Ketamine - Clinical Data
Our last post dove into the science behind ketamine's promise.
Now, we step out of the lab and into the messy, beautiful reality of patient care.
Imagine stepping into a raft, preparing to navigate a fast-moving river.
Upstream, researchers have mapped out the course—identifying the rapids and potential hazards.
As you drift downstream, it becomes clear that no amount of theory can prepare you for every twist and turn.
The current is powerful, the risks are real, and your goal is to guide the raft safely to calmer waters.
That seems to be the current landscape behind ketamine therapy.
Animal research showed us hope, but real-life treatment is a different beast.
It's a dynamic dance between hope and pragmatism, between pushing boundaries and ensuring safety.
Let’s get in the raft with those clinicians, ditching the hypotheticals and drafting through the concrete data.
We'll examine the clinical trials, analyze the statistics, and track patient outcomes.
Numbers alone may tell us the story of transformation and lives reclaimed.
Early Clinical Trials of Ketamine for Depression (2000–2010)
The first step in this adventure took place in 2000, with a groundbreaking study by Berman et al.
Seven patients, each battling major depressive disorder (MDD), sat down to receive an IV infusion of ketamine.
Within 72 hours, all experienced significant reductions in depressive symptoms, captured by the Hamilton Depression Rating Scale (HAM-D).
This trial shattered long-standing beliefs that antidepressants need weeks to work.
The idea of rapid relief became reality, and it happened in a matter of hours.
Fast-forward to 2006, and Dr. Carlos Zarate and his research team built on this momentum with 18 TRD patients.
Almost 70% of patients experienced a noticeable improvement in their symptoms within 110 minutes.
It was a long-awaited breakthrough for those who had endured years of searching.
The effects lasted up to a week for some.
Many relapsed within two weeks, sparking questions about long-term management.
These early trials were full of hope.
But further direction was needed.
Larger Trials and Replication Studies (2010–2015)
The early 2010s brought larger, more controlled studies to provide the evidence required to solidify ketamine’s place in depression treatment.
One key trial came in 2013, led by Murrough et al., where 72 TRD patients were given either IV ketamine or midazolam (a benzodiazepine used as a placebo).
Midazolam was an interesting choice because it mimicked ketamine’s sedative effects without offering the same antidepressant properties.
64% of the ketamine group experienced a reduction in depressive symptoms within 24 hours as compared to 28% in the midazolam group.
Many believed this study proved ketamine truly works as an antidepressant, not just as a placebo.
Once again, many patients reported feeling genuinely hopeful for the first time in years.
By 2015, a meta-analysis by Newport et al. pulled together data from seven ketamine trials, showing a rapid but transient effect.
The study found that a single-dose ketamine significantly boosted the chances of rapid recovery.
Compared to the control group, people given ketamine were nearly ten times more likely to experience a major improvement in their depression within 24 hours (odds ratio of 9.87).
Additionally, they were almost fifteen times more likely to achieve remission of depressive symptoms in the same timeframe (odds ratio of 14.47).
By 2016, Kishimoto et al. synthesized data from 14 randomized controlled trials (RCTs) to evaluate the efficacy of single-dose ketamine in treating unipolar and bipolar depression.
The analysis showed that ketamine’s antidepressant effects were fast-acting.
Benefits were observable within 40 minutes and peaking on day 1.
However, these effects diminished over the following days, with significant benefits lasting up to 7 days.
Previous studies had already hinted at this problem.
And these new findings really drove home the question–
“How do we safely sustain its benefits beyond the first week?”
Esketamine: Large-Scale Trials and FDA Approval (2017–2021)
Enter SPRAVATO® (esketamine), a nasal spray version of ketamine analog designed to offer similar benefits with easier administration.
The TRANSFORM trials were key to determining how effective esketamine could be for patients who hadn’t responded to traditional antidepressants.
TRANSFORM-1 Study (2017)
In 2017, the TRANSFORM-1 study enrolled 346 patients with treatment-resistant depression (TRD).
These patients were randomly divided into three groups—
56 mg of esketamine + new oral antidepressant
84 mg of esketamine + new oral antidepressant
or
A placebo + new oral antidepressant
The main goal was to see if their depression symptoms improved over 28 days, measured by the Montgomery-Asberg Depression Rating Scale (MADRS).
The results?
Patients in the 56 mg group saw significant improvements, with a nominal p-value of 0.027.*
* A p-value tells you if your results are reliable.
Lower p-values mean you can be more confident in your findings.
Usually, researchers want a p-value below 0.05 to trust their results.
However, the 84 mg group didn’t show enough improvement to reach statistical significance (p-value of 0.088).
The 56 mg dose couldn’t be officially tested as part of the trial's predefined rules, which required the 84 mg dose to show significant results first.
The 56 mg dose still gave patients meaningful improvement (“clinical significance”), offering hope for those struggling with TRD.
TRANSFORM-2 Study (2018)
In the TRANSFORM-2 trial, 227 patients with treatment-resistant depression (TRD) took part.
