Bioavailability, How it Matters
Introduction
The bioavailability of IV ketamine is defined to be 100%. But what does that definition really mean to us as patients? More importantly, what do the bioavailability estimates for other ROAs (injections, nasal, sublingual, rectal) mean? The answers to these questions are important in helping us choose to pursue ketamine therapy in-clinic (via IV or IM) or at-home (via nasal, sublingual or rectal self-administration.)
As non-professionals we are vulnerable to leaping to the conclusion that, at 100% bioavailability, IV is best. All the ketamine infused into our veins reaches the brain. No further consideration needs to be given to any other alternative. This article undertakes to go beyond this naive assumption.
Conclusion
Our conclusion is that bioavailability, per se, probably only matters to a small fraction of patients who are vulnerable to organ damage from ketamine. Particularly ketamine cystitis. If a patient knows s/he is vulnerable to cystitis then IV ketamine may be the only viable option.
The effectiveness of ketamine therapy does not necessarily relate to bioavailability. Nevertheless, effectiveness for some patients may relate to the route of administration (ROA). And bioavailability is intrinsically related to ROA. Moreover, ROA is intrinsically related to whether a patient must take ketamine in-clinic or, at less expense and greater accessibility, at-home.
The remainder of this article describes our reasoning to support this conclusion.
ROA, Cost and Accessibility
The most bioavailable ROAs, IV and IM, are only available in-clinic. The lesser bioavailable ROAs may be self-administered at-home. In-clinic administration is typically more expensive and less accessible. See https://ketaminetherapyformentalhealth.com/treatment-center/ There is a price to pay for high bioavailability. The question relevant to this article is whether the benefits of bioavailability justify the cost and inconvenience.
We hasten to add here that the choice of in-clinic vs at-home administration turns on several considerations apt to be relevant to different patients. A compelling case can be made for either venue option depending on a given patient’s circumstances. Bioavailability is just one of these considerations, and probably a less important consideration for most patients.
Measurement
To understand bioavailability we need a working understanding of how it’s measured. We offer here an oversimplified description. The numeric values used throughout are arbitrary, not necessarily realistic, and serve merely to simplify understanding. Researchers administer a dose of – say – 100 mg of ketamine to a subject via each of several routes of administration (ROAs). Waiting – say – 30 minutes after administration in each case, the researchers draw a blood sample and measure the quantity of ketamine in the sample in nanograms per milliliter. They find that the samples contain:
IV: 100 ng/ml
IM: 93
Nasal: 50
Sublingual: 25
Rectal: 25
Since the definition of IV bioavailability is declared to be 100%, we find that: 100 ng/ml / 100 g X 100% = 100% bioavailability.
It then follows that the bioavailability of IM is 93 / 100 X 100% = 93%; and, so forth. Again, these numbers are purely illustrative and not intended to be realistic.
There will, of course, be some variation from one administration to another. Differences between experiments on the same patient. Differences between patients. Different researchers will use different quantities of ketamine: 10 mg; 50 mg; 100 mg for all tested ROAs. They may use different quantities for each ROA: 10 mg for IV; 50 for Nasal; and 100 for sublingual, making an adjustment for quantity in calculating bioavailability.
Different researchers will draw the blood sample for analysis at different times: 10 minutes, 20 minutes or 30 minutes for all tested ROAs. Or, draw samples at different times for each ROA: 10 minutes for IV; 20 minutes for nasal, and 30 minutes for sublingual.
More than likely, researchers will take several samples for each ROA. One at 10 minutes, a second at 20 minutes, a third at 30 minutes, and several more thereafter. By doing so they can plot a curve of the blood level concentration over time as the ketamine is metabolized and eliminated. Doing some fancy math to interpolate between measurements they can calculate the total quantity of ketamine in the bloodstream over time which is represented by a value called “area under curve” (AUC).
The literature reflects a consensus that IV bioavailability is 100% by definition. Almost all reports of IM bioavailability are at or near 93%. Yet we hasten to add that one report finds IM bioavailability is only 60%. This paper uses a different method of measurement. We take no position as to which figure is closer to the truth. We only call out that if the 60% figure were correct then the 93% figure is overstated by (93% – 60% = 33%; 33 / 60 X 100% =) 55%; a remarkable difference.
Nasal bioavailability is often quoted between 45% and 50%; a reasonably narrow range (50% – 45% = 5%; 5 / 45 X 100% = ) 11%. But wider estimates are also reported. Likewise, sublingual bioavailability is usually quoted between 25% and 30%, a wider range (30% – 25% = 5%; 5 / 25 X 100% = ) 20%. As one “climbs down” the bioavailability ladder of ROAs there are more opportunities for variation in measurement. Nasal congestion will vary considerably as will the composition of the saliva in the test subject’s mouth.
