There are many different ways to put a medication into the body. You can swallow it, inject it, rub it onto the skin, inhale it, insert it as a suppository, etc. This is called the Route of Administration, which we’ll abbreviate here as ROA.
Intravenous (IV) infusion is by far the most common and most studied ketamine ROA for depression. If you tallied all the volunteers from all the ketamine studies to date, probably 98% of them received infusions. On this site and elsewhere you’ll see the terms “IV” and “infusion” used interchangeably.
The ROA makes all the difference in the world. You expect cough syrup to work if you swallow it, but what if you rub it on your skin? You expect a first-aid cream to relieve pain from a cut if you put it on the wound, but what if you snort it? Ketamine for depression is no different: it works best when it is administered with a particular ROA.
Ketamine can be put in the body with several ROAs:
sprayed into the sinus cavities (intranasal)
under the tongue (sublingual)
intramuscular injection with a syringe (IM)
The rate of delivery is also critical. Has your doctor ever given you an antibiotic for an infection? A typical regimen is one dose daily for a week. If you took the entire 7-day prescription in one gulp, do you think it would still work? What if you took one pill weekly, instead of daily? If you do, you’ll render the drug useless, but the only thing you’ve changed is the rate.
You don’t need to schedule your antibiotic to the exact minute, as long as it’s roughly once per day. But some meds require extreme precision for their rates, like anesthesia in the operating room. If it’s administered too quickly it can kill you. Too slowly, and you might wake up while your abdomen is open. An anesthesiolgist can recognize signs that the rate is too fast or slow, and fine-tune it accordingly. Ketamine for depression is no different: it works best when it is delivered to the brain at a certain rate.
If ketamine is put into your body with the right ROA, and delivered to your brain at the right rate, it will create unique conditions in the brain. These conditions trigger a delicate cascade of events in the brain that can relieve symptoms.
We’re grateful each time a physician is willing to embrace the research and use ketamine. However, we have serious concerns about ketamine being given via IM. Our concerns are based partly on our understanding of the importance of a precise rate, which IM does not produce; and even more on the firsthand reports we’ve had from IM patients. Most IM patients we’ve talked to report intense unpleasant side-effects very soon after the injection. In these cases, very strong dissociation occurred. Some described it as a “bad trip” or “terrifying”. In some cases, the patients also experienced tachycardia (a racing pulse), and in one case the doctor had to act to bring the patient’s blood pressure down, and nearly called emergency services. In all cases, the anesthetic effects of the ketamine were felt for 2-4 hours afterwards, as compared to an infusion where the effects dissipate within minutes. Among these patients, one got partial relief, but the rest got none.
We’ve talked with some of the anesthesiologists in our directory about these cases, and they were not surprised. With IM the initial absorption into the bloodstream can be very rapid, much faster than an infusion, causing intense side-effects. But much of the ketamine can remain in the soft tissues and continue to be slowly absorbed for hours until it is completely consumed, and the extreme variability in rate makes the likelihood of an antidepressant effect lower than IV.
In each of these patient examples, the doctor performing the IM injection was a psychiatrist. We like the idea of psychiatrists endorsing ketamine therapy, but we’re concerned that these particular doctors may have chosen IM because it was easier to administer than IV, and was something they could personally perform without additional training or effort. We don’t know any of those doctors, and we can’t judge their motives. But we find the prospect unnerving, especially in light of the frightening patient experiences and lack of relief.
We have found a single published study on IM ketamine for depression, but consider it to be of poor quality. It was not conducted by experienced ketamine researchers, but by a local hospital in a small city in southern India. There was no control group, and it was not double-blind. Only 18 subjects were given IM ketamine. With no other IM ketamine studies to reference, we feel there is simply no valid data on its efficacy. That does not mean IM ketamine is useless on depression. It means there’s no scientific proof yet. There are some patients who report positive results with IM, but we don’t know any who have also received IV in order to compare them directly.
The side-effect profile of IM ketamine worries us. First, we are concerned for the wellbeing of IM patients due to the reports we described. Secondly, we fear these severe side-effects could cause a backlash against all ketamine therapy, even the much more widely-used, better-tolerated IV method. If an IM patient makes the news due to serious complications, like a cardiac event, the general public can’t be expected to understand the important details explained here. They won’t understand that with IV the doctor could have simply shut off the ketamine instantly. The patient’s story will be oversimplified to something like “ketamine harms patient during depression treatment,” even if that harm was due mainly to using the wrong ROA.
