ve struggled with treatment-resistant depression, it could be the wonder drug you’ve been looking for. Talk to your doctor to find out if you’re a candidate for treatment, and to find a ketamine clinic near you.


Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression.


Anhedonia—which is defined as diminished pleasure from, or interest in, previously rewarding activities—is one of two cardinals ymptoms of a major depressive episode. However, evidence suggests that standard treatments for depression do little to alleviatethe symptoms of anhedonia and may cause reward blunting. Indeed, no therapeutics are currently approved for the treatment ofanhedonia. Notably, over half of patients diagnosed with bipolar disorder experience significant levels of anhedonia during adepressive episode. Recent research into novel and rapid-acting therapeutics for depression, particularly the noncompetitive NMethyl-D-aspartatereceptor antagonist ketamine, has highlighted the role of the glutamatergic system in the treatment ofdepression; however, it is unknown whether ketamine specifically improves anhedonic symptoms. The present study used a randomized, placebo-controlled, double-blind crossover design to examine whether a single ketamine infusion could reduce anhedonia levels in 36 patients with treatment-resistant bipolar depression. The study also used positron emission tomography imaging in a subset of patients to explore the neurobiological mechanisms underpinning ketamine’s anti-anhedonic effects. We found that ketamine rapidly reduced the levels of anhedonia. Furthermore, this reduction occurred independently from reductions
in general depressive symptoms. Anti-anhedonic effects were specifically related to increased glucose metabolism in the dorsalanterior cingulate cortex and putamen. Our study emphasizes the importance of the glutamatergic system in treatment-refractory bipolar depression, particularly in the treatment of symptoms such as anhedonia.

Over half of patients diagnosed with bipolar disorder (BD) suffer
from significant levels of anhedonia,1 defined as loss of enjoyment
in, or desire to engage in, previously pleasurable activities.2
Notably, anhedonic patients with affective disorders have a poorer
treatment prognosis than their non-anhedonic counterparts.3–5
Indeed, accumulating evidence suggests that standard treatments
for depression do little to alleviate anhedonia6 and may even
cause reward and emotional blunting,7–9 sexual anhedonia10 and
anorgasmia.11,12 Furthermore, the presence of anhedonia in a
major depressive episode (MDE) is a predictor of proximal suicide
completion.13 Critically, no US Food and Drug Administration approved
treatment currently exists specifically for anhedonia.

Dopaminergic signaling has been consistently correlated with
the anticipation, motivation and learning related to pleasurable
stimuli, but not to their consumption.22–24 Phasic bursts in
dopaminergic neurons in the ventral tegmental area (VTA) have
reliably been shown to co-occur with violations in reward
expectancy,25 underscoring the evidence for dopaminergic
signalling in reward learning. Furthermore, dopamine signalling
in the nucleus accumbens, an area of dense dopaminergic
projections from the VTA, has been strongly associated with
reward motivation in rodents.26 Functional neuroimaging in
humans indicates that structures such as the VTA,27,28 substantia
nigra,28 amygdala,28 putamen,28 caudate,28 ventral striatum,29,30
and orbitofrontal cortex28,31—all of which receive innervation
from or project to dopaminergic nuclei—are recruited during
reward anticipation.


The above is excerpts from the article link above. Anhedonia is different from depression as it is harder to treat . You may be less depressed, but you may have no motivation to pursue an interest. Ketamine can treat Anhedonia. This has to do with Glutamate signaling in the brain.


The noncompetitive N-Methyl-D-aspartate (NMDA) receptor
antagonist ketamine has shown remarkable consistency in rapidly
ameliorating depressive symptoms in both MDD39–43 and BD.44,45
However, it is unknown whether ketamine also possesses any
specific anti-anhedonic efficacy. Given the likely mechanistic
heterogeneity of depression, it is critical to understand the
specific targets of treatment response at both the clinical and
neural levels, as outlined in the research domain criteria.46
Ketamine acts directly on the glutamatergic system, which
appears to be critical in depression;47,48 however, little is known
about the specificity of the relationship between commonly
occurring symptoms during an MDE (for instance, anhedonia,
anxiety) and particular biological phenotypes. In a small sample
investigation, Walter et al. 49 found that MDD patients with high
levels of anhedonia had lower levels of glutamine, but not
glutamate, than healthy controls, but only a trend towards lower
glutamine than MDD patients with low levels of anhedonia, who
did not differ from controls.

Several notable findings emerged from this study investigating
the effects of the rapid-acting antidepressant ketamine on
anhedonia in currently depressed treatment-resistant BD patients.
Foremost among these findings is that ketamine, compared with
placebo, rapidly reduced the levels of anhedonia in these patients;
this reduction occurred within 40 min of a single ketamine
infusion and lasted up to 14 days. Furthermore, we found that
anti-anhedonic effects of ketamine remained significant even
when controlling for level of depressive symptoms, suggesting
that ketamine has a unique role in ameliorating anhedonia levels
independent of other depressive symptoms. This study also used
18FDG-PET to examine a subgroup of these patients and quantify
the rCMRGlu correlates of change in anhedonia levels associated
with ketamine treatment.

Ketamine acts primarily by blocking the glutamatergic NMDA
receptor. It may also upregulate α-Amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid receptor throughput.85 Although glutamate
is the major excitatory neurotransmitter, its role in
anhedonia has yet to be fully explored. Preliminary evidence
suggests that glutamate may have an integral role in both
anhedonia and depression.47,50 Ketamine is also a partial agonist
of the dopamine D2 receptor86,87 and has been found to increase
dopamine levels in the striatum, including the caudate and the
putamen.88 Intriguingly, Meyer et al.
89 found that MDD patients with co-occurring motor retardation symptoms exhibited lower
extracellular dopamine in the putamen compared with healthy
volunteers. Taken together, these findings suggest that the
glutamatergic system and its downstream modulation of dopaminergic
activity may be one potential route of the anti-anhedonic
efficacy of ketamine.


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