The Psychedelic Red Pill- Introduction, Ketamine’s Mechanisms

If you’ve ever wondered how deeply belief can influence reality, you’re not alone. 

We’ve explored how the placebo effect—a mere belief in healing—can trigger real changes in the body.

But what if there was a "red pill" that could take us even further, expanding the very boundaries of our consciousness?

Welcome to the world of psychedelics. 

The therapeutic potential of psychedelics is mind-blowing for those of us intrigued by the convergence of technology and medicine.

 

Technology's core purpose is to make things better, faster, easier.

Just as AI is revolutionizing how we work, 

Psychedelics could revolutionize how we heal. 

Psychedelics can resolve years of trauma or depression rapidly compared to traditional therapy.

Numerous professionals and patients attest to their potential.

Come with us as we dive into a space where ancient wisdom meets modern science, opening doors to new perception and healing.

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History of psychedelics

The term “Psychedelics” derived from the Greek words psyche (mind) and delos (manifest).  It essentially translates to “mind manifesting”.

These substances are renowned for offering a profound journey into the “unknown”.

They force us to challenge the very boundaries of what we perceive as reality.

For thousands of years, cultures around the world have used psychedelics in sacred ceremonies.

They have been seen as powerful tools for healing and gaining spiritual insight.

Take DMT (Dimethyltryptamine), for example—a powerful psychedelic naturally produced in our brain.

It is believed that DMT surges during life’s most pivotal moments, like birth and death.

In the 1960s, psychedelics became deeply intertwined with the counterculture movement that pushed against traditional values. 

As this cultural shift gained momentum, it likely alarmed those in power, contributing to the launch of the War on Drugs.

This crackdown led to widespread stigma and a decades-long pause in research.

But today, the tides are turning.

And we’re witnessing a psychedelic renaissance.

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Substances like psilocybin, MDMA, and ketamine are once again capturing the attention of scientists, reigniting a wave of exploration into their potential.

Each one offers something unique, with therapeutic possibilities that could change the face of mental health treatment.

It seems modern science is beginning to catch up with what ancient cultures have known for centuries—psychedelics could revolutionize mental health treatment.

They bring new hope for conditions like depression, PTSD, and addiction. 

Their potential goes beyond therapy.

These substances invite us to explore the very fabric of our reality.

Psychedelics often challenge users to question the nature of consciousness and the mysteries of the human mind.

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My “Red Pill” Journey

I’ll admit… Like many, I was skeptical at first. 

The idea of using psychedelics to expand consciousness or heal felt almost too out there to take seriously. 

And let’s be real: The idea of psychedelic therapy can be downright scary.

Their mind-altering effects can be unpredictable and still carry a lot of stigma.

Skepticism, fear, uncertainty—they all held me back. 

But something changed. 

Or maybe it’s better to say, I changed.

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I found myself in the midst of a therapeutic experience that was as terrifying as it was illuminating.

It felt like my identity was falling apart, layer by layer.

I was exposed to face the destructive people-pleasing tendencies and covert narcissistic habits that had quietly controlled my life.

The fear was overwhelming.

There were moments when I truly doubted if I could get through it.

But as I faced these ugly truths about myself with no defense mechanism, something inside me started to shift.

For the first time, I saw a glimpse of what it could be like to live authentically.

The old fears and habits that had held me back faded.

I felt grounded in a love that felt so real, honest, and pure.

Turns out, I’m not alone.

There’s growing evidence and testimonials that these substances could help with some of our toughest mental health challenges—like depression, trauma, and addiction.

In this blog series, we’ll delve into the science, real-world data, medical guidelines, ethical and practical issues, and personal stories surrounding psychedelics. 

Think of it as an invitation to expand our minds and consider the possibilities.

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Disclaimer

But before we go any further, let’s set something straight.

I’m not here to play the role of psychedelic guru.

I'm certainly not suggesting you try a handful of shrooms for fun (if you do, please understand the risks and be careful).

These substances are incredibly powerful and can be very dangerous, especially if they're sourced illegally—you could face serious legal and physical consequences.

Proper settings and medical supervision are absolutely crucial since we still have much to learn about how these medicines affect our bodies.

I chose to write about psychedelics to challenge the old stigma, explore new frontiers, and broaden our understanding of what’s possible.

Are you ready to take the red pill and see just how deep the rabbit hole goes?

The future of mental health, creativity, and spirituality might just be a trip away.

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Ketamine: Breaking Through the Fog

So, let’s start this journey where the rubber meets the road—with ketamine.

If you’ve heard of ketamine, it’s probably been in the context of anesthesia or, more recently, as a party drug with a reputation for inducing dissociation.

But ketamine’s history goes deeper than its modern reputation.

First synthesized in 1962 by Dr. Calvin Stevens at Parke-Davis, ketamine was developed as a safer alternative to phencyclidine (PCP).

PCP is an anesthetic from the 1950s that was effective but had severe side effects like hallucinations and delirium.

Ketamine, with its shorter duration and better safety profile, quickly became the preferred choice for anesthesia.

It was widely utilized in emergencies and on the battlefield.

As time passed, ketamine’s role expanded.

It became known not just as an anesthetic but also for its ability to induce altered states of consciousness, which led to its adoption as a party drug. 

