Administration: IV

Intravenous (IV) infusions are universally considered the “gold standard” in ketamine therapy. We believe that this designation is both:

• entirely justified; and,
• really unfortunate.

It is justified in light of the facts that:

• Intravenous ketamine is the most researched, almost to the exclusion of other routes of administration (ROAs).
• The provider has very precise control over the dose and rate of administration.
• Intravenous ketamine is 100% bioavailable, minimizing the impact of side effects (mainly urological).
• The prescriber has absolute control over the quantity and frequency of dosing, mitigating concern for addiction or excessive use.

It is unfortunate in light of the considerations that:

• Other ROAs appear effective for most patients; i.e., the perfect should not be the enemy of the good-enough.
• Intravenous administration is the most costly ROA and the least convenient because it necessitates travel to and from a clinic.
• Precision in quantity and rate of administration are not necessarily compelling considerations in the patient’s personal therapy (though they are important to researchers). Indeed, this consideration is frivolous.

Precision is probably the first argument to examine critically. Let’s imagine asking our IV nurse about precision. She is apt to say: ‘Doctor has ordered that I administer a dose of 100 mg to you for your very first dose. With my syringe and IV pump, I can be sure of delivering precisely 100 mg of ketamine +/- 0.01 mg.’

Now, let’s ask her: ‘How does doctor know whether my optimal dose might be 90, 100 or 110 mg?’ What if she (improbably) answered: ‘Well, of course, he has no clue whatsoever!’

Now think about this discussion. If the doctor is clueless about this patient’s optimal dose in a range of 90 – 110 mg, how much does it matter that she can deliver the ordered quantity of 100 mg +/- 0.01 mg?

Further suppose, in the course of your 6-pack of ketamine therapy, your doctor has titrated you from 100 mg to 110, to 115 to 118 to 120 mg, and has now ordered your 6th infusion to be precisely 123 mg.

Now, let’s ask her: ‘How does doctor know whether my optimal dose might be 122, 123 or 124 mg?’ Expect her answer to be: ‘Well, of course, he has no clue whatsoever!’

Once you contemplate these imaginary dialogues you will understand how much the precision advantage of IV has over other routes of administration.

If you are desperate for relief as soon as possible, consider IV infusions as a leading candidate ROA. They offer the highest probability of efficacy and promptness of relief. If you are squeamish about the prospects of a highly dissociative experience, you might want to consider sublingual/rectal ROAs first. You can easily titrate yourself from a very low dose, incrementing very gradually. If you don’t find relief from sublingual/rectal ketamine you can try nasal and ultimately try IV or IM if the less bioavailable ROAs don’t deliver results.

In IV ketamine administration, a patient must travel to a clinic, be prep’ed with an IV, and then the ketamine is infused over a 40-60 minute interval via pump or slow-drip. The provider has a great deal of control over the rate of administration. The patient might begin with a slow “drip” to see how she responds. As she grows accustomed to the effects of the drug, the quantity may be increased and then tapered off for the remainder of the infusion period. If the patient objects to the effects of the drug, the rate of infusion can be backed-off or stopped to cater to the patient’s intolerance. The effects of the drug become apparent within minutes.

In a research environment, the patient is apt to be given an up-front bolus dose, and then the rate of flow of ketamine is tapered off for the remainder of the 40-minute infusion. Researchers are a little less concerned with patient comfort and quite a bit more concerned with their scientific goals. By front-loading the ketamine dose, the patient’s blood concentration immediately reaches the targeted level. Then the slow-drip for the remainder of the session maintains the targeted level of ketamine in the blood.

Your provider might be inclined to front-load your rate of dosing. Before your first session, you should discuss this aspect of the provider’s protocol. If you are a bit squeamish, ask the provider to ramp up your rate of ketamine flow slowly at your first session so that you can see how you respond.

The bioavailability of ketamine administered intravenously is 100%, meaning that almost all of the drug is absorbed into the bloodstream and available for use by the brain.