These patients were randomly split into two groups–
Esketamine (starting at 56 mg, with some titrated to 84 mg) + New Oral Antidepressant
or
Placebo + New Oral Antidepressant
The results?
After 4 weeks, the Esketamine group showed significantly better improvement in depression symptoms compared to the placebo group (p=0.020).
Esketamine worked faster, especially in areas like feeling sad or emotionally numb.
In fact, some patients felt relief as quickly as 24 hours, which is much faster than typical antidepressants.
These improvements were backed up by better scores on another depression scale, the Patient Health Questionnaire-9 (PHQ-9), confirming esketamine's rapid and powerful effect.
TRANSFORM-3: Esketamine for Older Adults
The TRANSFORM-3 trial focused on a unique group—patients 65 years and older with treatment-resistant depression (TRD).
These patients often have more severe symptoms and respond poorly to traditional treatments.
This study enrolled 138 elderly patients who were split into two groups–
Esketamine (dosed between 28 mg and 84 mg) + New Oral Antidepressant
or
Placebo + New Oral Antidepressant
The main goal was to track improvements in depression symptoms after 28 days using MADRS.
The outcome?
While some improvements were seen, the results didn’t reach statistical significance.
The p-value hovered at 0.059—just shy of the 0.05 cutoff.
Still, it wasn’t all bad news.
Despite the mixed results, the trial confirmed that esketamine was generally well-tolerated in elderly patients, with side effects similar to those seen in younger groups.
This provided reassurance that esketamine could be a safe option for older patients.
REMS - Managing Safety Concerns
As promising as esketamine was, it wasn’t without its downsides.
Across the trials, common side effects included dizziness, dissociation, and increased blood pressure (We'll go over these side effects later).
These side effects, although worrisome, were handled with great care.
After each treatment, patients were closely monitored in a clinical setting for at least 2 hours to ensure their safety.
This built-in safety protocol may have been one of the reasons behind Esketamine (SPRAVATO®)’s approval despite its smaller phase 3 trial size with weak outcome.
ASPIRE-I Study (2020)
The ASPIRE-I trial, conducted between 2017 and 2018, focused on patients with major depressive disorder who had active suicidal ideation with intent (MDSI).
This study enrolled 226 patients who were randomly divided into two groups–
Esketamine 84 mg
or
A Placebo nasal spray
Both groups also received standard care, including hospitalization and a newly initiated or optimized oral antidepressant.
After just 24 hours, patients receiving esketamine showed a significantly greater reduction in depression symptoms compared to the placebo group, as measured by the MADRS (p=0.006).
However, there was no significant difference between the two groups in reducing the severity of suicidality.
Esketamine was generally well-tolerated, with common side effects including dizziness, dissociation, and nausea.
Overall, the study demonstrated esketamine’s potential for rapid reduction of depressive symptoms in patients facing an urgent crisis.
ASPIRE-II Study (2020)
The ASPIRE-II trial, like its counterpart ASPIRE-I, focused on patients with major depressive disorder who had active suicidal ideation with intent (MDSI).
The goal was to see if esketamine nasal spray could quickly reduce depression symptoms in this critical group.
The study included 230 patients, who were randomly split into two groups–
Esketamine 84 mg
or
A Placebo nasal spray
SImilar to the ASPIRE-I study, both groups received standard care (hospitalization and oral antidepressants initiation/adjustment).
The results were very similar to ASPIRE-I.
After just 24 hours, patients in the esketamine group showed significantly more improvement in their depression symptoms than those in the placebo group (p=0.006).
Again, there was no significant difference between the two groups in reducing the severity of suicidality.
Interestingly, despite the ASPIRE trials not showing a statistically significant reduction in suicidal severity, esketamine still received additional FDA approval for Major Depressive Disorder with Suicidal Ideation (MDSI).
This approval came with the condition that it doesn’t replace the need for hospitalization.
FDA’s decision was mainly due to its rapid relief from depressive symptoms which can be beneficial in suicidal crisis.
SUSTAIN Trials - How Long and How Safe?
Similar to ketamine, esketamine was proven to be both effective and relatively safe.
But the big question remained—
Would these effects last?
SUSTAIN-1 Study (2019)
The SUSTAIN-1 study focused on the long-term effects of esketamine for TRD.
Unlike earlier studies, this one looked at whether esketamine could help prevent relapse in patients who had already responded to the treatment.
The trial enrolled 297 patients who had achieved either stable remission or stable response after 16 weeks of esketamine treatment from TRANSFORM trials.
These patients were randomly divided into two groups–
Continue receiving esketamine alongside their oral antidepressant
Or
Switch to a placebo while still taking the oral antidepressant
The results?
Patients who stayed on esketamine had a much lower chance of relapsing compared to those on the placebo.
Specifically, relapse rates were 26.7% in the esketamine group versus 45.3% in the placebo group for those in stable remission (p = 0.003).
For those with stable response but not full remission, the relapse rate was 25.8% in the esketamine group versus 57.6% in the placebo group (p < 0.001).