This reputation has often overshadowed its potential as a legitimate therapeutic tool in mental wellness.

Personal Glimpse into Ketamine's Potential

During my clinical rotations at Miami Valley Hospital, two experiences reshaped how I think about ketamine.

The first moment came when one of the medical residents noticed something odd about the patients getting ketamine for pain.

They reported less pain and, notably, were calmer and more composed.

Interestingly, they also didn’t ask for benzodiazepines as often—the usual choice for anxiety with the big risk of dependency, withdrawals, and side effects. 

 

It was as if ketamine was doing more than just easing their physical pain.

What really caught my attention, though, was the change in our “frequent flyers”—patients who often returned due to chronic pain and anxiety.

After receiving ketamine, these patients started coming back less often.. If at all.

The second experience occurred in the ICU, 

Where managing the balance between sedation and agitation is crucial. 

The attending physician, known for his innovative thinking, observed that ketamine had a calming effect on patients who were too agitated for typical sedatives to work. 

He challenged the usual protocols and suggested we utilize ketamine more often in the ICU.

His suggestion forced me to question the boundaries I drew around its capabilities.

These encounters planted a seed of curiosity in me.

If ketamine could calm both body and mind in such high-stress hospital settings, what other benefits might it offer?

It was the beginning of a journey that continues to this day, as we uncover the multifaceted potential of this remarkable drug.

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From Despair to Hope: Ketamine's Rapid and Robust Effects

Imagine sinking in quicksand.

Each struggle pulls you deeper, with no escape in sight.

For those battling treatment-resistant depression (TRD),

that quicksand is their everyday reality.

Traditional antidepressants (like SSRIs) can take weeks, even months, to offer a rope—

if they work at all.

Ketamine acts like a branch that suddenly appears, pulling you to solid ground in a matter of hours.

The effectiveness of ketamine in alleviating severe depression is quite clear. 

What’s more fascinating is the mystery of how it works.

Even after decades of study, scientists are still piecing together the complex puzzle of ketamine’s effects on the brain.

In the following sections, we'll dive deeper into existing proposed mechanisms of Ketamine's effects on the brain.

But before we get too deep into the science, let’s talk about what this looks like in real practice. 

Imagine battling depression that just won't quit.

You've tried everything – therapy, pills, lifestyle changes, brain stimulation…

But nothing works.

You feel exhausted and hopeless.

Then you discover ketamine therapy.

Within hours, your thoughts quiet down, and you can finally take a deep breath.

The world seems less gray, and you find pleasure in the simple things again.

Maybe things can get better after all.

Remarkably, these antidepressant effects can sometimes last for weeks.

It’s not a permanent cure, but for the first time in a long time, patients feel hope.

Today, S-Ketamine (Esketamine) stands alone as the only psychedelic with an FDA approval for clinical use.

It is approved for treatment-resistant depression (TRD) and major depressive disorder with suicidal thoughts or actions (MDSI).

It's a legitimate, legal, research-backed tool that's becoming part of mainstream psychiatric care.

Of course, this doesn’t mean ketamine is without its challenges.

The effects can be profound, but they can also be unsettling or even dangerous if not properly managed.

So, why start with ketamine?

Because it’s paving the way for what’s to come.

It’s a proof of concept that psychedelics can serve as a powerful medicine for some of the most debilitating mental health conditions.

As we continue this journey into the world of psychedelics, keep ketamine in mind. 

It’s our first step into a larger, more complex world where the boundaries between science and spirituality, medicine and mysticism, start to blur. 

If ketamine can break through the fog,

I wonder what other psychedelics can do for mental health..

The Science Behind Ketamine - It’s Not That Simple..

The science behind ketamine can be a bit dense and confusing, and honestly, researchers are still piecing together the full picture.

I see this complexity of ketamine's effects as good news.

It suggests the potential for personalized treatment, as researchers are still uncovering exactly how it works.

Let’s explore some of the leading theories that scientists are piecing together.

Understanding Depression in the Brain

Depression is a complex disorder that profoundly alters brain function.

At its core, depression is associated with disrupted communication between neurons (brain cells), especially in the prefrontal cortex and hippocampus.

These two regions of the brain are known for regulating mood, memory, and decision-making. 

In depression, these areas often show reduced activity and even shrinkage.

It often leads to symptoms like persistent sadness, cognitive difficulties, and emotional numbness.

But what’s happening under the surface?

Let me break down some of the proposed mechanisms that contribute to depression.

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1. Neurotransmitter Imbalance (Monoamine Hypothesis)

Ever heard of the monoamine hypothesis?

 

It's the idea that depression comes down to low levels of brain chemicals like serotonin.

This theory is why we have so many antidepressants targeting these chemicals.

But, even after all these years, scientists are still debating and looking for other explanations.  

Depression is complicated, and there's always more to learn.

2. Neuroplasticity and Synaptic Function

The traditional view of depression, centered on imbalances in brain chemicals, is evolving.

We now understand that depression also impacts the brain's ability to change and adapt, a process called neuroplasticity.

This adaptability is crucial for our mental well-being.

It allows our brains to form new connections and pathways, enabling us to learn, grow, and respond to life's challenges.

Chronic depression can disrupt this process, particularly in the hippocampus.

Hippocampal disruption can lead to fewer new connections and even the weakening of existing ones.

