Ketamine Science: Dirty Drugs, Dissociation, & Depression

For the drug nerds out there 🤓 We’re going into the weeds with this one… Take a deep dive with us into the fascinating and perplexing pharmacology of ketamine.

“Dirty drug” is a term used in pharmacology to describe substances that can’t quite decide which receptors to target — and ketamine is perhaps the dirtiest of them all.

Officially, ketamine is classified as a “dissociative anesthetic.” 

“Dissociative” means it has the power to induce a “decoupling” of the physical body from one’s conscious experience.

In high doses, they lose touch with the environment around them and often "forget" who or what they are — at least, until the effects of the drug wear off.

This dissociated state is so strong it can be applied as an anesthetic agent to cut off one's awareness from the body and any pain or emotions it may experience. Doctors can essentially perform surgeries without them noticing.

Most anesthetic agents have negative downstream effects — they alter breathing, cause the heart to slow down to a trickle, or leave nasty side effects lasting hours or days after the session — but not ketamine. This fascinating compound exerts powerful anesthesia — yet has almost no autonomic inhibition. It doesn't stop us from breathing and wears off quickly with almost no lasting side effects — allowing for fast postoperative recovery.

Even more impressive is the recent studies demonstrating ketamine’s rapid antidepressant action. It’s also one of the most promising candidates for new treatments against chronic, treatment-resistant pain conditions like CRPS and migraine headaches.

Ketamine has even been shown to enhance neuroplasticity — speeding recovery from brain injuries potentially lending a hand in learning and memory.

At first glance, ketamine appears to be a miracle drug — the solution for all our problems.

I’ll say right off the bat… it isn’t… and there are certainly drawbacks to ketamine’s promising benefits — but the way ketamine goes about achieving these many feats is fascinating. 

Today we’re going to focus on how ketamine works, and save the darksides of this enigmatic chemical for another day.

Let’s dig into it. Here’s what we know so far about ketamine’s mechanism(s) of action.

Antidepressant Effect

Studies dating back to the early 2000s (and even earlier) have demonstrated impressive antidepressant action from ketamine. Its effects are considered rapid but temporary (lasting up to 2 weeks before fading away).

Researchers are still scrambling to understand the full extent of ketamine’s powerful antidepressant effects and why it works so well for some but not for others — but there are a few good theories for what’s going on.

The main antidepressant mechanism likely comes from ketamine's ability to enhance neuroplasticity. This pathway relies on ketamine's impact on mTOR, AMPA, and possibly the sigma-1 receptors.

Dysfunctions in the mTOR pathway (and other difficulties forming new synaptic connections in the prefrontal cortex and hippocampus) have been found to play a vital role in the development of chronic, treatment-resistant depression. Ketamine’s unique ability to upregulate mTOR activity is a groundbreaking new approach for depression therapy.

The sigma-1 (and possibly sigma-2) receptors are also believed to play a role in ketamine’s antidepressive effects, but researchers are still working to understand this extremely complex system of chaperone proteins and how drugs like ketamine interact with them. Some researchers believe the sigma-1 pathway could become a new class of antidepressants in the future.

Another mechanism is the dissociative state induced by ketamine itself — during which users often experience a state described as “euphoric nothingness.” During this state, the user is aware of themselves but has lost all form of attachment to their identity. While in this headspace, users can take an unbiased look at themselves for who they truly are and identify some of the unconscious influences that have been controlling the way they think and act.

In Jungian psychology, this is called the shadow. 

Removing these unconscious elements that often drive depression and anxiety requires us to identify them first — followed by support from a skilled therapist to integrate these aspects into our conscious mind so they no longer influence us from the sidelines.

Analgesic Effect

Some doctors prescribe ketamine (off-label) for its analgesic effects, but research suggests it isn’t anywhere near as effective as conventional opiate painkillers for most types of pain. 

Ketamine does have opiate-like effects, but this is mild and is not considered one of ketamine’s main mechanisms.

With that said, ketamine can be a powerful painkiller for people with specific types of pain conditions. Most notably, pain caused by the “wind-up phenomenon.” 

The wind-up phenomenon refers to a gradual increase in pain response to stimuli that are normally not painful. It’s believed to be involved with some chronic, often untreatable, pain conditions such as fibromyalgia, migraine headaches, and CRPS (complex regional pain syndrome).