Overall, esketamine reduced the risk of relapse by 51% to 70%.
The study confirmed that continued treatment with esketamine, in combination with an oral antidepressant, can help patients maintain their progress and prevent relapse.
As for side effects?
Nothing new.
They were consistent with what had been seen before (i.e. Dizziness and dissociation).
SUSTAIN-2 Study (2020) - Is It Safe?
SUSTAIN-2 Study followed patients over a full year to assess whether esketamine remained safe and tolerable over the long term.
The trial enrolled 802 patients including two groups–
New Esketamine + New Oral Antidepressant
or
Continuation from TRANSFORM-3 study (>65 years old)
During the 48-week maintenance phase, patients received esketamine at doses ranging from 28 mg to 84 mg.
Doses were adjusted based on individual response and tolerability.
The results?
Dizziness, dissociation, nausea, and headache were among the most common side effects.
Most were mild and resolved the same day.
Only a small number of patients (9.5%) discontinued due to adverse effects (like anxiety and dizziness), and the treatment was generally well-tolerated over the long term.
In terms of effectiveness, patients saw sustained improvements in depression symptoms throughout the study.
Importantly, most patients continued to benefit from reduced dosing frequency, requiring esketamine only once weekly or every other week.
SUSTAIN-3 Study - Safety + Efficacy
The SUSTAIN-3 study focused on the long-term safety and effectiveness of esketamine for patients with TRD.
This study followed patients who had previously participated in earlier esketamine trials and provided an in-depth look at the impact of long-term treatment.
The study enrolled 1,148 patients, with participants receiving esketamine nasal spray at doses ranging from 28 mg to 84 mg.
Patients could be treated for up to 4.5 years, with dosing tailored to individual needs—typically weekly or every other week.
The results?*
*This is an interim result. The final outcomes of the study have not been published as of October 2024.
Esketamine continued to show sustained effectiveness, with 46.1% of patients achieving remission (MADRS total score ≤12) by the end of the maintenance phase.
Additionally, most patients were able to maintain their progress with weekly or biweekly dosing.
Common side effects included dissociation, dizziness, nausea, and headache, most of which were mild or moderate and resolved the same day.
Importantly, no new safety concerns were identified, and cognitive function remained stable throughout the long-term treatment.
Additional Evidence
In 2021, a systematic review by Wajs et al. analyzed data from five clinical trials with a total of 705 subjects.
Esketamine with an oral antidepressant, reduced the risk of relapse by 51% in patients who had achieved remission (compared to those receiving a placebo + antidepressant).
This review highlighted esketamine’s unique value in offering long-term remission, especially when paired with traditional antidepressants.
You'd think after all these data and years of FDA approval, esketamine would be readily available, right?
Sadly, that's not the case.
The practical barriers to access remain perplexing, bordering on the absurd.
We'll talk more about this frustrating reality and future directions in our next posts.
Ketamine vs. Esketamine
So we know both ketamine and esketamine work well in depression.
But which one is better?
A 2020 meta-analysis, compared 24 clinical trials of IV ketamine and intranasal esketamine.
IV ketamine had a higher response rate (RR = 3.01) than esketamine (RR = 1.38), suggesting that IV ketamine produces stronger immediate effects.**
** From a pharmacist’s perspective, two factors may explain why esketamine can be less effective—
Metabolism Difference
Esketamine doesn’t convert well into 2R,6R-HNK, a metabolite that MAY lead to longer-lasting antidepressant effects.
Dosing Issues
Esketamine has a fixed dose, while IV ketamine is adjusted based on body weight, allowing for more precise dosing with IV ketamine.
This makes dosing with IV ketamine more accurate, whereas esketamine might result in under- or over-dosing.
For example, an 84 mg dose of esketamine equals the typical IV ketamine dose (0.5 mg/kg) for a 177 lb person, accounting for esketamine’s lower bioavailability (48%).
Since the average U.S. male weighs 199 lbs and the average female weighs 170 lbs, esketamine's fixed dosing might not be ideal for all patients.
From a practical standpoint, esketamine is easier to give, less likely to cause dissociation, and it's FDA approved for mental health conditions.
It’s a more legally sound choice for regular use in smaller clinics (i.e. primary care) and patients with insurance.
Patient Outcomes and Real-World Applications
In the real world, not every patient responds equally to ketamine or esketamine.
Some see immediate, profound relief, while others need multiple doses before improvements appear.
Some do not experience relief at all.
These nuances highlight the importance of personalized treatment, where clinicians carefully tailor protocols to each individual’s needs.
As we step further into this fast-moving river, one thing is clear–
Ketamine and esketamine are saving and transforming many lives.
But the journey requires careful navigation, ongoing maintenance, and a commitment to understanding the unique needs of every patient.
Efficacy of Ketamine vs. ECT: A Historical Perspective
For decades, electroconvulsive therapy (ECT) has been one of the most reliable tools when all other treatments fail.
But as we know, a new path has emerged in recent years—one paved by ketamine, offering a different route with fewer barriers and much faster results.