3. The HPA Axis: When Stress Turns Toxic

Remember our blog post about stress?

We talked about cortisol, the hormone our bodies release under pressure.

Think of cortisol like a smoke alarm.

When there's a little smoke, it beeps — warning us about danger.

Cortisol also plays other important roles in maintaining body functions, such as regulating metabolism and immune responses.

But what if that alarm kept going off all the time, even without smoke?

It would be exhausting. That’s what happens with chronic stress.

The brain’s alarm system, called the HPA axis, stays stuck "ON," flooding the body with cortisol.

It starts with the hypothalamus.

When something stressful happens, the hypothalamus releases corticotropin-releasing hormone (CRH).

CRH tells the pituitary gland to release adrenocorticotropic hormone (ACTH), which makes the adrenal glands release cortisol.

Normally, once the stress passes, cortisol levels drop, and the HPA axis calms down.

But with chronic stress, cortisol keeps coming, and the body doesn't get a break.

Chronic exposure to high cortisol has been shown to shrink certain regions of the hippocampus (such as the CA3 region), which is the part of the brain that helps with memory and emotions.

Think of it as a leaky roof slowly rotting the structure of your house.

This also may be the reason why some patients with depression experience memory issues.

4. Brainwave Changes

When scientists measure brain activity using EEG (a test that measures brain activity), they often focus on gamma rhythms—brain waves that oscillate between 32 and 100 Hz. 

Gamma rhythms are essential for tasks such as memory processing, attention, creativity, and emotional regulation.

They serve as the brain's internal communication network, ensuring that different regions of the brain work in harmony.

In people with depression, these gamma waves are often weaker.

If our brain is a skilled chef in a busy kitchen, gamma rhythms are the precise timing needed to prepare a perfect meal.

When the timing is off, dishes burn, ingredients spoil.

The meal and the kitchen becomes a disaster.

Could this be why depression has such a profound impact on both our thoughts and emotions?

Understanding the link between gamma rhythms and depression could lead to new treatments or therapies aimed at restoring these brain waves to healthy levels.

5. The Inflammatory Hypothesis: The Brain's "Immune Response" Gone Wrong

Beyond neurotransmitters and brain circuits, scientists are now exploring the role of inflammation in depression.  

It's like having a construction zone in your brain, where the immune system's repair crew is constantly at work… Even when there's no damage to fix. 

This ongoing activity, with its constant commotion and disruption, can interfere with communication between brain cells and drain your mental energy. 

This persistent internal construction project can contribute to the feelings of mental sluggishness and lack of motivation often experienced in depression.

We'll cover this mechanism in depth later on.

Ketamine’s NMDA Receptor Antagonism and Glutamate Modulation

Now, how does ketamine fit into this complex puzzle called depression?

Ketamine is widely known as an NMDA (N-methyl-D-aspartate) receptor blocker.

These receptors are typically activated by glutamate.

As covered in our previous blog on sleep, glutamate is our brain’s most abundant excitatory neurotransmitter.

Glutamate functions like the fuel that keeps our brain running.

It plays a crucial role in learning, memory, and mood regulation.

In someone with depression, it’s as if the brain’s “traffic” has too many speed bumps.

Neural signals can’t move as freely, leading to sluggishness and an inability to effectively process emotions.

Ketamine steps in by blocking these NMDA receptors, particularly on inhibitory neurons.

Ketamine removes these “speed bumps” and allows neural traffic to flow more freely in areas like the prefrontal cortex.

Ketamine also blocks NMDA receptors in the brain's sensory processing areas.

This mechanism is thought to produce ketamine’s dissociative and analgesic effects.

Interestingly, some scientists and healthcare providers actually believe these dissociative effects might be necessary to unlock ketamine's full potential.

But the jury's still out on that one – we need more research to settle the debate.

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**FYI

Recent animal studies suggest that the antidepressant effects of ketamine might be more closely related to its action on NMDA receptors in the lateral habenula (LHb), rather than the hippocampus, which was previously thought to be the primary site of antidepressant action.

The lateral habenula is a small brain structure involved in processing negative emotions and aversive stimuli.

By blocking NMDA receptors in this region, ketamine may disrupt the abnormal activity associated with depression.

Interestingly, this NMDA receptor antagonism in the LHb has been linked to the subsequent release of serotonin.

While these findings have only been observed in animal models so far, they provide a new direction for understanding how ketamine produces rapid antidepressant effects.

Clearly, more research is needed to fully uncover the mechanisms involved and to determine how these insights could translate to human treatments.

The Role of AMPA Receptors

Ketamine's effects on the brain go beyond simply blocking those "brakes" (NMDA receptors). 

In the hippocampus, ketamine also hits the "gas pedal" by boosting the availability and activity of Calcium-Permeable AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors, or CP-AMPARs.  

It’s a mouthful, but think of these as the brain's fast lanes for signals.

Normally, a protein called calcineurin acts as a speed limit on these fast lanes, keeping things in check.

Ketamine lowers calcineurin's activity, essentially flipping a switch that makes more CP-AMPA receptors available.

This allows signals to zip through more efficiently, leading to a surge in new connections between neurons.

It's like ketamine is helping the brain build new pathways around the roadblocks that depression has set up.

This rapid increase in connectivity is thought to be a key reason why ketamine can bring such quick relief from depression.

