Your Complete Guide to Ketamine as a Psychedelic Medicine

What is Ketamine?

Ketamine has a long-standing and well-studied history as a dissociative anesthetic, and recently as a valid treatment option when addressing mental health conditions such as depression and anxiety —including treatment-resistant varieties, as well as PTSD, OCD, substance use disorder (SUD), and suicidal ideation.

It is currently the only clinician-prescribed psychedelic medicine available for use in therapeutic modalities, and is available to the general public in most countries in the world. It has a proven and favorable safety and efficacy profile. Psilocybin is also growing as an accessible medicine in some states and countries like the Netherlands.

Ketamine has been FDA-approved since the early 1970’s, and is a Schedule III controlled substance classified by the DEA, while other psychedelic compounds have remained Schedule I since their initial classification. This greatly increases the access clinicians have and the ability to study and research the effects of ketamine.

With its dissociative psychedelic properties being proven beneficial, ketamine’s vast potential as a tool in the treatment of mental health continues to be uncovered.

History of Ketamine

Ketamine was first synthesized in 1962 by Calvin Stevens, an Organic Chemistry professor at Wayne State University in Michigan. In 1970 it was approved by the FDA for medical use as a dissociative anesthetic by the US government. It was used mainly to induce and maintain anesthesia in patients undergoing major surgery, due to its pain-relieving and dissociative properties.

Many studies were conducted around the safety, efficacy, and tolerance of ketamine as a dissociative anesthetic, and because it has become a generic drug that is easily affordable for treatment application, ketamine was added to the WHO’s list of essential medicines.

In the early 2000’s, there was more deliberate scientific inquiry and research into ketamine’s antidepressant effects, which were known but not directly explored. These initial studies came back with promising results.

Currently, ketamine is still used as an anesthetic with major benefits:

• Doesn't impair respiration
• Doesn't stimulate moderate bronchodilation
• Doesn't increase heart rate (important when a patient is in shock)
• Has anti-inflammatory effects

It is also being prescribed off-label by licensed practitioners for mental health conditions such as depression, anxiety, PTSD, OCD, and more.

Legality of Ketamine Treatment

Ketamine is legal for use by registered practitioners, and historically has a high safety profile in surgical and therapeutic use since its synthesis in the 1960’s. Its scope of treatment and potential use-cases continue to grow and develop as ketamine is studied further.

The use of ketamine is regulated, meaning it can only be administered or prescribed by licensed clinicians with the authority and expertise to support its effective use. When used within the context of a surgical procedure or as prescribed by a licensed clinician, it is perfectly legal to use. Any other use of this medicine outside of a clinician’s prescription and directive would be considered illegal.

Ketamine has been approved by the Food and Drug Administration (FDA) for medical use as an anesthetic since 1970.

Ketamine is also available for “off-label” prescription by a licensed clinician. “Off-label” can, understandably, be a confusing term. A common misconception about “off-label” prescribing is that it’s potentially illegal or otherwise untrustworthy.

“Off-label” prescription is when a medicine is used to treat another condition outside of its original medicinal intent as noted by the FDA. Ketamine is currently listed as a Schedule III compound under DEA guidelines. This means it is generally accepted to have medical value for specific purposes, and must be administered by a licensed provider to be distributed effectively.

This is a relatively common practice, with studies showing that one in five prescriptions are given off-label. Fully labeling a medicine for FDA-approved use is a time and cost-prohibitive process, and is typically sought out by pharmaceutical companies looking to apply the medicine for a specific consumer use case.

Generally, when a drug or compound is approved for medical use, it is approved to treat a very specific ailment or serve a very particular purpose. Originally, ketamine was approved for use as a general anesthetic in surgeries that do not require skeletal muscle relaxation. This is an example of “labelled use.”

Fortunately, new science and research is emerging showing that ketamine can be highly effective in treating treatment-resistant depression, anxiety, PTSD, OCD, chronic pain, and a growing list of other applications. In addition to off-label ketamine prescriptions, the FDA recently approved derivatives such as esketamine for treatment of adults with treatment-resistant depression.