In this section, we’ll explore the ongoing journey of these two treatments and how they’ve shaped the fight against (TRD).
ECT: The Long-Standing Champion for Treatment-Resistant Depression
ECT has long been the gold standard for TRD, particularly in cases of severe depression or when suicidal ideation is involved.
It works by inducing controlled seizures using electrical stimulation.
This triggers complex changes in the brain's chemistry and function, often leading to noticeable mood improvements within 1 to 2 weeks.
But despite its remarkable efficacy, ECT comes with trade-offs.
Patients undergoing ECT often report discomfort, memory loss, confusion, and cognitive side effects.
These effects can linger long after the therapy has ended.
ECT also requires general anesthesia.
The risks associated with ECT increase for older adults or individuals with pre-existing medical conditions (like glaucoma or cochlear implant).
Comparing the Two: Key Clinical Trials
Both ECT and ketamine have their unique pros and cons when it comes to treating tough depression.
So, which one's the better choice?
Let's break down the key differences and see how they stack up.
Several clinical trials have explored whether ketamine could match or even surpass ECT in treating TRD.
A landmark study published in 2023 (ELEKT-D trial) sent shockwaves through the psychiatric community, providing long-awaited pivotal insights in this critical area.
This large-scale, open-label, non-inferiority trial involving 365 participants found that ketamine was indeed non-inferior to ECT in reducing depressive symptoms.
This means ketamine wasn’t worse than ECT in treating depression (Ketamine actually yielded slightly better results).
However, the trial emphasized ECT’s longer-lasting effects, particularly in patients who had previously failed multiple antidepressant treatments.
On the other hand, ketamine once again demonstrated its faster onset of action.
It may be more valuable in situations where rapid relief is critical, such as during suicidal crises.
Let’s Talk Safety…
Both ketamine and esketamine (Spravato) show promise in rapidly addressing TRD.
But the safety profiles of these drugs are complex and require a comprehensive analysis of both short-term and long-term effects.
This discussion includes analysis of the physical, psychological, and neurological impacts of these drugs.
Short-Term Effects: Cardiovascular and Cognitive Impacts
Cardiovascular Effects
Ketamine has been well-documented to cause temporary increases in blood pressure and heart rate due to its sympathomimetic properties (i.e. norepinephrine release).
About 44% of patients receiving IV Ketamine experience blood pressure spikes, and 12% of those require intervention to lower it (Rodrigues et. al., 2020).
The cardiovascular effects tend to peak within 30 minutes and normalize after 2-4 hours.
Esketamine users experience similar cardiovascular effects but with lower frequency and severity.
Between 8-19% of esketamine users report significant blood pressure elevations, but fewer require medical intervention (SPRAVATO Package Insert, 2023).
How much impact does ketamine have on vitals?
A recent meta-analysis (Vankawala et al., 2021) shows that sub-anesthetic doses of ketamine and esketamine are associated with significant yet modest increases in..
Systolic blood pressure (12.61 mm Hg on average)
Diastolic blood pressure (8.49 mm Hg)
Heart rate (4.09 beats per minute)
In both cases, patients with underlying heart and vascular conditions are at heightened risk and should be closely monitored.
Dissociative and Cognitive Effects
Dissociation is a hallmark side effect of both drugs.
62% of ketamine users and 41 to 48% of esketamine users experience dissociative symptoms (Acevedo-Diaz et. al., 2020) (SPRAVATO Package Insert, 2023).
These symptoms often include a feeling of detachment from reality.
In some cases, this dissociation can trigger or escalate into short-term psychosis-like symptoms, especially in schizophrenic populations (Beck et. al., 2020).
The intensity of dissociation increases with dose.
The duration of dissociative effects varies.
Ketamine-induced dissociation can be more intense and prolonged (especially at higher doses).
Esketamine users generally experience milder dissociative effects that last 1-2 hours.
Short-term cognitive impairments such as memory disturbances and confusion typically resolve within a few hours post-administration (Acevedo-Diaz et al., 2020).
Long-Term Effects: Bladder, Renal, and Cognitive Complications
Bladder and Renal Complications
Ketamine-induced ulcerative cystitis is a concerning long-term complication, particularly in chronic high-dose users.
30-51% of chronic users suffer from urinary symptoms such as dysuria, urgency, and hematuria (Morgan et al., 2012).
The prevalence of these symptoms in clinical use remains unclear.
Most data linking ketamine use to bladder issues came from recreational users, making the issue controversial.
A few studies suggest that this condition can be relieved or mitigated with the cessation of ketamine use (Shahani et al., 2011).
However, for some users, the damage may be irreversible, with permanent bladder wall thickening and decreased bladder capacity.
Kidney swelling (Hydronephrosis) has been observed in 51% of high-dose users with ketamine-induced bladder issues.
Severe cases of hydronephrosis can result in renal failure, particularly in patients with bilateral obstruction of the kidneys (Chu et al., 2011).
Again, most of these findings are tied to non-medical use, and clinical patients receiving controlled, low doses appear to face significantly lower risks (Morgan et al., 2012).
