Benefits of Ketamine: A New Pinch Hitter for Depression? – Part 1

By: Michael Lam, MD, MPH; Carrie Lam, MD; Jeremy Lam, MD


young adult that is sad could use the benefits of ketamine to help depressionDepression is no longer a so-called “first world problem” – it’s a worldwide epidemic of huge proportions. It’s estimated that around 350 million people around the world have depression. That’s almost 5% of the global population. Around 16 million people in the US alone have had at least one episode of major depression. There are several types of depression, as there are several options for care. Recently, the benefits of ketamine have been getting promising results for managing depression and suicidal cases short-term.

Though the exact benefits of ketamine for depression are not yet fully understood, this new function is still being studied and tested. As more and more people discover they have depression, the need for effective, safe, and affordable therapies are increasing, and this article explores the benefits of ketamine for depression and its effects on the body.

Recognizing Symptoms of Depression

Mental health conditions are identified through symptoms, and that’s how you will know whether you or someone you know might be suffering from depression. Symptoms of depression can be categorized into two types: the physical and the mental/emotional.

The physical symptoms of depression include:

  • Fatigue, which can sometimes be so severe that you can’t function
  • Insomnia or sleeping too much
  • Loss of appetite or overeating
  • Weight loss or weight gain
  • Body aches that have no traceable cause

The mental/emotional symptoms of depression include:

  • The feeling that a dark cloud has come over your life
  • Deep feelings of sadness
  • A feeling of emptiness
  • Remorse or regret over the past
  • Difficulty concentrating
  • Difficulty making decisions
  • An inability to enjoy life or the things that used to give you pleasure
  • Irritability
  • Restlessness
  • Anxiety
  • Loss of interest in activities
  • Inability to be effective at work or school
  • Thoughts of suicide and death

depressed woman being comforted by a man. she may see the benefits of ketamineThese symptoms of depression will differ from person to person, and from one type of depression to another, so it’s also important to know the type of depression you are facing and, if possible, its causes, so that you can address it properly.

If you experience major depression for longer than two years, then this can be categorized as persistent depressive disorder. You can also experience one episode of major depression or recurring episodes. Although many people experience depression without being able to identify a particular cause, there are some types of depression that are caused by specific mental, physical, and environmental factors.

Seasonal Affective Disorder (SAD) is a type of depression that is caused by the lack of sunlight. Many of those that suffer from SAD are affected in winter and feel better in the summer. For this type of depression, getting to places with more sun or getting a sun lamp can help, as well as taking a good vitamin D3 supplement.

Around 10-15% of women experience postpartum depression. This can be due to different factors, like hormonal changes, lack of sleep, the stress of being a new parent, and huge changes in lifestyle and circumstances. If this is your situation, ask your doctor about your best options, and give yourself time to adjust to your new role as a mother.

Depression Associated with Mental Health Conditions

Other mental health issues can include depression as a component, such as bipolar disorder, where a person experiences periods of manic highs alternating with periods of depression. Psychotic depression is when the depression is accompanied by other mental health symptoms, such as paranoia, hallucinations, and delusions.

Bipolar disorder and psychotic depression present a bigger challenge for care, yet also pose greater risks, and so they need to be addressed appropriately. Though the benefits of ketamine have not been tested for these specific situations, there will hopefully be more studies in the future.

Depression and Suicide Risks

Suicide is one of the risks of unmanaged depression, and sometimes even those receiving care are still at risk for suicide. Unfortunately, the rate of suicide across the world is so high that suicide was the 17th leading cause of death in the year 2015, and the 2nd leading cause of death for people aged 15-29. Around 800,000 people commit suicide every year, with 78% of that number in middle-to-low income countries. Countries in Eastern Europe have the highest suicide rates worldwide.

man standing on a ledge may see the Benefits of ketamine in preventing suicideWith one person dying from suicide every 40 seconds, suicide is a public health issue rather than an individual or familial one. The other frightening estimate that is linked to suicide rates is that for every suicide that is completed, there are around 20 attempts.

Thankfully, there are proven methods of suicide prevention and intervention techniques that can be implemented. One of the benefits of ketamine is that it has been a very powerful and fast-acting method for preventing suicide. But once the initial crisis passes, the focus needs to be on more long-term management of mental health issues, including depression. That’s what makes testing the benefits of ketamine for long-term use very important.

How Depression Can Affect Your Life

Other than suicide risk, depression can have major health and life consequences. First of all, it can deter you from making your health a priority. People with depression find it very difficult to maintain the motivation to eat healthy, exercise, or pay attention to the state of their environment. If you suffer from depression, especially long-term, you are much more likely to resort to smoking, taking drugs, or drinking alcohol in order to seek relief.