However, at higher doses, this delicate balance may shift, especially in people with high estrogen receptors (ERα).

The NMDA blockade becomes more dominant, leading to a general slowdown of the hippocampus. 

In essence, low doses of ketamine act like a fine-tuning mechanism, optimizing the brain's communication networks.

Higher doses essentially dim the lights on the whole operation*.

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*These dose-dependent antidepressant effects are shown to be prominent in female rats only. Meaning high ketamine dose may not work as well in females. 

Proposed mechanism behind this effect may be related to differences in sex hormones and its direct effect on hormonal receptor activation (I.e estrogen receptor alpha).

Neuroplasticity and Synaptogenesis: Fertilizing the Brain

One of the most exciting aspects of ketamine’s action is its potential to promote neuroplasticity, the brain’s ability to adapt and reorganize itself.

Ketamine stimulates the release of brain-derived neurotrophic factor (BDNF) in the inhibitory interneuron of the prefrontal cortex through various proposed mechanisms, including indirect AMPA receptor activation.

BDNF acts like fertilizer for the brain, encouraging the growth of new synapses—connections between neurons—that are essential for healthy brain function (in moderation, of course).

These new connections can help reverse the damage caused by chronic stress and depression, which often leads to a reduction in synaptic density. 

By fostering this regrowth, ketamine might help restore communication pathways in the brain, making it more resilient and better able to manage stress.

*** This BDNF activation seems to only happen in prefrontal cortex regions, not hippocampus.

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The Role of the mTOR Pathway: A Master Switch for Growth

Now we know ketamine blocks those NMDA receptors and boosts AMPA activity to release BDNF, but it doesn't stop there.

It also taps into the genetic signaling pathway called the mTOR (mammalian target of rapamycin) pathway.

Think of the mTOR pathway as the brain's project manager, in charge of monitoring and making sure the brain has all the resources it needs to build and strengthen connections.

Here's how it all ties together—

When ketamine blocks those NMDA receptors, it's like easing up on the brakes in the brain.

This leads to less activity of a protein called calcineurin, which normally keeps those AMPA receptors in check.

With calcineurin out of the way, it's like flips a switch on those AMPA receptors, making them more active.

Now, remember those CP-AMPARs, the 'fast lanes' we talked about?

This increased AMPA activity helps create more of them, letting signals zip around the brain even faster. 

This boost in neural communication triggers the mTOR pathway, our brain's construction crew.

It kicks into high gear, producing the building blocks needed to create and maintain strong connections between neurons.

Simply put, ketamine's action on AMPA receptors triggers a chain reaction that activates the mTOR pathway.

This helps repair and build those crucial neural connections to support the brain's overall ability to bounce back from the wear and tear of chronic stress and depression.

It's like ketamine is giving your brain the tools and resources it needs to rebuild itself, which might explain why it can improve mood and cognitive function so quickly.

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Brain Rewiring 101: How Ketamine Tunes Your Mind's Radio

Imagine your brain as an old radio, stuck on a station that plays the same repetitive tunes.

 These loops are driven by the Default Mode Network (DMN).

In depression, DMN is known to control background thoughts and persistent negative patterns.

Ketamine acts as a reset for this cycle.

Rather than just switching stations, ketamine recalibrates your brain's frequency range. 

As the repetitive tunes fade, your mind begins to explore new, refreshing patterns. 

This shift reflects a fundamental change in how your brain processes information.

It allows us to break the cycle of negative thinking.

In addition, brainwave studies indicate that ketamine enhances gamma waves.

A randomized, double-blind, crossover trial showed that ketamine significantly boosts gamma power (to 30-50 Hz range) immediately and up to two hours post-infusion compared to midazolam, an active benzodiazepine placebo (S de la Salle et al., 2022).

This effect can continue for six to nine hours after infusion (Nugent et al., 2019a; Nugent et al., 2019b), showing a sustained impact on brain activity.

These gamma waves sharpen our thoughts and make details more vivid.

For those with Treatment-Resistant Depression (TRD), this rewiring can be life-changing.

It can open you up to healthier, more flexible ways of thinking.

This might explain why many mental health professionals view ketamine as a potential breakthrough for patients who haven't found success with traditional therapy.

** A study by Nugent et al found ketamine use in healthy individuals can induce depressive symptoms - emphasizing the importance of proper diagnosis and patient selection.

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Ketamine’s Anti-inflammatory Effects

Remember the link between depression and inflammation?

Well, it turns out ketamine might be a powerful weapon against these inflammatory storms.

We’ve already discussed how depression is more than low serotonin levels.

It’s a complex web of brain structure and frequency changes, neuroplasticity issues, and the heavy toll from chronic stress.

Now, here’s another piece to this puzzle: neuroinflammation.

As discussed, chronic stress can act like a persistent irritant, leading to a state of constant inflammation.

Our brain’s thermostat gets stuck on high, creating what we might call a “brain fever.”

This ongoing inflammation disrupts the delicate balance of neurotransmitters, hindering the brain’s ability to adapt and form new connections (neuroplasticity). 

This exacerbates the heartbreaking paradox we discussed: in its attempt to protect itself, our brains end up causing more harm.

Ketamine steps in, not just as a mood booster, but potentially as a powerful anti-inflammatory agent. 

