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Get High and Kick Depression?

Two birds – one stone, right? If you’re in the practice of using ketamine to get high and kick depression at the same time, you better take a step back.  Let’s talk about it.

The recent Time magazine article that touted ketamine as a hallucinogenic antidepressant highlighted the practice by some physicians of providing ketamine by intramuscular (IM) injection. The author described the “trip” a patient had to subject herself to for ketamine’s antidepressant benefits.

We decided to respond to that article, to show the psychiatrist-supervised perspective.

Ketamine IM Injections

The trouble with IM injections of ketamine is two-fold.

First, the bioavailability is inferior to intravenous infusions.

Second, and maybe more importantly, once the medication is injected into the muscle, any side effects can’t be stopped and treated. There’s nothing to do but wait it out. And patients can have risky, unpleasant experiences.

This just isn’t necessary. When carefully supervised IV infusions are used with precision of state-of-the-art infusion pumps, the treatment experience can be managed safely and efficiently — even pleasantly — for the patient.

Use of Ketamine Must Be Controlled and Precise

Ketamine has been used for 50 years by anesthesiologists under tightly-controlled conditions, with great success.  Does that mean it should be for sale on the drugstore shelf? With maybe a little dosing cup for dosing at the consumer’s discretion…?  Certainly not.

Yes, ketamine is used on the street for its dissociative properties, but at great risk and personal cost to the user. Serious risk, addiction, and terrifying side effects are not only possible but not uncommon in people who use ketamine excessively, and illegally.

For 20 years, psychiatrists have been hearing from patients who used ketamine to get high, at frighteningly high doses — that they thought it helped their depression.

And these doctors cautioned their patients about using any drug without physician supervision. Because of the dangers of overdose, addiction, or side effects that can be dangerous at high doses.

Now we’re all hearing from psychiatrists who warned their patients against using ketamine unsupervised for the “trip.”  Those same doctors are wishing they’d listened more closely, and pursued more study about the reasons their patients described ketamine this way.

And … at the same time, we’re hearing of the consequences street users have suffered from ingesting extremely high amounts of ketamine, and the damage they’ve suffered.

Get High and Kick Depression? Better Rethink That.

Let me tell you about an article I ran across last week. It was published in Vice, September 29, 2017, and entitled, “What It’s Like to Self-Administer Ketamine for Depression.” I can imagine the idea of figuratively watching someone abuse ketamine to self-medicate sounds appealing to some readers.

It actually showcases one user’s (known as “Jack”) experience who buys ketamine on the street, and “self-doses” to treat his depression.

This young man describes his on-again off-again bouts with depression … that turned vicious when he dropped out of graduate school.

He invites a journalist to observe him taking ketamine and his response during and afterward. As you read the article, you’ll see blatant examples of the dangers that go with leaving it to the recipient to determine dosage.

It’s Not the Ketamine That’s Costly – It’s Doing It Right that Costs Money

And you can’t do it right without physician supervision. Certainly not on the street, or with a pile of powder on your coffee table.

The author of the article points out that uncontrolled ketamine purchased on the street is a great deal less expensive than treatment provided by medical doctors. As we’ve talked about before, that’s not surprising, since doctors have to invest in costly equipment and specialized staff to properly monitor each patient and supervise and respond to side effects and reactions appropriately.

I can see how anyone suffering with treatment-resistant depression who doesn’t have the funds for ketamine treatment would seek alternate ways to access much needed help. I get it.  But, the answer is not to risk self-destruction by using it without professional guidance.

This article showed that Jack not only began with a much higher than recommended initial dose, but once the experience subsided, he snorted more and more until all he had was gone.

This is the Best Method documented for achieving addiction status, and is verified by hordes of addicts as the Short Cut to Serious Side Effects. The more you take the more you want. The more you indulge the more damage you suffer. 

Overuse of Controlled Drugs

Have you ever suffered with serious pain?  If you were in the hospital, they might have given you IV morphine. It can really help pain. 

But if you stay in the hospital, and they continue to give you morphine every 2 hours for 3 weeks … you know what will happen, right?

The morphine doesn’t seem as effective as it did at first, and you find you need more of it more often to get the same relief. This is true with a majority of controlled drugs. And this is how addiction begins.

With medical supervision, the hospital may provide a week or so of morphine, then they may change to a different medication to prevent addiction. And a medically supervised dose of ketamine is minuscule in comparison to the amount our friend Jack used.

Self-Prescribing Leads to Over-Indulging

The author of the article made the statement that maintenance doses are needed every 2-4 weeks. This is certainly possible for some individuals, but it’s not the norm. If someone needs a maintenance or booster dose at all, they’re more likely to need it between 2-6 months. But, they may not need it at all.