The 100% figure is definitional, not empirical. A given quantity of ketamine infused into the bloodstream produces a concentration of ketamine and metabolites in the blood, establishing the benchmark against which other ROA bioavailability figures are observed. Because the ketamine is circulating throughout the body it’s not the case that 100% of the ketamine reaches the brain. If – theoretically – a new ROA were discovered whereby ketamine could be injected directly into the brain, its bioavailability would be some multiple of 100% by this IV benchmark.

The higher bioavailability ROAs minimize bioload and reduce the potential for bladder damage. The drug is delivered directly into the bloodstream, bypassing the digestive system and other organs that can affect absorption and the metabolization of ketamine into other molecules. IV and IM maximize these considerations. Nasal in a mid-level bioavailable ROA, with sublingual/rectal being the least bioavailable. “Oral” – i.e., swallowing, is the least bioavailable and causes diversion of ketamine into other metabolites believed to be less useful for mental health indications.

How much emphasis to give bioavailability is debatable. The difference between IV and IM is too small to likely make a difference (100% vs 93%). If nasal/sublingual/rectal bioavailabilities (50%, 30-25%) are effective and safe for a patient, then their “impoverished” bioavailabilities shouldn’t rule them out.

An IV can only be performed in a clinic by a nurse or physician trained to perform such a procedure. There is a remote risk (0.4% or less) of a laryngospasm; i.e., a clenching of the vocal cords that interferes with respiration. Clinical personnel need to be trained to respond to such an event. If the clinical personnel are not, in fact, trained to respond to a laryngospasm then the illusion of in-clinic safety of this consideration is unfounded.

Some patients are needle-adverse and prefer to avoid IV or IM ROAs. Other patients take comfort in being in a clinical environment when undergoing – for the first time in their lives – a highly dissociative experience typified by hallucinations, loss of connection with their bodies, and sudden and uncontrolled eruptions of emotions. But a patient might be less comforted by stranger nurses in the next room than she would be comforted by the immediate presence of a significant-other in her own home.

IV doses are, nearly universally, quoted in terms of milligrams per kilogram of body weight. Most research on ketamine for mental health therapy is in the vicinity of 0.5 mg/kg.

A provider is apt to titrate a patient’s doses somewhat below the 0.5 benchmark, incrementing doses in successive administrations in search of an optimal response. E.g., the first dose might be 0.4 mg/kg, then 0.45, then 0.5, 0.55, 0.6, 0.75, 0.9, 1.0 and possibly a little higher. These figures are purely for illustration and should not be interpreted as some standard or convention.

In titrating a patient, the provider is striving to achieve a balance among competing considerations:

• Clinical efficacy: getting the patient to a dose that releives her symptoms as soon as possible;
• Catering to an individual patient’s squeamishness to the startling dissociative experiences and eruptions of emotional traumas;
• The patient’s budget constraints. In-clinic administration is expensive. Each infusion costs the patient a lot of money. The provider wants his patient to get the best bang for her buck.
• A careful search for the “Goldilocks” dose for the individual patient: neither too little nor too much. Instead, a dose that is just about the right quantity to achieve the optimal response.

If time-to-relief and money were no object, the provider would titrate in very small increments, repeating each dose quantity to observe a consistent response. E.g.:

0.4, 0.4, 0.4, 0.4 and then . . .

0.45, 0.45, 0.45, 0.45 and then . . .

0.5, 0.5, 0.5, 0.5

and so forth. But at the cost of IV administration, this isn’t cost-effective. The provider will make some compromises. E.g., 0.4, 0.45, 0.5, 0.5, 0.5, 0.55 . . . A provider might think that the smaller doses are at least helpful and ease the patient into the experience. He might anticipate a response to the benchmark dose of 0.5 and repeat that dose several times to see if a good response is observed. If not, resume incrementing doses. But all of this is guesswork.

This author’s first provider prescribed sublingual lozenges. Twenty doses of 200 mg, then 30 doses of 300 mg. Then 400 mg. He took his own sweet time observing my reports of my response to each dose before prescribing the next increment of quantity. Neither he nor I was concerned with the cost. Each 10 doses cost me $300; $30 per dose. Compre this cost of a slow deliberate titration to the cost of IV: $300 – $600 per dose.