Ketamine has the ability to dial down that inflammatory “fever,” like a skilled technician resetting our brain’s faulty thermostat.

Studies (Chen et al., 2018) have shown that ketamine can reduce levels of key inflammatory markers observed in treatment-resistant depression such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α).

Interestingly, ketamine's anti-inflammatory ability may be context-dependent.

In the absence of such an inflammatory trigger, ketamine doesn't seem to significantly alter the immune system's balance (Loix et al., 2011). 

This suggests that ketamine acts more like an immune system modulator, fine-tuning its response, rather than simply suppressing it across the board. 

This distinction is crucial, especially considering ketamine's frequent use in anesthesia before surgery, where a balanced immune response is vital for recovery.

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Ketamine's anti-inflammatory mechanism

Ketamine’s anti-inflammatory magic likely involves several mechanisms working together.

First, ketamine appears to inhibit the Nuclear Factor Kappa B (NF-κB) pathway, which is a key player in the body’s inflammatory response.

By dampening this pathway, ketamine reduces the production of pro-inflammatory cytokines (i.e. IL-6 and TNF-α).

Ketamine is also thought to influence the kynurenine pathway—a complex chemical factory in your brain where the essential amino acid tryptophan is converted into various products. 

Some of these products, like kynurenic acid (KynA), are neuroprotective and promote brain health. 

Others, like quinolinic acid (QUIN), are neurotoxic at high levels and contribute to inflammation and cell damage.

In depression, more QUIN are produced and less KynA, fueling the flames of inflammation. 

This brings us back to the tragic irony of depression–

Our brain's defense mechanisms worsens the very condition it's trying to fight.

Ketamine steps in as a regulator, helping to rebalance this factory’s one-sided output.

It seems to slow down the “bad” production line by reducing the activity of the enzyme IDO (indoleamine 2,3-dioxygenase) involved in the first step in the kynurenine pathway. 

This slows the production of harmful inflammatory byproducts.

At the same time, ketamine promotes the “good” production line, boosting the activity of enzymes that convert kynurenine into KynA and other neuroprotective metabolites.

It’s like ketamine is optimizing the factory’s workflow, ensuring that it produces the right products in the right amounts to support brain health.

Ketamine's ability to reduce inflammation and potentially enhance neuroplasticity may explain its rapid and powerful antidepressant effects.

This is particularly promising for those who haven't found relief with traditional antidepressants.

* FYI: Studies hint that ketamine's anti-inflammatory action may be particularly helpful for those struggling with both depression and obesity (Freeman et. al., 2020).

Opioid Receptor Involvement: A Complex Relationship

As if that weren't enough, ketamine seems to interact with the opioid system in the brain. 

Now, you might be thinking,

"Opioids? Isn't that the stuff that gets people addicted?".

Well, it's true, but it's also more complicated than that.

A small, controversial study from Stanford revealed that if you block those opioid receptors before giving someone ketamine, it actually dampens the antidepressant effect (Williams et. al., 2018).

So, it seems like those opioid receptors, especially the mu-opioid receptor, might be playing a key role in how ketamine works its magic against depression.**

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** Ketamine’s action on this specific mu-opioid receptor seems to be weak.

This may explain why a large bolus dose can be used safely for analgesia (up to 4.5 mg/kg bolus per package insert) without the respiratory complications commonly present with traditional opioids.

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Interestingly, blocking those opioid receptors didn't stop the dissociative effects of ketamine, the feeling of being disconnected from reality.

This is a big deal because for a long time, we thought ketamine's antidepressant effects were mainly due to blocking NMDA receptors.

But now, it seems like there's this whole other layer involving the opioid system.

This discovery sparked a debate that continues today—

Does ketamine's antidepressant power stem primarily from its subtle effects at low (non-dissociative) doses, high (dissociative) doses, opioid receptor activation, or perhaps a combination of these and other undiscovered mechanisms?

Based on available literature, ketamine's antidepressant action might depend on a delicate balance amongst its effects on the glutamate, inflammatory, and opioid systems.

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Differences in Ketamine Metabolites: A New Perspective

So, we're on the hunt for a better version of ketamine, one that keeps the amazing benefits but ditches the downsides.

Well, it turns out, the solution might be hiding in plain sight.

Recent animal studies suggest that a whole team of ketamine metabolites (byproducts) might be just as crucial for its antidepressant action.

Think of ketamine as the star quarterback, but the team’s success also relies on other players (metabolites) doing their jobs.

One key player on ketamine’s team is a metabolite called (2R,6R)-hydroxynorketamine, or (2R,6R)-HNK for short.

This metabolite has drawn attention because it seems to offer some of ketamine’s antidepressant effects without the dissociative side effects.

It’s like getting all the benefits of a strong cup of coffee without the jitters.

A well-designed research study suggests that (2R,6R)-HNK might be the real MVP when it comes to antidepressant effects.

It appears more effective at lifting mood and promoting positive brain changes than its counterpart, (2S,6S)-HNK.

However, most of this research comes from animal studies, and scientists are still cautious about how these findings translate to humans.

The future goal of ketamine research should be to specifically harness the benefits of (2R,6R)-HNK or other metabolites in humans without the unwanted side effects associated with ketamine itself.  

Though research and development are underway, it might be a few years before a safer alternative to ketamine becomes available. 