Over-indulging leads to irreversible damage.

Still, when you consider that the author’s source for this information may have been Jack, you easily guess he’s probably ingesting — or snorting — huge amounts of a controlled substance and way too often.  A substance that can do great harm if use exceeds therapeutic doses.

Like damage to the bladder … that causes excruciating pain, bleeding ulcers on its lining, and fibrosis — or hardening — of the bladder walls. Once that happens, the bladder can’t be repaired. And at your young age you have to wear a diaper the rest of your life, or a catheter. Then, it can lead to kidney failure … and you can’t live very long without your kidneys.

We Can’t Trust Ourselves When We’re Medicated

Back to the drugstore: you don’t find morphine on the drugstore shelf with a syringe included for dosing at home, for the same reason you don’t find ketamine there. Because left to their own devices, many people will follow “what feels good.” And if a little bit does a little bit of good, then it stands to reason that a whole lot will do a whole lot of good.

But as fun as that may sound, when it comes to controlled substances, it’s a dangerous myth. 

Most of us believe we’d use a medication like this only according to instructions. And some would. But, what we’d never do with a clear mind, we just might do when we’re not ourselves. When we’re under the effects of a dissociative drug.

You can see why the government must control medications like this. Because a clear-headed doctor must decide the dosage and delivery for a drug that can be harmful if misused. A drug like ketamine can impair a patient’s reasoning power, and he or she will easily use too much. 

Sometimes going the cheapest route may seem like a solution when you’re in pain. I really get that.  But taking that direction can cost you your life.

Use Medications WITH MEDICAL SUPERVISION…  Or Else.

Our friend Jack has an uncertain future. His heavy and frequent use of ketamine in massive doses to treat his depression is giving him periods of relief from the suffering of depression, but it’s slowly eroding his life at the same time. He doesn’t know at what point this self-treatment will backfire. But once it does, he won’t escape the consequences.

Don’t blame the messenger.

With all this said, the problem isn’t with ketamine. Ketamine is a powerful drug that’s restoring lives every day in psychiatry. When lay people take ketamine into their own hands and and use it casually at home, tragedies happen.

Medical doctors educate and train in the intricacies of the human body – its reactions, responses, toxicities. Scientists create a powerful medication like ketamine to be offered by these professionals to relieve suffering in their patients.

Ketamine Can Work Miracles When Used Properly

In my practice, we take every precaution and precisely dose each patient to achieve the best possible response, without any of these risks. At Innovative Psychiatry, we continue to document a strong positive response in 80% of our patients with treatment-resistant depression. And because of the precision and safety measures we use, we don’t see the serious side effects ketamine addicts see every day.

Ketamine treatment is the most extraordinary medication for treating severe depression and suicidal thoughts available today. If you’ve suffered long, and have tried other antidepressants without real improvement, call us. We’re leading a paradigm shift in psychiatric treatment.

While ketamine isn’t for everyone, with an 80% success rate, it may be just what you need to feel yourself again. To have the freedom to live again, enjoy relationships, and restore what’s most important to you.

Call us, and schedule an appointment. Let’s work together to get your life back on track. Safely.

To the restoration of your very best self,

Lori Calabrese, M.D.

Nobody likes a copycat.

They’re boring. Tired from the get-go. Out to ride on somebody else’s coat tails. They want to steal some of the glory.

Is esketamine just a ketamine wannabe copycat drug?

You may have heard some things about it.  Like it’s a nasal spray. Esketamine intranasal. It’s supposed to be an easier form of ketamine … a spray instead of an IV infusion. Small enough to slip into your pocket … dangerous enough to share or slip into somebody’s drink.

Maybe you’ve wondered how to find it. Or if it works like ketamine…? …or if it’s better? Drugs like esketamine are ketamine copycats …. wannabe’s ….. that are similar to ketamine but different, too.  They’re in the works, up and coming and eagerly awaited — and you should know how they operate and their relationship to ketamine for depression.

So let’s get it out on the table about esketamine, and it’s counterpart arketamine, and answer some of those questions.

As you may already know, IV ketamine treatment for depression and other psychiatric mood disorders has been enjoying a groundswell of recognition and application across the US and around the world. More and more physicians are reading the literature, the clinical studies, talking to other physicians, and referring patients for this treatment — people who haven’t benefitted from traditional SRIs and SNRIs (serotonin and serotonin-norepinephrine reuptake inhibitor) antidepressants, and many of the other antidepressants and mood stabilizers on the market.

Skeptics Wait for the Copycats

Those who are reluctant to offer ketamine, or are skeptical about its safety in psychiatry, prefer to wait for newer medications to receive FDA approval.