For more on ketamine’s legality, you can read our full overview of the legal status of ketamine here.

Is Ketamine Safe?

It has been widely and safely used by anesthesiologists during surgeries involving young children and aging seniors, and those in between.

Ketamine is used in many socio-economic environments due to its relatively low cost, and continues to be used in a clinical setting because it is considered safe, well-tolerated, and effective in what it does.

A factor indicating the safety profile of ketamine as a medicine is that it is used in a variety of medical and therapeutic settings to treat a broad (and growing) number of symptoms and conditions.

Some of these applications include:

• Anesthesia for surgery
• Analgesia for a wide variety of painful conditions, medical traumas, or procedures
• Combating major depression and anxiety symptoms
  

With the emergence of science that has validated other therapeutic indications for ketamine treatments (depression, anxiety, OCD, PTSD) more and more clinicians have begun to follow the science and treat conditions with off-label prescription of ketamine.

This, along with a paradigm shift in emerging mental health treatments, has helped drive ketamine from the hospital into outpatient clinics, and application through telemedicine. Outpatient clinic models vary greatly and you can receive treatment from anesthesiologists, psychiatric or primary care clinicians, and in some settings, a psychotherapist paired up with a prescriber.

Ketamine does not require the use of expensive or complex medical tools such as external oxygen sources, electricity supplies, or large clinical teams. Simplifying the treatment process helps avoid the possibility of adverse effects through medical or application error.

No medicine available is without risks, potential side effects, and contraindications — symptoms or conditions that an individual may be experiencing that indicate treatment may not be suitable. This is why ketamine is a regulated medicine, used in structured procedures and administered by medical professionals.

Some of the contraindications include:

• Uncontrolled high blood pressure or glaucoma, increased intracranial pressure, or heart problems.
• Pregnant or breastfeeding woman
• Thyrotoxicosis (excess thyroid hormone)
• Psychosis and active mania with or without psychosis
  

As with any compound, it’s easiest to consider this in terms of the half-life of ketamine. A half-life is how long it takes for 50% of the compound to be excreted from the body.Ketamine metabolizes quickly in the body, with a half-life of around 2.5 hours. This means that after 2.5 hours, 50% of the ketamine has been excreted from the bloodstream. For comparison, coffee has a half-life of five hours. Given this, after about 10-12 hours since the initial dosing, a majority of the ketamine is out of your system. This is independent of the subjective experience, which subsides after about an hour.

Ketamine’s metabolites can remain in the body for almost two weeks, metabolites are smaller by-product molecules from the metabolic process, or the process of breaking down larger molecules for use or processing in the body.

Overall, this is one of the advantages to work with ketamine: it’s very well tolerated across a large population, it has a fast onset and manageable total duration, and is metabolized and processed through the body quickly as well.

Given the range of patients that receive it in medical and therapeutic settings, and research supporting the efficacy of its mental health treatment modality, ketamine is considered a safe and well-tolerated medicine.

Neuroscience of Ketamine

Depending on which clinical context ketamine is applied in —the anesthetic or psychiatric— its effects on the brain and neurological pathways differ.

Glutamate production and BDNF

At lower doses shown to have an antidepressant effect, ketamine appears to increase the release of glutamate, a neurotransmitter. The ketamine then preferentially blocks glutamate at the NMDA receptors but doesn’t block glutamate binding to adjacent AMPA receptors. The net effect is to increase AMPA activation. The effect is magnified by the way ketamine induces the neuron to make additional AMPA receptors.

By increasing the level of glutamate transmission and shifting its balance of activation from NMDA to AMPA receptors, ketamine increases production and release of BDNF (brain-derived neurotrophic factor). Referred to as “fertilizer for the brain,” BDNF is a protein that helps promote the growth, maintenance, and survival of neurons, enhancing neuroplasticity.