As of now, only ketamine and S-ketamine (Esketamine, Spravato®) are on the market.

Ketamine: A Multifaceted Mechanism Beyond the Brain

Ketamine’s influence extends to the cardiovascular system, a crucial area often overlooked in discussions about its therapeutic potential.

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Sympathetic Nervous System and Cardiovascular Response

Ketamine exerts significant effects on the cardiovascular region, primarily by activating the Sympathetic Nervous System.

This activation leads to an increase in norepinephrine levels—a key neurotransmitter involved in the "fight or flight" response.

The rise in norepinephrine causes blood pressure and heart rate to climb, even at subanesthetic doses used in depression treatment.

This response is believed to be a direct consequence of ketamine's inhibition of the norepinephrine transporter (NET), which normally reabsorbs norepinephrine into nerve cells. 

By blocking NET, ketamine leaves more norepinephrine in circulation, thus elevating cardiovascular activity​​.

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Genetic and Gender Influences on Cardiovascular Effects

Interestingly, your genetic makeup can influence how your body responds to ketamine.

For instance, individuals with a specific polymorphism (mutations) in the NET gene (rs28386840) may experience a stronger cardiovascular response, characterized by a more pronounced increase in blood pressure.

Research also suggests that women may be more susceptible to these effects.

Female subjects experienced higher diastolic blood pressure increase than men during ketamine administration.

This underscores the importance of personalized treatment strategies when using ketamine, particularly for individuals with preexisting cardiovascular conditions​.

Risks Associated with Ketaminergic Technology

Ketamine is a double-edged sword.

It offers a powerful weapon against depression, but it also carries the risk of harm, addiction, and overdose if used carelessly.

Its potential for abuse is well-documented, and the fact that it influences similar brain pathways as notoriously addictive substances like opioids raises red flags. 

The recent tragic loss of actor Matthew Perry, linked to ketamine addiction and overdose, serves as a reality check that this medication should not be taken lightly.

By understanding its strengths and limitations, and developing strategies for responsible use, we can maximize its therapeutic potential while minimizing its risks.

Pharmer’s Perspective - We’re still guessing

We've covered a lot of ground on how ketamine might work its magic, and there's still a lot we're figuring out.

We're like a bunch of toddlers with a 10,000-piece puzzle.

We've got enthusiasm, but the final image is still a bit... abstract.

Take those NMDA receptors, for instance.

We know ketamine blocks them, but other drugs do that too (like MK801 or memantine).

 

However, they don't have the same antidepressant punch. 

Clearly, something more is going on that we haven't quite identified yet.

Same with the relationship between ketamine and the opioid system.

As we mentioned earlier, the jury's still out on exactly how ketamine interacts with the opioid system.

There are some promising clues, but also conflicting evidence.

Given the serious risks associated with opioids, we need to tread carefully and keep digging for answers through more research.

 

We've got this amazing cake called ketamine, and we can taste all the different flavors – NMDA & AMPA receptors, mTOR pathway, opioid system, even some anti-inflammatory action.  

Yet, we're still trying to figure out the exact proportions (dose) and the secret techniques (mechanisms) the baker used to make it so darn good.

The goal is to produce more effective, healthier (less side effects) versions of ketamine to target different disease states.

It's also important to re-emphasize that most human studies (though not all) mentioned in this blog post have focused on measuring targeted markers in the blood.

To truly understand how ketamine affects inflammation within the brain itself, we need more studies that look directly at the central nervous system.

Ketamine is rapidly gaining recognition as a transformative tool in mental health. 

With high-profile figures like Elon Musk openly discussing its use, the stigma surrounding this medication seems to be fading. 

Label me “glass-half-full”, but we may be on the cusp of something truly groundbreaking.

What’s Next? From Science to Real-Life Impact

We've explored the science, now let's examine the evidence.

In our next post, we'll look into the clinical trials that have shaped our understanding of ketamine for mental health conditions.

We'll analyze the data, confront the hard numbers, and explore the potential risks.

Informed hope paves the way for a responsible psychedelic renaissance.

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Table 1.  Proposed Mechanisms of Action of Ketamine