So … ketamine was FDA-approved for use as in anesthesia for adults, adolescents, and children more than 50 years ago. And no pharmaceutical company will pay for the studies required to get this medication for anesthesia to be FDA-approved for a new indication — treatment of depression — because it can’t be patented again.   

Typically, it’s the big drug companies that fund all those whoppin’ huge human trials needed for FDA approval of a new drug for a specific indication. They hope that if their drug is patented and then approved for a specific indication, the profits would not only reimburse the costs of trials, but rake in billions more.

They’re not interested in ketamine because the patent expired. 

They’ll never spend the millions it takes to get it approved for depression or other psychiatric disorders because it went generic.

What big drug companies can do, and are doing, is making a very small change in the structure of generic ketamine that they can patent. And by patenting it, they can own it for years, fund studies, push for FDA approval for different indications or conditions … like depression … or suicidal thinking … and enjoy the profits that pour in. 

It’s business. Drug companies aren’t Mother Teresa. Let’s just be honest.

So … how are the drugs they’re patenting and seeking FDA approval for related to ketamine, which is already available? How do they compare?

Esketamine Wants to be Better than Ketamine

Sometimes drug companies develop a “new” drug similar to an established drug by splitting it in half. 

They can do this easily with ketamine because it’s racemic. That means it’s made of 2 mirror image molecules attached to each other.  Sort of like Siamese twins.

If you were to split ketamine right down the middle, you’d have two “new” molecules that are mirror images. 

The one that’s facing left is the S molecule of the original one, S-ketamine or esketamine, and the one facing right is R-ketamine or arketamine.

(OK … scientists aren’t creatives. Phonetic spelling is just fine.)

Interestingly enough, these two molecules behave differently from each other. What’s more, they both behave differently from original racemic ketamine compound.

This is pretty surprising because most people figure that mirror image molecules are identical in what they are and do …  just maybe half as strong as the compound they come from.

Well, when joined together, esketamine and arketamine bring the balance to ketamine that makes it work so remarkably well. But unlike Siamese twins, when ketamine is separated in half, there are different sets of characteristics in each half.

And here’s where it gets interesting.

Mirror Image Twins – Completely Different  Characteristics

Now, we know that ketamine is described as possessing rapid, robust antidepressant effects consistently in 75-80% of cases with treatment-resistant depression. Suicidal thoughts can evaporate. PTSD symptoms, anxiety, OCD, and even phobias relent.    

When you slice the ketamine molecule in half, because it’s racemic, you get two molecules that are mirror images of each other.  So how do they behave in comparison to ketamine?

• Arketamine is the phonetic name of “R” ketamine – the half (called the “enantiomer”)  of the original racemic ketamine molecule that faces Right. Standing alone it is its own molecule, and presents its own strengths and weaknesses.

Arketamine is far less potent as an NMDA receptor antagonist than either ketamine. It possesses 4-5 times less affinity for the NMDA receptor — that means its binding or sticking power to the NMDA receptor is 4-5 times weaker. But this is surprising: its binding there is even 4-5 times weaker than its sister, esketamine. So, arketamine is very weak compared to esketamine as an anesthetic, analgesic, or sedative hypnotic drug. 

But arketamine appears to be FAR more potent than esketamine as a rapid acting antidepressant.

Why?

It could be because it’s an AMPA receptor agonist. That means it’s an initiator or activator of the AMPA receptor. It’s less potent as a NMDA receptor antagonist, but shows stronger and longer-lasting rapid antidepressant actions than esketamine, so seems like more of an obvious choice for treating depression if a drug company wanted to develop and patent a ketamine mirror image molecule for depression. (We wonder why nobody is doing this.)

But again, ketamine has already mastered that job.

Arketamine is also considered more relaxing for the patient, less dissociative, and probably less likely to encourage abuse.

• Esketamine, on the other hand, is the phonetic name of “S” ketamine and is the half of  the racemic ketamine compound that faces Left. Now, esketamine is a true-blue NMDA blocker. And … it’s 8 times more powerful as a dopamine reuptake inhibitor than its sister, arketamine.

Esketamine is far more potent as a NMDA receptor antagonist, and as such provides more benefit for pain relief, reward sensations … and a higher likelihood for abuse, but less benefit as an antidepressant.

Wait.  How could that be?

FDA Approval Doesn’t Mean It’s the BEST

When a study was conducted to explore this, it turned out that ketamine’s antidepressant power isn’t caused just by its inhibiting of the NMDA receptor — or even mostly by inhibiting it — but it acts in a number of ways including a super-important very cool way — by activating and sustaining a different glutamate receptor, the AMPA receptor, through a metabolite called hydroxynorketamine.