“K-Cramps” and Gastrointestinal Effects
A third of chronic ketamine users report experiencing K-Cramps, intense abdominal pain that is thought to result from prolonged ketamine use (Morgan et al., 2012).
While the etiology is not fully understood, abnormal liver and biliary function has been theorized and observed.
Some users attribute K-cramps to the ingestion of ketamine residue when snorting the drug.
Evidence does not seem to support this hypothesis (Acevedo-Diaz et al., 2020).
Ketamine and Psychosis: Breaking Down the Risks
As ketamine gained its popularity in mental health and recreational space, many raised concerns about its potential connection to psychosis.
But what does the research really tell us?
Studies show that ketamine can cause symptoms that resemble psychosis – things like hallucinations, delusions, and feeling disconnected from reality.
But, the good news is, these effects usually don't last and don't seem to lead to long-term psychosis in most people (Morgan et. al. 2009), (Morgan et. al., 2012).
Existing Mental Health Conditions
The picture changes for those with pre-existing psychiatric conditions.
Studies show that ketamine can trigger or worsen psychotic symptoms in individuals with schizophrenia (Lahti et al., 1995).
Even small doses can lead to psychosis in this patient population.
This highlights that while ketamine may not cause psychosis in healthy people, it can have a serious impact on those already vulnerable.
The Psychological Side of Things
This is a key aspect of Ketamine that's often overlooked.
Ketamine therapies often lead to intense psychological experiences.
Some people report near-death experiences or a complete shattering of their sense of self, sometimes called "ego death".
These experiences, while temporary, can be deeply unsettling and even traumatic.
When your sense of identity dissolves, it can trigger fear, confusion, and panic that might linger long after the drug wears off.
This can leave emotional scars if not dealt with through therapy or other support.
The Bottom Line
Occasional ketamine use may not cause long-term psychosis in healthy people.
However, it's crucial to recognize the lack of long-term safety data and potential psychological impact it can have.
For clinicians, the temporary dissociation and intense experiences some patients face shouldn't be dismissed.
With the right support and guidance, any potential difficulties can be used as a treatment opportunity (i.e. psychotherapy integration).
Cognitive Impairment and Neurological Changes
Frequent ketamine use causes cognitive impairments, particularly in working and episodic memory (Morgan et al., 2012).
A review by Strous et al. (2022) found that chronic ketamine abuse is linked to a reduction in gray matter (processor) and damage to white matter (conductor) in the brain.
While the review provides useful insights, the studies were mostly observational.
It’s hard to prove that ketamine directly causes these brain changes with this data alone.
Plus, the different (and unknown) dosages used and the presence of other drugs make the results harder to interpret and controversial.
Despite these challenges, the evidence suggests that long-term, high-dose ketamine use (and abuse) can harm the brain.
It's important to weigh these risks carefully, especially when considering ketamine for long-term therapeutic use.
These long-term cognitive changes often correlate with the amount and frequency of ketamine use/abuse.
Drug Interactions
Knowing how ketamine reacts with other drugs can make a huge difference in its safety and effectiveness.
How Does Ketamine Get Processed in the Body?
Like most drugs, ketamine needs to be broken down (or "metabolized") so your body can use and dispose of it properly.
This job is handled by special enzymes in your liver called Cytochrome P450 enzymes (often shortened to "CYPs").
Ketamine is mainly processed by CYP2B6, CYP3A4, CYP2C9, and CYP2A6 enzymes.
Here’s where it gets tricky—
Everyone's body works a little differently.
Some people have genetic variations in these enzymes, which means they break down ketamine either too fast or too slow.
If your body is slow at breaking down ketamine, the drug could build up in your system, increasing the risk of side effects.
If your body is fast at breaking down ketamine, the drug may get cleared out before it reaches effective levels in your blood.
Drugs That Slow Down Ketamine Breakdown (Langmia et. al, 2022)
Let’s talk about some common medications that can slow down ketamine’s metabolism.
One big example is ticlopidine, a drug used to prevent strokes.
When people took ticlopidine with ketamine in a study, their bodies had 2.4 times more esketamine in their system than usual.
This can lead to stronger and longer-lasting effects.
Another common interaction happens with clarithromycin, an antibiotic often prescribed for respiratory infections.
Clarithromycin can triple ketamine levels, potentially leading to severe side effects like extreme sedation, hallucinations, or even more severe complications (Langmia et. al, 2022).
Even something as simple as grapefruit juice can be a problem.
Grapefruit juice has a reputation for messing with many medications, and ketamine is no exception.
Drinking grapefruit juice (3 cups) while using ketamine can triple the amount of ketamine in your bloodstream.
So, while it’s healthy for breakfast, it’s not the best choice if you’re undergoing ketamine therapy.
Drugs That Speed Up Ketamine Breakdown (Langmia et. al, 2022)
On the flip side, some medications can speed up how quickly ketamine leaves your system.
This means ketamine might not work as well, and you might need a higher dose to get the same therapeutic effect.