Mechanism of Action	Key Findings	Strengths	Comment	Citations
NMDA Receptor Antagonism	Ketamine blocks NMDA receptors, reducing the inhibition of AMPA receptors and leading to increased synaptic plasticity and rapid antidepressant effects.	Demonstrates rapid onset of antidepressant effects, significant for treatment-resistant depression.	NMDA antagonism alone does not fully explain the sustained effects of ketamine, suggesting other mechanisms are also involved. Ketamine’s primary target region for NMDA antagonism may be in the lateral habenula, not the hippocampus.	(Kavalali & Monteggia, 2012) (Moghaddam et al., 1997) (Zanos et al., 2023) (Yang et al., 2024)
AMPA Receptor Activation	Ketamine enhances AMPA receptor activity, which increases synaptic strength and plasticity, contributing to its rapid antidepressant effects.	Supports the rapid and sustained antidepressant effects observed in clinical settings.	AMPA receptor activation alone does not account for all the effects of ketamine, indicating a complex interplay of mechanisms.	(Zaytseva et al., 2020) (Lepack et al., 2016) (Neis et al., 2016) (Cavalleri et al., 2018)
mTOR Pathway Activation	Ketamine activates the mTOR (mammalian target of rapamycin) pathway, which promotes synaptic protein synthesis and neuroplasticity.	Provides a molecular explanation for ketamine's ability to rapidly enhance synaptic plasticity.	The activation of the mTOR pathway is complex and may not fully explain the variability in patient response to ketamine treatment.	(Zhou et al., 2014) (Fukumoto et al., 2018) (Abelaira et al., 2017)
Neuroplasticity and Synaptogenesis	Ketamine induces rapid neuroplasticity and the formation of new synapses, particularly in the prefrontal cortex and hippocampus. This is thought to be mediated through the release of BDNF (brain-derived neurotrophic factor) and the subsequent activation of synaptic plasticity pathways.	Directly addresses the deficits in neuroplasticity seen in depression, offering a robust therapeutic effect.	Limited by the short duration of these effects, which necessitates repeated dosing, potentially increasing the risk of side effects.	(Suzuki et al., 2017) (Pham & Gardier, 2019) (Caffino et al., 2016)
Frequency Changes and Gamma Power	Ketamine significantly increases gamma power (30-50 Hz) in the brain, particularly in individuals with Treatment-Resistant Depression (TRD). This increase is linked to enhanced cognitive functions, creativity, and awareness, and correlates with its rapid antidepressant effects.	Provides a measurable biomarker of ketamine’s effectiveness in real-time, supporting its use in TRD.	Gamma power changes are consistent across multiple studies, but the exact mechanisms remain under investigation, particularly regarding the timing and duration of effects.	(Abdallah et al., 2017) (de la Salle et al., 2022) (Nugent et al., 2019a) (Nugent et al., 2019b)
Opioid Receptor Involvement	Ketamine’s antidepressant effects are partly mediated through the opioid system, particularly the μ-opioid receptors. Blocking these receptors with naltrexone significantly reduces ketamine's antidepressant effects.	Highlights the complexity of ketamine's mechanism of action, providing a new target for antidepressant therapies.	Raises concerns about the potential for abuse and dependency, given the involvement of opioid receptors. This necessitates careful clinical monitoring.	(Williams et al., 2018) (Joseph et al., 2021) (Zhang et al., 2021)
Neuroinflammation and Immune Modulation	Ketamine may reduce neuroinflammation by modulating the immune system, particularly by decreasing pro-inflammatory cytokines like IL-6 and TNF-α.	Offers a new avenue for treating depression, particularly in patients with elevated inflammatory markers.	The exact relationship between neuroinflammation and ketamine’s effects remains underexplored.	(Ogyu et al., 2018) (Kopra et al., 2021) (Lazarevic et al., 2021) (Herzog et al., 2020) (Pham et al., 2020)
HPA Axis and Cortisol Modulation	Ketamine may influence the HPA axis and reduce cortisol levels, which are often elevated in patients with depression.	Provides an explanation for ketamine's effectiveness in stress-related depression.	The impact of ketamine on the HPA axis is not well understood, and the effects may vary significantly among individuals.	(Herzog et al., 2020) (Zanos et al., 2023)
Role of Ketamine Metabolites (e.g., HNK)	Ketamine’s metabolite, (2R,6R)-HNK, is thought to contribute to its antidepressant effects without the dissociative side effects seen with the parent compound. This metabolite may act on different receptors, including opioid receptors, and could be responsible for some of the therapeutic effects observed with ketamine.	Highlights the potential for developing new treatments based on ketamine’s metabolites, which might reduce side effects.	The specific actions of ketamine metabolites like HNK are not fully understood, and their contribution to the overall effects of ketamine requires more research.	(Fukumoto et al., 2018) (Herzog et al., 2020) (Suzuki et al., 2017) (Zanos et al., 2016)
GABAergic Effects	Ketamine potentiates GABAergic inhibitory postsynaptic currents in neurons, particularly at high concentrations. It has been shown to increase GABA levels in the brain. The effects on GABA uptake and GABA receptors, particularly GABA_A, are inconsistent, with conflicting evidence regarding the functional relevance at clinical doses.	Potentiation of GABAergic activity may contribute to its anesthetic and antidepressant effects.	High concentrations needed for effect; clinical relevance is unclear at therapeutic doses.	(Zanos et al., 2018) (Gage & Robertson, 1985) (Lin et al., 1992) (Mantz et al., 1995) (Wood & Hertz, 1980)
Monoaminergic Effects (Dopamine & Serotonin)	Ketamine interacts with dopaminergic and serotonergic systems, showing some evidence of receptor binding and transporter inhibition. However, the functional significance is debated, with some studies suggesting limited direct effects at clinically relevant concentrations.	May contribute to the psychotomimetic and rapid antidepressant effects of ketamine.	Conflicting evidence on the direct impact on dopamine and serotonin receptors; relevance at therapeutic doses is questioned.	(Zanos et. al., 2018) (Aalto et al., 2002) (Breier et al., 1998) (Can et al., 2016) (Kapur & Seeman, 2002)
Heart Rate and Blood Pressure	Increases in both parameters are mediated through sympathomimetic pathways, while also producing vasodilation and decreased peripheral resistance.	Comprehensive analysis of heart rate and blood pressure across different ketamine doses.	The cardiovascular response varies based on dose and patient factors, including NET polymorphism and gender.	(Liebe et al., 2017)

