So, ketamine has been in the news a lot lately.

Celebrities are using it, sometimes  with tragic or weird consequences. Psychiatrists are prescribing it in record  numbers for treatment-resistant depression.

And for a lot of people, it has become  the recreational drug of the moment. But what is it? It has properties of a hallucinogen,  a pain killer, and an anti-depressant,   but it doesn't fit neatly  into any of those categories.

Today, we're going to explore what ketamine is  and what the research says about its safety. [♪ INTRO] It’s been more than 60 years since  scientists first synthesized ketamine. One of its original uses was as  an anesthetic during surgery. And we’ve been successfully  using it to keep people from   feeling pain in the operating room ever since.

You can get it sent right into your bloodstream! Or, less traditionally,  orally, rectally, or snorted. I’m sure someone has tried them all, but  you wouldn’t need to for a surgical context.

Doctors are pretty good at  getting stuff into your veins. And that’s great because ketamine  can do a lot for you during surgery. Aside from pain management,   ketamine during or right after surgery  can prevent the onset of depression.

Now, when you go in for a surgery,  there’s a lot to manage post-op. And depression might not cross your mind. But one serious post-surgical depression  you’ve probably heard of is post-partum   depression, which can manifest after a C-section.

If you’re at higher risk of  experiencing post-partum depression,   you might benefit from ketamine or esketamine. Both have data to support their  use in these circumstances.   Yes, I just threw in a whole new vocab word! Ketamine is a mixture of two mirror  image versions of a molecule.

Those versions are esketamine and arketamine. Since some papers have reported that  esketamine is more potent than arketamine,   a lot of what we know today  is focused on the S version. In fact, forget arketamine!

In some contexts, like recovering from surgery,   esketamine has even stronger  effects than ketamine! So a lot of researchers today  study both ketamine and esketamine. And they’re both associated with reducing  your postpartum depression symptoms.

Those usually manifest within about a month,   and that’s exactly the time period that  studies have shown improvements in. And it’s not just good for postpartum depression. Post-operative depression can  happen for more than one reason,   and seems to be associated with inflammation.

The good news is ketamine has an anti-inflammatory   effect and can take care  of those symptoms as well. A meta-analysis published  in 2024 concluded that both   ketamine and esketamine have significant  benefits to your quality of recovery,   including depression and pain, in  the first day after your surgery. And you don’t have to get a surgery for  ketamine to help out with your depression.

Esketamine even has FDA approval to  manage treatment-resistant depression. So if you’ve been trying all sorts of  therapies to manage your depression   symptoms, but nothing has helped, this  might be what your doctor turns to. Even when you’re in an acute crisis.

One trial gave 15 suicidal emergency  department admittees ketamine. And in a matter of hours, 12 of  them had no suicidal thoughts. That sounds pretty life-saving to me!

The effects of a single dose are  surprisingly long lasting, too. When the researchers followed up to check in  on suicidal ideation over the course of hours,   days, weeks, an even a month,  suicidal ideation never relapsed. Sure, it’s a small sample of people.

But those results are remarkable! Which makes you wonder why it isn’t more accepted! Until you find out that we  don’t know exactly how it works.

We started out using ketamine as an anesthetic,   and our understanding of how it works  begins with its anesthetic properties. So let me take you back to 1983,   when we learned that ketamine works through  NMDA receptors to reduce brain cell activity. Those receptors are all over the place,   including on brain cells that respond to pain,  which may be behind the anesthetic effects.

The idea is: a molecule like your  main excitatory chemical, glutamate,   binds to a receptor on a brain cell’s membrane. That signal can open the flood gates for calcium  to rush into the cell, ramping up its activity. But if the receptor is covered up by ketamine,   the cell won’t react like it otherwise  would when glutamate comes along.

So when ketamine’s around in a high enough dose,   the brain cells that usually  respond to pain don’t. But if it’s around in lower doses, it  can have a totally different effect. Subanesthetic doses of ketamine  can make you dissociate.

Which generally looks like hallucinations and  disconnection from what’s going on around you. Ketamine might have this effect by switching  which brain cells are active and which are not. It blocks NMDA receptors.

