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Annie Lennon
Annie Lennon

How Does Ketamine Work Differently from Other Psychedelics?

And why this differences is important in considering use cases.

Key points

  • Ketamine and psychedelics work in profoundly different ways.
  • Whereas ketamine works by relaxing the brain's inhibitory architecture, psychedelics work by overriding it.
  • Because ketamine and psychedelics have different mechanism of action, they may be better suited for different use cases.
Charles Thonney/ Pixabay
Source: Charles Thonney/ Pixabay

Co-authored by Dr. Jeffrey Becker, MD

Drugs like LSD, psilocybin and DMT are known as ‘psychedelics’ due to the quality of experience they invoke. They are grouped by their similar actions on the body’s serotonin receptors. Ketamine, although considered a psychedelic by some, is profoundly different. And its differences may make it preferable as a treatment for various mental health disorders.

Psychedelics are known to conjure powerful and sometimes challenging experiences. Depending on the person’s pre-existing mental state, intention and the environment in which they take the drugs—together known as set and setting—they can evoke deeply moving encounters that can be both challenging and illuminating.

This is one of the reasons why treatment protocols call for at least one therapist to be present at all times during treatment, so they may ensure these powerful experiences are more constructive than destructive.

Subjective experiences of ketamine, however, are often quite different. While treatment protocols also involve at least one therapist to be present throughout, people using ketamine for therapeutic purposes report it to be substantially gentler than psychedelics.

Whereas psychedelics can evoke challenging states of mind and thoughts early on, ketamine more consistently evokes a gentle ‘lifting’ of existential burden. This is often referred to as a ‘dissociative’ effect and seems to somewhat free people from their anchors to physical reality.

While the space they enter is often said to be strange, they often report a sense of dream-like familiarity, something that is less common with psychedelics.

What causes the differences between ketamine and psychedelics?

Ketamine and psychedelics work in profoundly different ways. Ketamine primarily works by relaxing chandelier cells in the brain, which have powerful control over when pyramidal cells (neurons that do the lion’s share of ‘thinking’) fire and pass their messages on to other neurons. They do this by literally wrapping around pyramidal cells’ axons (tail-like structures that send information from one neuron to another) with a ‘stranglehold’ grip.

In relaxing this grip, ketamine allows the brain’s pyramidal cells to become more active and more interactive. This then produces an expanded state of awareness of a more whole self.

Psychedelics, on the other hand, work differently. They directly stimulate pyramidal cells in a way that overrides the grip of the chandelier cells. Rather than relaxing them, psychedelics work by overwhelming them.

In addition, as psychedelics work on the body’s serotonergic system, they can affect the gut, increasingly known as the ‘body’s second brain.’

Humans have a high density of serotonin receptors in the gastrointestinal tract, and activating these can cause both nausea and vomiting. While there may be therapeutic value in purging during psychedelic sessions, it can be unpleasant.

The jury is out though on whether 'purging' helps or not. Many subjects report feeling that it can be beneficial as it helps unite the body, mind and spirit to clear outdated programming and offload maladaptive beliefs.

Given the fundamental differences between how ketamine and psychedelics work, it is easy to see how psychedelic experiences can be more turbulent than those with ketamine.

Visualizing the difference

To visualize this, think of two means of increasing water flow into a building. Ketamine increases flow by increasing the diameter of the pipes, thus allowing more water to be delivered without substantially increasing pressure. Following the metaphor, psychedelics instead increase water pressure in the same-sized pipes.

With the first mechanism, you would expect the water to flow more smoothly, and gently. With the second, though, you might expect some turbulence and vibration that may become loud and uncomfortable.

Regardless of the method used, water flow increases, or in the case of ketamine and psychedelics, pyramidal cell activity and interaction increases. The key difference between the two methods is how they achieve the outcome, as opposed to the outcome itself.

This in mind, having both mechanisms available is of great value. In this new age of consciousness medicine, it is very helpful to have multiple tools and mechanisms for clinical use. This comes as variations in a patient’s personality, circumstance and health condition can make different methods preferable for different clinical goals.

When is ketamine the better option?

Ketamine’s softer nature may be particularly valuable in treating patients with depression who experience significant levels of anxiety and fear, or have trouble letting go of control. This is because these traits can make entering and accepting altered states of mind hard. Ketamine’s ability to directly relax the defensive neuro-architecture (chandelier cells) can be thus very valuable in clinical care.

Moreover, while a ketamine experience can still be quite powerful, the intensity of the experience is very much determined by the dose and rate of delivery. This gives clinicians a lot of control over the treatment and allows them to tune it according to the patient’s needs and comfort level in real-time.

However, one of the issues raised by clinicians and researchers with ketamine is how long its positive effects remain. Repeated treatments are often necessary, if not the norm.

When are psychedelics the better option?

The effects of psychedelic treatments seem to last longer than those with ketamine. This may be due to their more challenging nature. After all, they force the defensive neuro-architecture to submit and accept a larger conscious state, rather than take a nap as it is happening.

With ketamine, it may be more that “while the cat’s away, the mice will play,” but remember that the cat comes back and doesn’t submit to the newfound will of the mice easily.

As such, psychedelic therapies may be preferable for patients with significant long-term suffering and trauma who have seen the benefits of other treatments fade quickly. It may be that patients’ sense of self in these cases is so constricted that the extra push from psychedelic therapies could be highly beneficial. In this regard, there may be some wisdom in the adage: “No Pain, No Gain.”

In the end, despite contrasting these differing mechanisms it is important to remember that they are clearly complementary and not in opposition. It is wonderful to have a wide range of options for healing and to have different tools for different moments and needs.

The growing field of consciousness medicine may do well to think in modes that are “Both/And” rather than “Either/Or” when assessing the value of the new tools becoming available. This is not to imply that the treatments should be administered simultaneously, but instead that the same patient may find value in each mode at different points in their recovery.

Dr. Jeffrey Becker is a board-certified psychiatrist with an integrative and holistic approach to mental health. He is also the Chief Science Officer of Bexson Biomedical, a startup developing ketamine-based pain relief systems to tackle the opioid crisis.

About the Author
Annie Lennon

Annie Lennon is a science writer.

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