You may also begin to isolate yourself and withdraw from social interactions, leaving you feeling more alone and without hope than before. Loneliness is quickly becoming another health crisis, to the point that a Minister of Loneliness was recently appointed in the UK to try to find solutions for this epidemic.

Self-harm is another risk, though it is more likely in adolescents and teenagers that suffer from depression. Depression can also cause a lot of conflict and stress at work and at home, adding more pressure to an already difficult life situation.

The Benefits of Ketamine for Depression

Traditionally, ketamine was used as an anesthetic and has been used for this purpose for the last few decades. But the doctors using it began to notice interesting unintended effects: the lifting of depression within a few hours, and the fact that it was so robust it could deter desperate suicidal cases quickly.

These dramatic effects prompted researchers to begin looking into the benefits of ketamine for managing depression, especially the type of depression that is resistant to other drugs. So far, two main hypotheses have been presented to explain how ketamine acts on depression.

On one hand, studies done by National Institutes of Health (NIH) are looking at the metabolite that the body creates when it breaks down ketamine as the possible answer to how ketamine rapidly lifts depression, sometimes in hours, or even minutes.

The other, older hypothesis is that ketamine blocks N-methyl-D-aspartic acid (NMDA) glutamate receptors. Glutamate is one of the brain’s main excitatory chemicals.

But when the NIH started doing human trials with other blockers of NMDA receptors, they failed to get the same antidepressant benefits of ketamine.

This inspired further studies on ketamine’s unique abilities to give fast and effective relief from depression without any of the usual anesthetic, addictive, or dissociative side effects that usually come with ketamine use.

What they found was that the metabolite created when the body broke down ketamine – hydroxynorketamine (HNK) – is what has the antidepressant effects. When they would block the metabolism of ketamine, thus blocking the creation of HNK, the ketamine would lose its antidepressant capabilities. Furthermore, they also found that, unlike ketamine itself, the metabolite HNK did not actually block the NMDA receptors, showing that perhaps it was not solely responsible for producing the antidepressant effects.

woman outdoors having a drink and enjoying the benefits of ketamineThere are two forms of HNK: (2S,6S) HNK, and (2R,6R) HNK. Only the latter of these two worked on depression and did not produce the dissociative, addictive, euphoric effects that ketamine is known for. This is excellent news, as further development of these trials could eventually give us a safe, fast, and effective therapy for depression without the potential for abuse.

In the meantime, that benefits of ketamine for depression are being seen in clinics all over the country even though it hasn’t yet been studied enough. It was only very recently that the FDA gave a formulation of ketamine, called esketamine, designation to be used for major depression. And, because those who suffer from treatment-resistant depression and suicidal ideation need relief very quickly, many doctors are using ketamine now, before the researchers and FDA can produce conclusive results and give their approval.

Of course, the benefits of ketamine shouldn’t be seen as a magic bullet. At this time, its best used for short-term relief, just long enough to get you through a crisis and into a more holistic program that suits your needs.

Depression and AFS

Depression is something that needs to be managed with long-term, holistic lifestyle changes that support both a healthy mind and a healthy body. It is a chemical imbalance that is not only produced by thoughts. Thus, common conditions that lead to undetected chemical imbalances can also lead to depression and vise versa.

Depression can cause health problems beyond discouraging you from pursuing a healthy lifestyle. The imbalance in neurotransmitters and the added stress it causes can overwork your adrenal glands, leading to Adrenal Fatigue Syndrome (AFS), and an imbalance in your entire NeuroEndoMetabolic (NEM) Stress Response.

AFS is a dysregulation in the amount of cortisol that the adrenal glands secrete in response to stress. When you are faced with chronic stress, such as that caused by depression as well as the life pressures that depression causes, your adrenal glands overwork in order to produce more cortisol. In the beginning phases of AFS, your overall cortisol levels increase.

Cortisol is your body’s main anti-stress hormone, and although it is a necessary hormone for many important functions, its overall increase creates a lot of problems in the body.

Symptoms of AFS include fatigue, easily gaining weight and difficulty losing it, insomnia, waking up in the middle of the night, difficulty getting out of bed in the morning, hair loss, infertility, PMS, low libido, lowered immunity, food and drug sensitivities, salt and sugar cravings, as well as brain fog, anxiety, and mild depression.

tired man sitting on bed that has not experienced the benefits of ketamineThis shows that depression and AFS have a two-way relationship. While depression can be a cause of AFS, it can also be a symptom, though that’s truer with the more mild forms of depression than with major depressive disorders.

AFS and depression sometimes also have a common cause, inflammation of the gut, which will be discussed in more detail below.