This was a laboratory study, and although more studies are needed to verify this finding in humans, this is huge.

Really huge.

Because it seems like when you read about ketamine, and esketamine, you just hear about the NMDA receptor all the time.  (Sometimes it’s called NMDAR so they don’t have to write out “receptor.”)  As though it’s the new key to treating depression.  The one new hot receptor that holds the key to the treatment of depression.

It’s so much more complicated than that.

Compared to ketamine, every other NMDA receptor antagonist drug that has been tested so far to treat depression and suicidal ideation has produced only modest results. They’ve kind of failed. They don’t work.

But researchers and the company making esketamine are betting that this one does.

Although esketamine is the weaker mirror image molecule for treating depression, it showed a 67% response rate when it was first studied as an IV infusion. It showed promise in FDA Phase II trials, and it’s the one now in FDA Phase III trials. It does other things, too, besides antagonizing the NMDA receptor … for instance, it increases glucose metabolism in the frontal cortex of the brain. Some think this action contributes to the tendency for esketamine to produce dissociative or hallucinogenic activity.

Of course, stronger hallucinogenic effects increases the likelihood of abuse.  

We’re especially worried about this with a nasal spray.

Breakthrough Therapy Designation

In November of 2013 and again in August of 2016, esketamine received Breakthrough Therapy Designation by the FDA. For treatment-resistant depression the first time, and for treatment of major depressive disorder and imminent risk of suicide the second time. This status is given to a drug that’s urgently needed to treat a serious or life-threatening disease or condition and the drug has shown evidence for providing substantial improvement over existing treatments.

It helps expedite and remove delays and obstacles in the FDA approval process.

As I’ve mentioned before, lifting depression and suicidal thoughts are things that ketamine has already mastered. Everyone in the field and in the trenches knows this.

So back to the wannabes…

Currently, esketamine is in Phase III trials toward gaining FDA approval in the US, and 6 specific studies using intranasal esketamine are being conducted here … More than 30 have been launched in the US in the past couple of years and in Argentina, Austria, Belgium, Brazil, Canada, Czech Republic, France, Lithuania, Poland, Turkey, and the UK. The world is on fire with this. And the urgency is evident. Some studies center around using esketamine in intranasal form in conjunction with an SRI or SNRI. Interesting … but maybe not what you’d be looking for if those haven’t worked for you or you’ve had intolerable side effects.

Why the Focus on Esketamine…?

So back to the point. In spite of esketamine’s breakthrough status with the FDA, in spite of the fact that it comes from ketamine, it doesn’t seem to possess the characteristics that make ketamine so effective as an antidepressant. Hmmmm. A recent paper in the journal Nature demonstrated that the NMDA receptor is, in fact, not the target for its antidepressant effects, but rather AMPA.

Esketamine doesn’t have much impact on AMPA receptors.

As you can see, the studies (and the controversies) go on. There’s huge interest in ketamine, ketamine-like drugs, glutamate and AMPA receptors, and the way up and coming antidepressants work — and different opinions about this — around the world.  Neuroscientists pore over the data, set up new preclinical and clinical studies, check and double-check each other’s findings around the world. Drug companies hope their own candidate for FDA approval will come out on top.

So Why Arketamine and Esketamine: Ketamine Wannabe Copycat Drugs?

Since ketamine already has all the features we want, and esketamine seems to have far weaker antidepressant benefits, why don’t we stick with what we KNOW works great?

Well, let’s be honest. Because of money. FDA approval means that insurance companies will probably pay for esketamine to be used in depression, and that makes it available to people who don’t live near a ketamine clinic or who cannot afford ketamine infusions that aren’t covered by insurance. And convenience — no needles, no IVs. And I predict that the pharmaceutical company that’s promoting FDA approval for esketamine will market it as superior, safer, and readily available.

But is it superior?  That hasn’t been tested yet in a head-to-head study.

It’s half the molecule…it drips, it runs down your nose or down your throat if it’s not aimed right…it’s not as reliable…it’s not as bioavailable…it still has the same side effects…and it may not work as well.

Gee.

Cheap Ways to Make Billion$

Janssen is doing the same thing with ketamine.

Tiny Adjustments = Recycling

 So drug companies recycle:  they split old molecules, or try to invent a new delivery system….you know…they make something extended release, controlled release, change the release mechanism, turn it into a patch, or into a nasal spray.

Ultimately they want to make their drug available, bring it to more people, offer something effective and safe and well-tested and versatile. These are all good things. With esketamine … get it FDA-approved as a nasal spray.  Small enough to slip into your purse like a lipstick. Well-known enough to have patients clamoring for it after they see it advertised on TV.

Risk, addiction, and rape could be just around the corner … with a spray.