The mTOR pathway

Ketamine also stimulates a cell pathway called mTOR (mammalian target of rapamycin), which regulates many processes involved in cell growth, including synthesizing the proteins needed for long-term memory. In combination with increased BDNF production, mTOR stimulation improves connectivity in the prefrontal cortex and hippocampus, key areas of the brain associated with emotional regulation, increased synaptic plasticity, and the potential to reverse the synaptic damage that occurs in these areas when the brain is subjected to chronic stress.

Due to these neuroplastic effects, regrowth of synaptic transmitters can happen within a few hours of a sub-anesthetic ketamine dose. When the atrophied neurons can repair the damage and regrow their connections with other neurons, symptoms of depression and anxiety improve.

Cell structures and other neurotransmitters

Another possible mechanism for ketamine is its action on structures within the neuron. Some studies suggest that ketamine accumulates in lysosomes (organelles that contain digestive enzymes) and synaptic vesicles, which might then trigger mTOR signaling. Ketamine can also trigger increased release of dopamine and noradrenaline. Research related to these mechanisms is complex, with more being uncovered as it advances.

Neuroscience of Depression

The impacts of stress and depression on the brain aren’t just at the molecular and cellular level. Depression impacts connectivity at the brain macro level as well. By using functional magnetic resonance imaging (fMRI), researchers have been able to see how people with depression seem to have weaker connections within larger neural networks, which can be seen in the prefrontal cortex.

The prefrontal cortex is the seat of higher-level cognitive processes, including executive function —the ability to control short-term behaviors in favor of self-control, planning, decision-making, problem-solving, and long-term goals. When the subregions of the prefrontal cortex aren’t communicating well, as is the case in depression, executive function can be dysfunctional. Ketamine seems to help improve global connectivity in this portion of the brain and improve the linkages among the subregions.

For more on ketamine’s neuroscience, read our comprehensive overview here.

Psychological Basis of Ketamine

Ketamine use in the treatment of mental health conditions is still an emerging area of research and study. More trials are underway to demonstrate the depth and breadth of ketamine’s applications and potential.

There are multiple core areas of research that have already been published:

• Ketamine as a treatment for major depressive disorder (MDD) / treatment-resistant depression
• Ketamine as a novel treatment for general anxiety and social anxiety disorders
• Using ketamine to manage bipolar disorder (BPD), obsessive-compulsive disorder (OCD), and substance use disorders (SUD)
• Ketamine as a treatment for managing suicidal ideation
  

As more studies emerge, the results are promising: From the rapid onset of results, to long-lasting effects, ketamine as a novel treatment in the mental health space is showing to be highly effective.

There are a number of features that make ketamine therapy remarkable and effective as a medicine for the mental health field.

Rapid onset and visibility of results and positive outcomes  

Unlike some traditional pharmacological interventions such as SSRIs (selective serotonin reuptake inhibitors), which can take up to 6 weeks to begin showing desired outcomes, some clients working with ketamine therapy report seeing results within hours of their first treatment.

Long-tail endurance and durability of its outcomes

The second core benefit is what is called the durability of the benefits — those that extend beyond just the dosing session or the immediate hours following administration.

Early research has highlighted enduring effects from a single treatment that remain noticeable weeks after the dosing session.

Addresses and heals underlying drivers of the conditions

Along with the immediate mood-regulating effects of a ketamine session, there may be longer-term neurochemical and biological benefits from ketamine.

Some of these benefits may include increasing the presence of brain-derived neurotrophic factor (BDNF) in the brain, which can help create new, healthy neural connections.

The dissociative and psychedelic subjective experiences ketamine induces can provide new behavioral insights, clarity into life circumstances, and surface deep-embodied emotions or feelings. Integrating and addressing what comes up in ketamine therapy can lead to more resiliency, positive affect, and brighter futures for clients.