The doses typical of ketamine therapy for mental health are very low compared to quantities used for anesthesiology. And anesthesiologists often run ketamine clinics. Consequently, one occasionally hears of a mental health patient being administered remarkably high doses via IV in a ketamine clinic. A beginning dose above 0.5 mg/kg is remarkable. A beginning dose of 1.0 mg/kg calls for a frank discussion with the provider.

It is especially important for IV (and IM) patients to ask their providers on the occasion of each administration what dose will be administered. And to confirm (two hours later, after the patient has recovered and is about to leave the clinic) what dose was actually delivered. It’s always possible that the nurse/physician will decide to reduce or increase the dose sometime during the infusion period, according to the patient’s response to that particular administration. Patients should keep a log of planned and actual doses and note their subjective responses during the infusion and in the hours and days following each infusion.

Typically, ketamine clinics offer a package of 6 “loading doses.” These are delivered, typically, twice a week for three weeks. Sometimes, three times a week for two weeks. Occasionally, the package is as few as 4, or as many as 8.

Most patients who will (eventually) respond do respond in a month or so. Some more patients will respond in two months. Presumably, these time-periods are predicated on doses at the therapeutic quantity for the individual patient. One should not expect to microdose for 3 or 7 weeks and then take a therapeutic dose for one week and expect to see results in this time-frame.

If these one- or two-month estimates are true, then six infusions in two weeks seem a bit short of what would be necessary to expect results; i.e., to rule-out a declaration of “non-responsiveness”. A regimen of 8 doses in 4 weeks would conform to the one-month period. Twelve doses in six to eight weeks would conform to the two-month period.

Infusion patients are typically invited to carry on with a maintenance program such as:

• weekly for four weeks
• bi-weekly for eight weeks
• monthly for six months
• quarterly for six months
• as-needed thereafter

The foregoing is merely illustrative. There is no standard or convention. The intervals are individually tailored to each patient’s reappearance of symptoms. If symptoms don’t reappear in an interval (e.g., bi-weakly) then the next booster will be scheduled for a longer interval (e.g., monthly). If symptoms do reappear, the previous more frequent schedule will resume for a while.

It appears, anecdotally, that IV and IM ROAs have somewhat better durability than the less bioavailable ROAs. This is merely an impression and is not reported in the literature. But if true, then the cost-effectiveness of IV/IM ROAs might be competitive with that of the less bioavailable ROAs.

Pricing of in-clinic ROAs (IV, IM, and Spravato) is per administration, often with a package discount. Therefore, if your booster intervals in maintenance are quarterly rather than monthly, IV/IM will probably cost less than your monthly cost of at-home nasal/sublingual/rectal ROAs. Conversely, if your booster intervals in maintenance are monthly or more frequent, then at-home nasal/sublingual/rectal ROAs will be less costly.

You must also take into consideration your time and transportation inconveniences with in-clinic ROAs. In the month(s) of your initial loading doses, you are apt to be desperate enough to take time off from work and arrange transportation to the clinic. You have to make this work. How will work/home obligations and transportation work in subsequent years of maintenance? They might not be tolerable; in which case, you might switch to at-home ROAs for maintenance. Or, they might work-out just fine. Taking a day off work once a quarter to spend half a day at your ketamine clinic might be just fine.

If you are a patient, you are not particularly invested in researchers‘ motivations. You want good-enough results at the lowest cost and inconvenience. You need not be influenced by the volume of popular press, research papers, or commentaries of other patients. Consider your own personal circumstances when choosing the IV ROA compared to the alternatives available to you.

Ketamine via the IV ROA is certainly the first option to study and consider; but it’s not the only one. And it isn’t necessarily your best choice. Carefully consider the discussion of the in-clinic vs. at-home alternatives, your options in cost and transportation, before you settle on your preference for environment and ROA.