Ketamine's ability to reduce or even prevent wind-up pain conditions from taking hold relies on its effects on the NMDA receptors.

NMDA receptors in the spinal cord play a crucial role in synaptic plasticity and are involved in the amplification of pain signals associated with wind-up phenomenon.

Dissociative Effect

Ketamine’s dissociative effects are primarily caused by its ability to block the NMDA receptors.

Other NMDA inhibitors cause similar effects — even those with nothing else in common with ketamine, such as DXM (dextromethorphan), xenon, and nitrous oxide.

Some theories suggest this disconnection results from interruptions in communication between different regions of the brain — particularly those involved in sensory perception and self-awareness. 

Other mechanisms that play a role in ketamine’s dissociative action are the kappa-opioid receptors, sodium ion channels, and shifts in serotonin and dopamine balance.

Anesthetic Effect

Anesthetics are drugs used to induce a temporary loss of sensation or awareness — typically to prevent pain and facilitate amnesia during medical procedures.

Ketamine is considered a premier anesthetic for 3 major reasons:

1. It’s safe to use — Other anesthetic drugs such as halothane or methoxyflurane are known to damage liver and kidney tissue.

2. It’s extremely reliable —  it consistently induces anesthesia effectively across a wide range of patients with different medical conditions.

3. Postoperative recovery is fast and has few side effects.

Ketamine kicks in quickly when injected and wears off quickly once the surgery is finished.

The powerful dissociative state induced by ketamine means users don’t feel or remember anything that happened during the surgery.

The only catch is that ketamine may not suitable for people with certain heart conditions and is too short-acting for longer surgical procedures. In these cases, drugs like Propofol or certain benzodiazepines like midazolam are used instead.

For shorter surgeries, the poweful dissociative (and prohibitively expensive) xenon gas is preferred.

Ketamine’s anesthetic action is driven by its ability to inhibit NMDA receptors (which are heavily involved in the regulation of consciousness.

Neuroplastic Effect

Neuroplasticity refers to the brain's ability to form and reorganize synaptic connections.

Ketamine has the unique and highly sought-after ability to promote the formation of new connections and repair of damaged connections in the brain.

Several studies have reported an increase in something called “spinogenesis” after exposure to ketamine. Spinogenesis is the process of forming new dendritic spines on neurons. These spines are small, protruding structures that lead to the formation of new connections between nerve cells.

Ketamine-induced spinogenesis is useful for repairing damage following a brain injury, treating dysfunctional neural pathways associated with depression, and possibly aiding in learning and memory.

The mechanisms involved include ketamine’s impact on the AMPA and NMDA, sigma-1 (and possibly sigma-2), mTOR, and adrenergic pathways.

Ketamine Target Receptors

Let’s shift focus a little bit and dig into the specific receptors ketamine targets.

These are just the most prominent receptor targets, simplified to help us gain a better understanding of how this peculiar drug works — but keep in mind, ketamine pharmacology is exceptionally complex. Despite more than 50 years of research, scientists are still striving to understand the complete pharmacological profile of this chemical.

Glutamate Receptors (NMDA & AMPA)

Glutamate is the most prevalent neurotransmitter in the central nervous system. It’s involved with learning, memory formation, and synaptic plasticity.

There are three main glutamate receptors in the brain — the NMDA (N‐methyl‐D‐aspartate), AMPA (alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionic acid), and KA (kainate) receptors. 

Both NMDA and AMPA are heavily involved in neuronal signaling and synaptic transmission, and both are believed to be primary targets of either ketamine or its metabolites norketamine and hydroxynorketamine.

The NMDA (N-methyl-D-aspartate) receptors are considered the primary mechanism for the dissociative, amnesic, psychosensory, and neuroprotective effects of ketamine. 

Ketamine works by preventing glutamate from binding to the NMDA receptors. When this happens, sensory signals traveling to cortical regions of the brain are received but can’t be interpreted. This means the brain receives signals pertaining to sight, touch, sound, and pain, but is unable to interpret or make sense of the data. 

This effect, possibly combined with ketamine's impact on the kappa-opioid receptors, sodium channels, and norepinephrine, is believed to be responsible for the drug's bizarre psychedelic and dissociative qualities.

An important trickle-down effect of NMDA inhibition is the reduction of the wind-up phenomenon — which is characterized by increased pain sensitivity and chronic pain states such as fibromyalgia, migraine headaches, complex regional pain syndrome (CRPS), and more.