Think of it this way. Imagine you need major surgery and have to choose between two options. In one, the anesthesiologist drips IV anesthesia into your veins steadily throughout the surgery, fine-tuning the rate constantly to make sure you stay unconscious and your heart keeps beating. In the other, the anesthesiologist gives you an IM injection just before the surgeon cuts you open, and then he goes home, hoping that the injection is absorbed at the perfect rate to balance sedation vs. cardiac arrest, and that it lasts long enough to get you through the entire surgery. In essence, this is the same choice a ketamine therapy patient makes when weighing IV infusion vs. IM injection.
For a doctor who wants to employ ketamine to fight depression, IM represents the lowest barrier to entry. It’s easy. And for the patient, it could be cheaper than IV. But based on our understanding it does not represent the best chances for depression relief, and it can create intense side-effects. As patients seeking the best possible degree of relief in the most predictable way with the most tolerable side-effects, IV is far preferable to us.
Why are IV Infusions the most effective ROA? Let’s use baking a cake as a metaphor. The first thing you need to bake a cake is the right ingredients, in the right quantities. If you mix them in the wrong proportions, or skip an ingredient, your cake will be ruined. The ketamine recipe that works is simple: 100% ketamine and nothing else. When you deliver ketamine to the brain via IV, you are providing exactly the right ingredients. The ketamine travels from the IV directly into your bloodstream, then directly to the brain, without making any stops along the way. But if you swallow an oral dose of ketamine, first-pass metabolism breaks it down into other chemicals as it travels through the intestinal tract and liver before it reaches the brain. You’ve just changed the recipe by reducing the available amount of the critical ingredient, and by adding a large quantity of extra ingredients (metabolites).
About 84% of oral ketamine will be metabolized into other chemicals. What if you replaced 84% of the flour in your cake recipe with something else? You can’t simply gross up the quantity of flour to account for the 84% loss. Yes, that would ensure the batter contained enough flour, but now it would also contain a huge quantity of “something else”. There would be 5x more “something else” than flour. It’s not going to work.
Once you’ve prepared the batter correctly, you have to bake it. This is where rate comes in. You have to apply heat to your batter, and it has to be delivered at the right rate.
Your recipe calls for 350°F for 30 min. What would happen if you set the oven to 550°F? Or 200°F? Or what if you constantly varied the temperature instead of holding it steady? Obviously, any one of these changes will ruin your cake. You might think you could take it out of the oven sooner if the temperature is too high, or vice versa, but anyone who’s ever baked a cake knows it just doesn’t work that way. The temperature and the duration must both be exactly right. With ketamine, we care about the rate at which it reaches the brain. IV infusion allows the rate to be set exactly. The doctor will simply set the drip speed to the target rate (the rate shown to work on depression) and then tightly control it for the duration of the infusion. A rate that’s too fast is like setting your oven temperature too high, and so on. Just like an anesthesiologist during surgery, an experienced ketamine infusion provider can recognize signs that your infusion is too fast or slow, and can fine-tune the rate accordingly. IV is the only ROA that allows the rate to be controlled.
But why can’t we control the rate of other ROAs? Consider an IM injection. Let’s follow a single ketamine molecule from the moment it exits the syringe until it reaches your brain, to see if we can figure out what the rate will be. After the molecule is injected into your soft tissues it will be absorbed into the bloodstream. How fast? Well, it depends on a bunch of things:
Was it injected into muscle or fatty tissue?
Where exactly on the body was it injected? How far from the heart?
What are your unique circulatory conditions at the precise location inside your body where the molecule was deposited?
And lots more…
There is simply no way to control how fast the molecule will be absorbed into your bloodstream. Once it leaves the needle, it’s completely out of anyone’s control. Your body will get around to it at its own unique pace. You can’t pinpoint it and calculate that “this molecule will be absorbed after exactly 230.84 seconds”. There is an obvious element of randomness, and all the other ketamine molecules in this dose are subject to it, too. Bottom line:
There’s no way to control – or even measure – the actual rate at which the ketamine gets carried to the brain.
The rate will vary randomly the whole time the injection is being absorbed into the bloodstream.