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Table 2. Key pharmacodynamic targets of ketamine and esketamine (Mclntyre et al. 2021)

Parameter	Ketamine (R- and S-enantiomers)	Norketamine (R- and S-enantiomers)	Hydroxynorketamine (HNK)	Dehydronorketamine (DHNK)
Routes of Administration	IV, IM, Oral, Intranasal, Inhaled (Nebulized)	Formed in vivo	Formed in vivo	Formed in vivo
Absorption - Bioavailability	IV: 100%, IM: ~93%, Oral: ~17%, Intranasal: ~39% for esketamine	High, assumed near complete conversion from ketamine	Data limited, likely lower than norketamine	Data limited, likely lower than norketamine
Distribution - Volume of Distribution (Vd)	S: ~190 L/70kg, R: ~180 L/70kg	Higher in R-enantiomer, CNS penetrance	High, significant CNS penetration	High (similar distribution as ketamine)
Distribution - Plasma Protein Binding	~25%	Similar to Ketamine	Similar to Ketamine	Similar to Ketamine
Metabolism - Primary Metabolic Pathways	CYP2B6 (major) and CYP3A4 (partial)	Formed by N-demethylation of Ketamine	Formed from Norketamine via CYP2B6 and CYP2A6	Formed from Norketamine via dehydrogenation (CYP2B6)
Metabolism - Active Metabolites	Norketamine, (2R,6R)-Hydroxynorketamine, Dehydronorketamine (DHNK)	(2R,6R)-Hydroxynorketamine, Dehydronorketamine	Not a precursor; considered an active metabolite	Not a precursor; considered an active metabolite
Excretion - Renal Clearance	Ketamine and metabolites are primarily excreted in urine, but the exact contribution of renal clearance might vary.	Excreted in urine	Excreted in urine	Excreted in urine
Elimination Half-Life	S-ketamine: ~2-3 hours, R-ketamine: ~3-4 hours	Norketamine: S: ~3.9 hours, R: ~6.5 hours	HNK: ~4.3 hours	DHNK: ~2.3 hours
Pharmacokinetic Variability - Influencing Factors	Age (in pediatrics), enantiomer type, body weight, disease state, concomitant medications, route of administration	Enantiomer type, body weight, time-dependent levels, disease state, concomitant medications	Dose-proportional PK, CNS exposure, time-dependent levels	Metabolite type, body weight, time-dependent levels
Special Populations	Variability in children, elderly, hepatic/renal impaired	Similar variability as parent drug, but can accumulate with renal impairment	Similar variability as parent drug, but can accumulate with renal impairment	Similar variability as parent drug, but can accumulate with renal impairment

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Table 3. Pharmacokinetics of Ketamine and Its Metabolites

Parameter	Ketamine (R- and S-enantiomers)	Norketamine (R- and S-enantiomers)	Hydroxynorketamine (HNK)	Dehydronorketamine (DHNK)
Routes of Administration	IV, IM, Oral, Intranasal, Inhaled (Nebulized)	Formed in vivo	Formed in vivo	Formed in vivo
Absorption - Bioavailability	IV: 100%, IM: ~93%, Oral: ~17%, Intranasal: ~39% for esketamine	High, assumed near complete conversion from ketamine	Data limited, likely lower than norketamine	Data limited, likely lower than norketamine
Distribution - Volume of Distribution (Vd)	S: ~190 L/70kg, R: ~180 L/70kg	Higher in R-enantiomer, CNS penetrance	High, significant CNS penetration	High (similar distribution as ketamine)
Distribution - Plasma Protein Binding	~25%	Similar to Ketamine	Similar to Ketamine	Similar to Ketamine
Metabolism - Primary Metabolic Pathways	CYP2B6 (major) and CYP3A4 (partial)	Formed by N-demethylation of Ketamine	Formed from Norketamine via CYP2B6 and CYP2A6	Formed from Norketamine via dehydrogenation (CYP2B6)
Metabolism - Active Metabolites	Norketamine, (2R,6R)-Hydroxynorketamine, Dehydronorketamine (DHNK)	(2R,6R)-Hydroxynorketamine, Dehydronorketamine	Not a precursor; considered an active metabolite	Not a precursor; considered an active metabolite
Excretion - Renal Clearance	Ketamine and metabolites are primarily excreted in urine, but the exact contribution of renal clearance might vary.	Excreted in urine	Excreted in urine	Excreted in urine
Elimination Half-Life	S-ketamine: ~2-3 hours, R-ketamine: ~3-4 hours	Norketamine: S: ~3.9 hours, R: ~6.5 hours	HNK: ~4.3 hours	DHNK: ~2.3 hours
Pharmacokinetic Variability - Influencing Factors	Age (in pediatrics), enantiomer type, body weight, disease state, concomitant medications, route of administration	Enantiomer type, body weight, time-dependent levels, disease state, concomitant medications	Dose-proportional PK, CNS exposure, time-dependent levels	Metabolite type, body weight, time-dependent levels
Special Populations	Variability in children, elderly, hepatic/renal impaired	Similar variability as parent drug, but can accumulate with renal impairment	Similar variability as parent drug, but can accumulate with renal impairment	Similar variability as parent drug, but can accumulate with renal impairment

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