These symptoms of AFS aren’t usually noticeable in the early stages. But in the more advanced stages of AFS, your cortisol levels drop sharply as your adrenal glands become exhausted. This leaves your body without its main stress fighter, and so the symptoms begin to worsen and may eventually become debilitating.

And, as you can see, depression and AFS share some symptoms, such as fatigue, brain fog, anxiety, weight issues and sleep problems. And so the benefits of ketamine could help in the short-term with AFS recovery, and AFS recovery can be part of a holistic therapy for depression.

Depression and The Neuroaffect Response

The NEM is the body’s global response to stress, where different organs and systems work together to combat and neutralize the negative effects of stress. These organs and systems can be categorized into six NEM circuits: the hormonal, the bioenergetics, the detoxification, the inflammation, the cardionomic, and the neuroaffect.

Although all six circuits are engaged in the stress response, some circuits are affected more than others when a specific stressor is present or when a specific preexisting condition is present. For example, with depression and anxiety, the neuroaffect response is usually much more affected and much more engaged than if the stressor was an infection or a heart condition.

The adrenal glands are always the first responders to stress, but they actually get their orders from the hypothalamus and pituitary gland, which we can think of as the control centers in the brain, through the Hypothalamic-Pituitary-Adrenal (HPA) axis. The HPA acts like a hormone cascade, with the hypothalamus signaling to the pituitary gland to secrete ACTH, which is a hormone that stimulates the adrenal glands into secreting cortisol and other stress hormones.

Cortisol takes part in vital functions like regulating blood sugar levels and blood pressure, maintaining heart and blood vessel function, suppressing the immune system, and neutralizing inflammation.

In a healthy individual, the HPA axis is switched off when the system no longer needs cortisol, and any extra cortisol circulating in the system is then taken as a sign for the hypothalamus to stop signaling the pituitary gland to secrete ACTH. That way, the adrenals get a break and cortisol levels go back to normal.

As we’ve seen, when stress is chronic, the adrenal glands are overworked, having to secrete a lot more cortisol than usual. This happens because of the signaling of the hypothalamus and pituitary gland, with more and more ACTH being released in order to stimulate the adrenals into secreting cortisol.

As this axis is engaged in the hormone circuit of the NEM, other hormone systems can be affected as well. These can include the thyroid and the gonads (female ovaries or male testes). This is partly why libido and fertility take a dive when you have AFS. The thyroid is affected by AFS, and that in turn can affect the bioenergetics circuit, which is composed of the thyroid, pancreas, and liver.

As the hormone and bioenergetics circuits become engaged in the stress response, with much of the activity beginning with the control centers in the brain, the central nervous system (CNS) is also engaged. This is why some of the symptoms of AFS include sleep disturbance, brain fog, anxiety, and depression. The neuroaffect response, which is composed of the autonomic nervous system (ANS), the brain, and the gut, becomes engaged in the stress response too.

young girl looking sad has not seen the benefits of ketamineAll three of these responses, but especially the neuroaffect, involve different neurotransmitters, and, unfortunately, when these neurotransmitters go out of balance, whether due to stress, health issues, or depression, they affect every organ and system in the body.

Neurotransmitters are responsible for your mood, your ability to handle stress, and your sleep patterns. These chemicals need to be in perfect balance for you to have a stable mood, get good sleep, rest when you need it, and have mental/emotional resilience when faced with stress. But no one is resilient to the point of immunity to stress, and the human body is not built to handle constant stress. And, unfortunately, our modern lives are rife with sources of stress – whether physical or mental.

One of the biggest stressors on the body is a bad diet, and the Standard American Diet is one of the unhealthiest there are. It’s high in fat, sugar, and processed foods, and low in fiber, nutrients, and water content. Fast food and microwave meals have become cheap and convenient options for our busy schedules, but their long-term effects on health are very destructive.

Interestingly, your diet has a lot to do with your mood, and that’s because of the gut-brain connection. Many of your neurotransmitters are actually made in the gut, including serotonin, which is your “happy chemical”, whose lack can cause depression, insomnia, problems with the immune system, gastrointestinal issues, and inflammation. Because a bad diet can cause inflammation in the gut, it can affect the production of serotonin in the gut.

Read Part 2

© Copyright 2019 Michael Lam, M.D. All Rights Reserved.


Dr. Lam’s Key Question

Traditionally, ketamine has been used as an anesthetic, and has been abused for its euphoric and hallucinogenic properties. Recently, however, its ability to provide powerful antidepressant effects, sometimes within minutes, has had the medical community considering the benefits of ketamine as the next possible ally in treatment-resistant depression.


Benefits of ketamine