In our cake metaphor, this is like having a broken thermostat on your oven. Let’s say you set the oven to 350°F, but the actual temperature fluctuates up and down by 100°F or so throughout the baking. The temperature isn’t correct, and it isn’t even steady. Your cake is ruined.
We won’t walk through this exercise for every ROA, but you get the idea. IV infusion allows ketamine to reach your brain without being chemically altered, at a rate that is carefully controlled. These are the conditions that trigger the delicate cascade of events that produce the antidepressant effect. All other ROAs change these conditions, either by replacing some of the ketamine with other chemicals, or by delivering it to the brain at an uncontrolled, variable rate.
And that is why IV is the most common ROA, and the most reliable.
Note: IV allows instant shut-off
In case of complications or adverse side-effects, IV infusion allows the doctor to shut off the ketamine instantly. With all other ROAs, there’s no stopping it once the ketamine dose is administered.
But does this mean that every ROA except IV is guaranteed to fail? No. Every patient has a different metabolism, blood chemistry, circulatory strength, etc. There may be instances where other ROAs create the necessary conditions in the brain – or close – to get some partial benefit. This brings us to intranasal.
After IV, intranasal is the second-most common ketamine ROA, although it’s still quite rare. It doesn’t provide the precision of IV – not even close – because intranasal’s rate of delivery to the brain is hugely variable. There is a single published study on intranasal for depression. The study indicates it may be effective, but it does not attempt to compare its efficacy head-to-head versus IV. Intranasal can be cheaper than an infusion. With intranasal, your doctor does not need specialized equipment, IV supplies, or the skills to insert an IV catheter and administer the procedure. Spraying a ketamine solution into a patient’s nose is simpler than performing an IV, and carries less risk. Some doctors will permit carefully screened patients to take intranasal ketamine home with them to self-administer. Only a small fraction of the administered dose will actually be absorbed (see below) so the dissociative effect, if any, will be smaller, and there is less potential for increased blood pressure and heart rate. All of this makes intranasal treatment technically simpler than IV, and generally cheaper.
A difficulty unique to intranasal is that there’s no way to know the exact dose you’re receiving. No matter how carefully you measure the amount sprayed into your nose, there’s no telling how much actually reaches your bloodstream. Some fluid will run back out your nostrils or down the back of your throat, or might be inhaled. Some will miss the nasal membrane or land on mucus, where it will not be absorbed. Many factors come into play: the shape of your nasal cavity, its moisture content, the accuracy of your aim, the condition of your nasal membrane, congestion, etc.
Imprecise dosing isn’t the only difficulty. Even if you could somehow measure the exact amount that lands squarely on your nasal membrane, the permeability of each person’s membrane is different and there’s no telling the speed at which the ketamine will actually be absorbed through yours. Considering all of the above, it’s easy to see that intranasal administration means an unknown dose will be delivered to the brain at an unknown, and uncontrolled, rate.
We neither encourage nor discourage intranasal use. We simply want you to understand that it is available. Some of us have gotten great results with IV, but not with intranasal. Some have benefitted from both. In our experience, patients who have tried both generally say that infusion provides a greater degree of relief that lasts longer; whereas intranasal is cheaper and more convenient but the relief is smaller.
If you are considering ketamine therapy, you’re probably weighing several factors like cost, likelihood of success, travel inconvenience, etc. But honestly, for many it usually comes down to cost alone because lifelong sufferers are often penniless. Being aware of the intranasal option allows you to include it in your personal calculus. If money were no object we’d recommend trying IV first. But to someone who is in agony, any relief at all might be enough to make a huge difference in their life – whether it comes from IV, intranasal, or otherwise. So we are not opposed to intranasal as an alternative.
We want to make one strong point about the intranasal route. If you are a brand new ketamine patient, and your first treatment is intranasal, and it doesn’t work, do not declare yourself a non-responder. There are plenty of patients who respond to IV ketamine but not to intranasal. You could be one of them. So you might still get tremendous relief from IV. Patients like us have tried dozens of meds over many years, and we are justifiably predisposed to declare failure quickly when trying a new one. Yes, you might truly be a ketamine non-responder. But a single intranasal failure doesn’t give you enough information to make that call. IV is the gold standard of ketamine therapy, and until you try it you can’t know for sure whether ketamine can help you or not.