Take rifampicin, for example.
This antibiotic, commonly used to treat tuberculosis, speeds up the breakdown of ketamine so much that it reduces ketamine’s levels by up to 86%.
Similarly, St. John’s Wort, a popular herbal supplement for depression, can cut down esketamine’s concentration by nearly two-thirds.
This means people taking these drugs might feel like their ketamine therapy isn’t working at all.
What Does This Mean for YOU?
If you’re considering or currently undergoing ketamine therapy, it’s crucial to talk with your healthcare provider about all the medications, supplements, and even foods you're consuming.
Even seemingly harmless things like grapefruit juice can make a big difference in how ketamine works in your body.
For healthcare providers, staying aware of these interactions is equally important.
Adjusting the dosage or changing medications can help prevent unwanted side effects and make sure patients are getting the most out of their treatment.
The good news is that with careful monitoring and open communication, these interactions can be easily and safely managed.
Risks of Misuse, Addiction, and Overdose
Ketamine’s medical potential is exciting, but it comes with serious risks.
Let’s break down the key concerns.
1. Ketamine Diversion: A Growing Concern
Ketamine has shifted from its original use in medical and veterinary settings to recreational and unsanctioned uses.
The FDA meeting revealed a 349% increase in illegal ketamine seizures in the U.S. between 2017 and 2022 (Palamar, J. J., 2024).
Many of these busts involved ketamine smuggled from abroad, often of non-pharmaceutical grade laced with contamination (Palamar et al., 2019).
2. Recreational Use: Increasing Ketamine use in the Club Scene
Ketamine’s recreational use in club and party scenes is growing.
The dissociative effects of ketamine are often sought after by users for the so-called “K-hole” experience.
It promises an out-of-body experience, a temporary escape from the mundane.
But the reality?
It's more like a psychedelic rollercoaster with a potentially devastating crash landing.
One minute you're floating in a blissful state of detachment, the next you're slammed with dissociation.
Intense nausea makes you curled up on the dark club bathroom floor, praying for the sweet release of unconsciousness.
19% of users experience harmful or unpleasant effects, with some even ending up in the ER (Palamar et al., 2021).
Picture yourself in a packed club, bass thumping, lights flashing.
And suddenly, you're in a K-hole.
You're disoriented, hallucinating, and vulnerable.
Your judgment is impaired.
What do you do?
Drive home?
Welcome to real-life Mario Cart.
Except the cars are real…
And so are the consequences.
Walk home?
You're a sleepwalker in a waking nightmare, a prime target for anyone with ill intentions.
The threat of assault is real, and the K-hole leaves you defenseless..
Not to mention ketamine from the street is a gamble, not a guarantee.
As mentioned earlier, dealers often mix it with dangerous fillers (even deadly fentanyl) to increase their customer base.
One hit could lead to addiction, overdose, or worse.
Ketamine bought illegally opens a door to a world of danger you might not escape.
Is a temporary high really worth risking your safety and the safety of others?
We can choose to ignore the potential problem.
But we cannot ignore its consequences.
3. Addiction: Escalating Risks
I'd love to believe ketamine is the answer we've all been waiting for.
But I also can't get around the fact that it carries a risk of addiction.
And that's something we need to take very seriously.
Tragic stories, like that of Matthew Perry, serve as a chill reminder of this risk.
Research shows that 60% of frequent ketamine users report compulsive use.
Many of these users felt the need to increase their dosage by a shocking 600% to achieve the same high (Morgan et al., 2012).
Tolerance builds rapidly, leading to a dependency that's hard to break.
Although ketamine and esketamine appear to have a lower risk of addiction under medical supervision, the danger remains.
The temporary enlightenment can blind us to the looming addiction.
It's a trap, even for those who should know better.
From patient to provider, addiction doesn’t discriminate.
The ultimate goal of medicine is to heal, not to create new wounds.
If you're struggling, please remember that there's support available.
You don't have to walk this path alone.
Healing involves confronting the underlying devil, as much as we wish to forget about it with temporary solutions.
4. Overdose - Ketamine and Alcohol
You might've heard ketamine overdoses aren't that dangerous.
Well, they're mostly right.
Compared to those nasty opioids, ketamine is less likely to send you on a one-way trip to the morgue.
The science behind it?
Ketamine weakly binds to mu-opioid receptors—the ones that really screw up your breathing when you take strong opioids.
That's also why it's the go-to drug in ERs and warzones.
When every breath counts, ketamine is often the ideal option.
But hold up, party people.
Just because ketamine's relatively safe in medicine doesn't mean you can go mixing it with whatever's in your cup.
Ketamine used with Alcohol is a whole different beast.
Alcohol alone can mess you up – nausea, liver damage, and passing out are all on the table.
It also dulls your gag reflex and impairs your breathing.
Now, throw ketamine into the mix...
You're already drunk, you take a hit of ketamine, and fall into the “K-hole”.
Suddenly, you're disoriented, nauseous, and struggling to breathe.
