Ever have somebody copy you? You know, try to be like you? Imitate what you do, where you go? try to get what you have? They wannabe like you. Well, maybe not just exactly like you — kind of like you and better than you all at the same time.
It’s happening with ketamine.
We’ve been talking for awhile now about the breakthrough of low dose IV ketamine. In fact, everybody’s been talking about ketamine for treatment-resistant mood disorders. We’ve expounded on its effectiveness in relieving suicidal thinking, treatment-resistant depression, and other psychiatric disorders. Did you catch the discussion about which route is most effective and why we use it? Check it out here.
You should know about all the ways it’s changing the horizon for psychiatric treatment. Like how it stops suicidal thinking within hours, rather than weeks. And how people who have lived with depression and despondency for years — no matter what medication they were taking — can feel depression just lift within hours. Maybe you’ve been there yourself, or you know someone who has.
But there’s more to talk about.
The discovery of ketamine’s therapeutic effects on depression has opened doors to more revelations of the chemical sort. Mechanisms of action. Delivery systems. Ways of leveraging the funding of pharmaceutical companies to develop more versions of ketamine, maybe with the same or similar benefits, but without any side effects …
Think of it like this:
Ketamine wannabes want to “be like” ketamine and wannado like ketamine — except better, without side effects, for longer.
But it turns out that’s easier said than done.
Since ketamine is no longer under patent, it’s unlikely that a pharmaceutical company would be interested in investing the necessary funds to 
conduct extensive trials and research about its effectiveness to treat mood disorders at this stage … at least on ketamine specifically.
Or that a company would shell out time and money to study long-term response and remission rates, or long-term safety, for a well-known generic like ketamine — even if it is being used in a new way in new settings to treat new conditions. There just wouldn’t be the return on investment in the long term.
However, by making changes in the molecules and targets that provide the therapeutic results for ketamine, new versions of the drug in the form of ketamine wannabe compounds that specifically target mood disorders are being designed and developed, and are in the race for FDA approval.
Ketamine Wannabe Drugs
So grab your chemistry lab goggles, and let’s explore some of these molecular discoveries among ketamine-wannabe molecules.
Ketamine is a racemic compound — it has two parts that are mirror images of each other joined together like Siamese twins. If we split it right down the middle where the mirror images join — presto! — we have two “new” drugs. One faces right and the other faces left. We call the left-facing one “S” or in the world of pharmaceuticals, “es–” as in esketamine. So it turns out in this case that changing the structure of ketamine slightly could give us the same benefit, hopefully fewer side effects, and easier use. In other cases, molecules like ketamine are coming down the pike that act on similar targets or in similar ways to help with depression without some of the potential side effects of ketamine.
They both wannabe and don’t wannabe like ketamine. They wannado better.
Esketamine
Esketamine has been approved in Europe for a decade and a half – specifically for anesthesia – and Janssen Pharmaceuticals has acquired a patent to utilize it in the US as an intranasal spray for treatment-resistant depression.
The Food and Drug Administration has awarded “breakthrough” status to esketamine to zoom its advancement through to approval with less interference from various obstacles and the usual red tape that slows everything down.
They plan to specify it for use it in a clinical setting (as opposed to at home) for the sake of controlling the dosage, as well as to prevent sale on the street.
Rapastinel
Another pharmaceutical company – Allergan in Dublin, Ireland – has designed a peptide in this same “ketamine-like” category. You may know that a peptide is a chain of amino acids bonded together in a specific way, and this one looks pretty effective as an adjunctive treatment in depression. It has characteristics like being fast-acting and long-lasting and it’s given as an IV infusion, like ketamine.
Ketamine’s action with NMDA receptors is to block ion channel activity. Here’s where rapastinel is different. It binds to the glycine site on the receptor and regulates or modulates it by changing the shape of that site. Pretty cool. The result is that rapastinel reportedly has a minimum of dissociative or out-of-body side effects that are sometimes experienced with IV ketamine infusions.
Rapastinel is in Phase III trials in the US as an adjunctive treatment for major depressive disorder, and more trials are expected in Europe and Japan. Soon, it’ll be ready for FDA approval for use in the clinical setting to treat depression.
AV-101
Still another pharmaceutical company in San Francisco is working to create a small molecule drug that possesses all the good traits of ketamine without its potential dissociative side effects: VistaGen Therapeutics.
This molecule is one that’s back on the scene from over 30 years ago. At that time, it couldn’t cross the blood-brain barrier to do its work. And consequently, couldn’t impact the depressive symptoms a person was experiencing.
But now, the molecule (which is considered to be a “pro-drug”) has been revamped and this current version does cross the blood brain barrier, And when it does, it’s metabolized from a pro-drug into an active drug that modulates a certain glycine binding site at the NMDA receptor — unlike ketamine and different from rapastinel.
So while ketamine completely blocks certain NMDA receptor ion channels, AV-101 just sort of regulates the receptor gently…which seems to result in gentler side effects.
A New Frontier – Ketamine and Ketamine Wannabe Drugs
There are plenty more versions of modified “ketamine wannabe” molecules in the wings, developing to hopefully even replace ketamine at some point. Hoping to improve on ketamine’s action. Aspiring to lesser side effects. Working towards easier administration. We’ll just have to see how that goes.
And one day this miraculous breakthrough medication – ketamine – may become obsolete like so many cornerstone discoveries of the past.
But right now, boy are these exciting times! We’re on the threshold of a brave new world in psychiatry. A world where people who’ve suffered without relief for years, even decades, can finally experience relief and build a fulfilling life.
One last thought…
All of the companies working with these small molecule drugs are investing in priceless research that’s opening more doors and windows of understanding –. which will, in turn, only increase the benefits for people who just haven’t responded to or tolerated anything else.
For example, we know that ketamine, rapastinel, and AV-101 all work at the NMDA receptor site. So it’s been assumed that that action is the key to their effectiveness. However, when researchers blocked the AMPA receptor, none of these drugs worked. I’ll say it again. None.
Which revealed that the AMPA receptor needs to be activated for the drugs to deliver their fast antidepressant, anti-suicidal results.
And this revelation may lead to more breakthroughs for more who suffer … through ketamine wannabe drugs.
We’re on this. We stay up at night. We watch closely to glean all we can from the research that’s exploding, so we can continue to provide the most up-to-date, cutting edge, 
fresh discoveries that neuroscience offers.
And…we’ll be here to help you find your best self.
So call us, and let’s find the right innovative solution for you.
To the emerging of your best self,
Lori Calabrese, M.D.