It fits into your life

Convenience is an important factor that makes ketamine therapy a useful and appealing treatment option.  The experience itself lasts around 60-90 minutes when using sublingual tablets, so it’s not a full-day commitment for those whose schedules don’t allow.

Because ketamine's benefits and durability can be long-lasting, you aren’t required to take a pill every day to see benefits.

Any side-effects are often minimal and subside quickly

With programs like Mindbloom, you can receive psychedelic therapy from the comfort of your own home, monitored by a close friend or loved one, while under the guidance of experienced clinicians and highly-trained guides.

The “felt” or physiological effects can last 1-3 hours (physical effects can still be felt after the session), and short term side effects such as altered sense of time, nausea, restlessness, and elevated blood pressure or heart rate typically subside shortly following the treatment experience.

With a relatively proven and promising efficacy profile for mental health treatment, coupled with the flexibility and adaptability of the treatment programs themselves, ketamine therapy can be a life-changing experience that doesn’t require you changing your life for it. It meets you where you’re at.

Alongside its dissociative properties, at certain doses ketamine can also induce novel subjective experiences or classic psychedelic phenomenology. This sense of experience or journey can provide important insights and felt experiences that can help us manage depression in the short and long-term.

“A ketamine psychedelic experience tends to offer up the possibility for transformation of the self by isolating the mind to some extent from external sensations, altering body consciousness toward an experience of being energy without form, and by amplifying and scrambling the contents of mind in unpredictable ways—all of this generating the potentiality for changes in consciousness that may be beneficial and persistent. Coming back from a ketamine journey as a somewhat different being is quite predictable.”
- Wolfson M.D., Phil. The Ketamine Papers: Science, Therapy, and Transformation (p. 646). Multidisciplinary Association for Psychedelic Studies. Kindle Edition.

Here are some of the positive phenomenological healing effects that can come through ketamine therapy:

• Emotional Regulation: An increased ability to understand and interact with emotions.
• Cognitive Distance: Feeling more ‘space’ or ‘distance’ between external events and an individual's reaction to them. This allows for more intentional behavioral responses, the rewriting of automatic triggers, and deeper introspection.
• Embodied Feelings: Visceral emotions and feelings returning to the body, potentially some that may have been discarded or forgotten (joy in a depressed person, for example).
• Novel Insights: Ketamine can facilitate crucial insights that when integrated, can provide powerful and significant changes to how the individual views themselves and the world around them.
• New Experiences: New experiences or states of consciousness can provide motivation, inspiration, or understanding of the next steps. This helps to clarify meaning and purpose and catalyze improvements to mood, emotions, and physical experience.

Effects of Ketamine

It’s important to distinguish the two ways in which ketamine treatments provide therapeutic value, as this will help you make a decision as to which one is right for you, and when.

The Biological Effects of Ketamine

There are the neurobiological effects and benefits when receiving ketamine. Through these effects, we would expect a general improvement in overall mood, an increase in brain-derived neurotrophic factor (BDNF), and bolstering of neurons that have been worn down over time by the body's physiological response to things like anxiety and depression.

The biological effects are dose-dependent, and happen regardless of an individual's subjective experience with the medicine.

Learn more about the neuroscience of ketamine here.

The Subjective Effects of Ketamine

There are also subjective or phenomenological healing effects that ketamine can provide depending on the dose. These effects include novel ways of thinking, disconnection from thoughts or emotions, dilation of time or space, out-of-body experiences, and more. These experiences vary between each individual and each treatment, but can be essential catalysts for deep transformation when treating mental health conditions such as depression or anxiety with ketamine.

The subjective effects have a ‘sweet spot.’ They need a certain dosage to surface, and can be overtaken by the dissociative or sedative effects at higher doses.

This ideal range for the subjective or phenomenological effects of ketamine is an important point to consider when looking at methods of treatment, and the results you want to achieve. An experienced clinician can help you make the right choice in this regard.