And in doing so, it shuts down  cells that are usually more active. At the same time, it ramps up activity in cells  that otherwise would have been less active. That swap could produce new patterns of brain  activity that get interpreted as dissociation.

On the scale of your whole brain,  ketamine might also shut down the   cellular communication that takes in  information from your senses and the   cellular communication that  interprets that information. So you’re suppressing the feedback that would  normally provide context for whatever’s going on. All of which might make you feel out of sorts.

And on top of that, ketamine doesn’t  just interact with NMDA receptors. It also interacts with opioid receptors,  nicotine receptors, dopamine receptors, and more. It’s no wonder this drug can  make you feel … different.

So that’s anesthesia and dissociation. But researchers are also trying to figure  out what makes ketamine an anti-depressant. And the answer might be all the  way down at the genetic level.

Both ketamine and esketamine affect how  genes get expressed in a variety of cells,   including those in the immune system. The immune system, of course,  is responsible for inflammation. And, as we said earlier, depression and  inflammation seem to be two peas in a pod.

So by changing the expression of  genes that regulate immune activity,   ketamine may be able to provide a  therapeutic effect for depression. That’s just one of the theories, though. Ketamine also seems to be  involved in neuron growth.

It just does so much! Which is part of what concerns some people. Odds are it’s doing more  than what you took it for.

And the risks of taking ketamine or  esketamine range from minimal to very serious. One of the main concerns is increased  blood pressure and heart rate. While this can be good in some anesthetic uses,   it’s not something you want to see if you’re  using ketamine for psychiatric purposes.

The good news is that a meta-analysis of 15  ketamine and esketamine studies found increases   that are still pretty mild and short-term, on  the order of an extra four heartbeats per minute. And, while the blood pressure increases  were high enough to be hypertensive,   they weren’t high enough to be an emergency, and  they lowered quickly after treatment stopped. That sounds pretty short term and mild.

But we’re talking about a summary of averages,   so any one person could have  something very different going on. Some individuals in these studies had a maximum  of 29 extra beats per minute, which is a lot! It’s probably why people who  know they have hypertension   are not allowed to participate in ketamine trials.

So if you’re thinking about how you  would fare on ketamine, think about   things like medications for psychiatric  conditions that raise your blood pressure. I’m looking at you SNRIs. And while some people take ketamine for its  dissociative effects, you might find that to   be a real problem if you’re just looking  for an anesthetic or anti-depressant.

Not everyone is in the market  for a weird “trip” when they’re   trying to relieve pain or improve their mood. Luckily, researchers report that  this effect usually comes in under   clinical levels and wears off relatively quickly. In the emergency room study, one person  who used ketamine did feel even more   dissociative than they did before, which  was already more than the average person.

But, considering the state he  was in before taking ketamine,   he still said the overall experience was good  and there was improvement of his suicidality. Given that person’s medical history,  the risk was worth the reward. But ketamine also has potential to  increase your suicidal ideation.

Maybe through the same  mechanisms that it decreases it. Just a reminder that even though it’s been  decades since we started using the stuff,   we still don’t really know how it works! And if you don’t get the dose  right, you can poison yourself!

Based on reports of negative ketamine outcomes  to the US Food and Drug Administration,   about 20% of those resulted in  hospitalization and about 5% in death. So there are rare but very real risks. Even with those reports, the  FDA has approved esketamine   nasal spray for treatment-resistant depression.

But it wasn’t a unanimous decision. There was a lot of concern  surrounding its risk of abuse. We know that people have been taking ketamine   outside of its prescribed  uses since its early days.

There’s a link between the  prescribed anti-depressant   use and eventual substance use disorder. When some people take it to reduce their  depression symptoms and then it wears off,   they sometimes take more and more. If that’s enough to give you second thoughts about  ketamine, the good news is that it’s inspiring the   creation of other antidepressants…They’re  just not as good as ketamine yet.

Other drugs that act on NMDA  receptors like memantine and   lanicemine haven’t proven to be  effective in treating depression. That’s why we need those researchers  to keep searching for answers and   figuring out which of ketamine’s many  targets produces life-saving effects. Once they understand all of that better,   maybe they can replicate it  without the unwanted side effects.

It’s proving hard to find a replacement  for something that does so much. At the end of the day, it really is a Special K. [♪ OUTRO]