Your body's natural defenses are down, and you're unable to move.
Not exactly a party if you ask me.
The FDA reported 41% of ketamine-related poisonings between 2019 and 2023 involved alcohol.
And it's not just a few isolated cases.
Poison control centers have seen ketamine-related poisonings double, with 20% of those being life-threatening.
This stuff isn’t a toy.
Ketamine needs to be treated with respect, in a safe space where someone's got your back if things go south.
Remember, a good time shouldn't come with a side of life support.
5. At-Home Ketamine Therapy: Convenience vs. Safety
Imagine living in a place like Winston, New Mexico.
It’s a small, quiet town.
But "quiet" can quickly become suffocating isolation if you're struggling with treatment-resistant depression (TRD).
The nearest ketamine clinic is in Albuquerque, more than 2.5 hours away.
Now, we learned that ketamine treatments aren't a one-and-done deal.
For TRD, the typical regimen might require trips 2 to 3 times a week during the early stages, and at once a week for maintenance.
So, let's do the math–
Every roundtrip means driving 5 hours just for 1 treatment.
Oh, and since ketamine infusions can leave you too impaired to drive, someone else has to come with you.
That’s 5 hours of someone else’s time too (per 1 treatment).
Between work, finance, family responsibilities, and the sheer emotional toll of TRD, it quickly becomes almost impossible to keep up with this grueling schedule.
Thankfully, the rise of at-home ketamine therapy has been useful for those in remote areas with barriers to access.
The DEA's temporary relaxation of controlled substance laws during COVID allowed many to access this potentially life-saving treatment.
Unfortunately, there's a dark side to this convenience.
Patients are sometimes prescribed massive amounts of ketamine to take on their own, at home, for weeks or even months (Hull et al., 2022).
No doctor visits, no supervision - just a whole lot of trust.
And that trust?
It's been broken.
There have been cases of patients stockpiling ketamine, misusing it, even selling it (Palamar, J. J., 2024).
One doctor was caught prescribing ketamine to over 3,000 patients across 44 states in just three years.
The situation became so concerning that the DEA had to shut down the clinic (Gilbert, 2023).
We're left with some tough questions–
What do we prioritize—easy access or long-term safety?
How do we help those in rural areas without opening the door to even bigger problems?
We need to address these questions before the consequences become too big to ignore.
For those in remote areas like Winston, NM, at-home ketamine therapy can be a lifeline.
In cases like Matthew Perry’s, convenience and accessibility may backfire.
It's clear we need a better system, one that balances access with accountability.
Because while ketamine can be a powerful tool for healing, it demands careful respect and attention from all parties involved.
6. FDA’s Response: Stricter Regulations Needed
With growing concerns and evidence surrounding ketamine misuse, the FDA has finally acknowledged the issue.
But honestly, the FDA’s response so far has been far too passive and weak.
Vague warnings and lousy panel meetings aren’t cutting it for many.
The agency can and should be doing far more.
It’s time for decisive action and guidance, not passive factual statements that we already know.
I’ll dig deeper into the messy reality of ketamine and esketamine therapy, and what needs to change, in my upcoming blog posts.
Conclusion: A Double-Edged Sword
As ketamine continues to expand in medical use, especially with at-home treatments, balancing its benefits with the very real dangers is crucial.
Proper regulation, public education, and strict supervision will be key to ensuring ketamine remains a safe and effective treatment option without exacerbating the risks.
***FYI for Healthcare Providers
Ketamine’s lethal dose (LD50) varies depending on the species, with rodent models showing an oral LD50 of approximately 600 mg/kg (Derelanko & Hollinger, 1995).
For humans, it translates to about 4.2 g for a 70 kg human (10:1 interspecies ratio).
Overdose deaths related to ketamine are usually rare but often associated with illicit or concurrent use of high doses of opioids, which significantly increase the risk of respiratory depression (Jann et al., 2014).
There are no approved antidotes specifically for ketamine overdose.
However, ketamine has been shown to exert weak agonist activity at the mu-opioid receptor.
Theoretically, opioid antagonists like naloxone COULD reverse its action on these receptors, especially when the patient presents with unstable respiration or is concurrently using opioids (Williams et al., 2018).
In reality, respiratory suppression due to ketamine alone is practically non-existent, even at high doses (e.g., 4.5 mg/kg).
Studies have shown that ketamine's primary effects do NOT suppress the central respiratory centers in a way that would lead to life-threatening respiratory depression in most patients (Green et al., 1999).
As mentioned in the previous blog post, naloxone will attenuate the antidepressant effects of ketamine, but not its dissociative symptoms.
Pharmer’s Perspective - Sarah’s Story
We’ve covered a lot of information about the efficacy, safety, and challenges of ketamine therapy in this blog post.
But what does all of this mean in the real world?
Let’s wrap it up with a patient case—Sarah.
Sarah lives in Winston, New Mexico, a small rural town.
For years, she has battled treatment-resistant depression (TRD).
She had tried every available option—antidepressants, electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), and cognitive behavioral therapy (CBT).