A 2019 study on individuals with major depressive disorder demonstrates the potential for longer-term positive effects:

“There was a significant improvement in depression, anxiety, and the severity of illness after 2 weeks and 1 month of the last dose of ketamine. Significant improvement at 1st [hour] of the first dose was seen in depression and anxiety and not for illness severity. There were transient adverse effects observed in some patients which subsided within 1 [hour].”

Where to Find Ketamine Treatment?

Using ketamine as part of your healing process is legal in many states and countries around the world. As it is a scheduled and regulated substance in most countries, you will need to find and work with a licensed clinician or practitioner who is able to prescribe and work with ketamine as part of their practice.

Depending on the method of administration you’d prefer, this will influence available clinics and/or practitioners you have access to. For intravenous (IV) or intramuscular (IM) ketamine application, you will need to find a clinic that has the capacity to work with this. Similarly for intranasal spray, you will need to find a practitioner who works with this method of administration.

If you are in the U.S., you are able to receive clinically prescribed rapid-dissolving oral tablets through Mindbloom's at-home treatment. Mindbloom currently provides virtual care to 75% of the U.S. population.

You can also search through practitioner forums, clinic listings, or take a look on Google to see if there are any practitioners or clinics in your areas.

How to Take Ketamine

While intravenous (IV) or intramuscular (IM) infusions are the most common method of delivery used in ketamine therapy, there are a range of options. Here’s a quick overview of the different methods one can expect when working with ketamine.

Oral Tablets or Troches

Oral tablets or troches (pronounced “tro-keys”) are compounded tablets from a pharmacy that are absorbed into the brain/bloodstream sublingually, or held in the mouth. Dosing can vary from 10-800 milligrams (mg) per tablet on average, depending on the compounding pharmacy and the order from the clinician.

Rapid-dissolving oral tablets are the method utilized by Mindbloom Clinicians, allowing for a greater flexibility in treatment based on the client’s response to the medication. Tablets also provide powerful experiences, but without the risk of infections or introducing harmful agents into the bloodstream — contributing to an increased safety profile.

IV Infusion or IM Injection

Intravenous (IV) infusions or Intramuscular (IM) ketamine injections have similar effects. The difference is that IV is typically infused into a vein with a bag that drips the substance in while IM is injected directly into a muscle in the arm with a needle.

Nasal Spray

Ketamine nasal sprays are a synthesized mist stored in a spray bottle that is applied according to the delivery timeline outlined by the clinician. This is the latest delivery method to gain FDA approval with the introduction of Spravato. Spravato is Esketamine which is the S-form of ketamine. Esketamine is FDA approved for treatment resistant depression through nasal administration, while the use of Ketamine in any form is off-label.

The bioavailability and desired effect (sub dissociative, sub psychedelic, anesthetic) of each delivery method, which is the proportion of the compound that enters the body’s circulation, is what determines the typical dosing ranges.

Eligibility for Ketamine Treatment

Right now, ketamine therapy is the only legal avenue (not including clinical research trials) for someone to receive psychedelic therapy. Common reasons to seek this treatment are to help work through depression and anxiety.

When considering treatment options, whether psychological, or pharmacological, there can be contraindications to consider. Contraindications are specific circumstances that could make someone ineligible to move forward with the treatment.

Ketamine, due to some of its effects both physically and psychologically — has its own set of contraindications. All medical considerations are discussed in your consultation with a licensed clinician.

If you’d like to check your eligibility, you can take our survey here.

The Future of Ketamine Treatment

This is where the current state of ketamine treatments and psychedelic therapy programs are. As this world continues to grow and expand through research and awareness, new avenues may open up. New treatment modalities, such as the recent introduction and legalization of Spravato nasal spray — will increase access and awareness for ketamine treatment, and this page will update to reflect ongoing developments in this world.

If you have any other questions, or would like to know more about the world of ketamine treatments and psychedelic therapy, feel free to explore our additional free resources/information.

If you feel called to work with the medicine and experience it for yourself, feel free to reach out and let our team know.