Nothing seemed to make a difference.
Life felt like a constant struggle with no end in sight, and hope was fading fast.
Then came the opportunity to try ketamine therapy.
At first, it seemed impossible—how could she access this treatment when the nearest clinic was more than two hours away?
But when her doctor suggested telemedicine and the possibility of at-home ketamine nasal spray, Sarah’s world shifted.
The first time Sarah used ketamine, it was like waking up from a long, bad dream.
Colors seemed brighter, sounds more vivid, and, for the first time in years, she felt at peace.
Sarah could feel joy again, something she had almost forgotten existed.
She laughed more, smiled easier, and found gratitude in the simplest moments.
The darkness that had consumed her for years was finally breaking apart.
For once, Sarah believed that life could be fun again.
But Sarah’s journey wasn’t without its dark moments.
She recently tested positive for COVID-19 and was prescribed Paxlovid.
One morning, she drank a glass of grapefruit juice with her breakfast.
Later that day, feeling worn out, she had a glass of wine to unwind.
It was a typical day.
Nothing out of the ordinary, or she thought.
Then came her regular dose of ketamine nasal spray.
What she didn’t know was that the combination of Paxlovid, grapefruit juice, and alcohol would change everything.
Instead of the gentle relief she expected, Sarah found herself slipping into a place she had never gone before—a K-Hole.
Time warped, reality faded, and she was suddenly floating in a terrifying void and hallucination, disconnected from everything around her.
She felt as though she was teetering on the edge of life and death, experiencing a near-death sensation she wasn’t prepared for.
The sense of helplessness and fear was overwhelming—what had once been her medicine had turned into a nightmare.
That long night left Sarah traumatized, haunted by the fear that she might not return from the depths of that experience.
Yet, even after this nightmare, Sarah didn’t lose faith in the healing potential of ketamine.
The treatment had given her so much—relief, clarity, hope.
It had shown her a version of herself she thought was gone, a version that laughed, loved, and felt alive.
But the experience had also taught her the power of ketamine.
Like any powerful tool, this medicine must be handled with care.
Sarah now approaches her treatment with a deeper understanding of the risks and the importance of knowledge and awareness.
She realizes that while telemedicine made it possible for her to access life-changing therapy from her rural home, it also comes with challenges.
The convenience of at-home treatment had made it easy, but it also meant navigating potential drug interactions, temptations from addiction, and side effects on her own.
Today, Sarah continues her journey with ketamine, now more mindful and respectful of the delicate balance between healing and harm.
What’s Next?
We've seen the science, the numbers, the potential, and the risks.
But how do we translate all this knowledge into safe and effective treatment?
In our next post, we'll explore the clinical guidelines and consensus from different organizations, offering a practical roadmap for ketamine therapy.
Table 1: Medications for Managing Adverse Effects in Ketamine Infusion Therapy for Chronic Pain^
| Medication | Purpose/Effect | Recommendation |
|---|---|---|
| Benzodiazepines (e.g., Midazolam, Diazepam) |
- Attenuates psychomimetic symptoms - Mitigates sympathomimetic symptoms - Reduces nausea |
- Recommended for preemptive use in specific cases, though evidence is limited (Grade C). - Especially useful for anxiety, nausea, and minimizing sympathetic responses. |
| Butyrophenone (Haloperidol) |
- Antiemetic properties - Sedative effects - Reduces psychomimetic symptoms |
- Used to manage psychosis-related side effects and emergence reactions. |
| Clonidine (α2 Agonist) |
- Reduces sympathomimetic effects - Decreases incidence of psychomimetic reactions |
- Preemptive use supported, but with limited evidence (Grade C). - Recommended for mitigating sympathetic system overactivity. |
| Diphenhydramine (Antihistamine) | - Treats dystonia (rare side effect) |
- Recommended only if dystonia occurs. - Dystonia is a rare side effect, but diphenhydramine is indicated in those instances. |
| Benzodiazepines (Seizure Management) | - First-line treatment for seizures |
- Benzodiazepines are recommended as first-line agents in case of seizures during infusion therapy. - Barbiturates or propofol may follow if the seizures are persistent. |
| Barbiturates or Propofol | - Treats persistent seizures | - Used when seizures are resistant to benzodiazepines, though infrequently required. |
| Antidepressants, Antihistamines, Anticholinergics | - Not recommended as premedication for subanesthetic ketamine treatment for chronic pain |
- No evidence supporting preemptive use for chronic pain management. - These medications are not recommended prior to ketamine infusion. |
| Overall Conclusion | - Limited direct evidence for preemptive use of benzodiazepines and α2 agonists | - Grade C recommendation with a low level of certainty for preemptive use of medications prior to ketamine infusions for chronic pain management. |
^ Currently, no definitive guidelines exist for ketamine use in mental health conditions like depression or PTSD.
As a result, the recommendations used here are based on consensus guidelines for ketamine in chronic pain management (Cohen et al., 2018).
While ketamine shows promise in psychiatric care, formal mental health guidelines are still pending.
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