The bioavailability figures cited above are those we regard as plausible. Nevertheless, there is no consensus on bioavailability rates for the lesser ROAs. ChatGPT returns the following ranges for the respective ROAs:
ROA Low High
IM 30% 50%
Nasal 20 50
Sublingual 10 40
Observe that the ChatGPT response for the highest value for IM does not approach the consensus figure of 93%. ChatGPT’s low value for sublingual is dramatically lower than the consensus range. Suffice it to say that the quotes for bioavailability by ROA should not be taken as precise. The science of ketamine bioavailability is not settled. Quoted figures are probably a useful guide to ranking and a starting point for comparison. Nevertheless, each patient needs to be titrated individually for each ROA. E.g., a patient who responds well to a dose of 100 mg of IV ketamine might start with a 300 or 400 mg dose of sublingual ketamine for maintenance. Protocols for titration are beyond the scope of this bioavailability article and will be addressed in a separate article.
Some researchers will measure only the original ketamine molecules found in the bloodstream. Others will measure metabolites, principally norketamine, as well. Metabolites are believed to have some therapeutic impact but there is no firm view as to the characteristics of such benefit.
Suffice it to say that there is enough variability in the methods of measurement to question the meaningfulness of quoted bioavailability factors.
Circulatory System
What we are really interested in is not the percentage of ketamine to be found in the bloodstream. We want to know what percentage of the ketamine taken reaches the brain. (We make the reasonable assumption that the therapeutic benefits all come from the effect on the brain, not any other organs of the body.) How does ketamine reach the brain from each of the various ROAs?
It’s clear that the only route to the brain for each ROA is through the bloodstream. Ketamine needs to reach the arteries feeding the brain. Yet, ketamine in the circulatory system likewise reaches all the other organs of the body from head to toe. Each organ gets its proportional opportunity to be affected by the molecules of ketamine reaching its respective arteries. We can think of it as a race for some of the ketamine to reach the brain before all of the ketamine is metabolized and excreted (primarily through the kidneys).
There is one likely exception to the foregoing. The plumbing of the arteries from the nose runs directly to the brain. Therefore, to some undeterminable extent, ketamine administered nasally gives the brain the first crack at the molecules before they are returned through the veins to the heart to circulate throughout the brain/body generally.
An observation that troubles us is the following. Our model of bioavailability is premised on the notion that ketamine travels from the point of intake to the point of excretion via the bloodstream. If, and to the extent, that this is true: Where does the missing ketamine go? E.g., if only 25% of sublingual ketamine is found in the bloodstream, where does the remaining 75% go? Apparently, the methods researchers use to measure ketamine in the bloodstream fail to account for most of the drug.
In the case of por oral (PO, i.e., swallowed) ketamine, the low levels of bloodstream-measured ketamine might be explained by elimination through the digestive tract. However, we don’t find this conjecture persuasive. The digestive tract is composed of mucosal membranes. Ketamine has an ample opportunity to become absorbed into the bloodstream from these membranes. Ketamine in the digestive tract is subject to first-pass metabolism. Which again raises the question of whether to measure ketamine per se or also its metabolites. (Similarly, rectal, by defecation of the ketamine not absorbed into the bloodstream. In the lower intestine we aren’t dealing with first-pass metabolism.) However, we are unpersuaded that so much ketamine is swallowed with saliva in the sublingual ROA. Even less so with the nasal ROA.
Our inability to account for the percentages of ketamine “lost” from the lesser bioavailability ROAs leaves us troubled by the meaningfulness of these measurements. Are researchers measuring the right molecules? Using the right methodologies? Taking samples at the right times? Until research reveals answers to these questions we continue to search for other ways of evaluating ROAs and their relative effectiveness.
Effects: Therapeutic and Side-Effects
Pharmaceuticals have effects. These are classified as:
– therapeutic effects
– side-effects
– – positive side-effects
– – negative side-effects
– – – annoying
– – – serious
To a greater or lesser extent, effects are related to the quantity of the pharmaceutical dosed. As we increase the dose, we get more therapeutic effects. But at the cost of more side-effects. The relationship isn’t necessarily proportional. There are increasing or decreasing effects to scale.
Researchers and clinicians generally believe that the therapeutic benefits of ketamine rise, and then fall, in a dose-response curve shaped like a bell-curve. Very low doses produce a negligible response. Greater doses produce a better and better response up to a peak “sweet-spot”. Any further increase produces a worse response.
Since the cost of the drug itself is relatively low, to get the best therapeutic effect clinicians want to find each patient’s sweet-spot dose for each candidate ROA. Suppose, for a hypothetical patient, that’s:
IV 100 mg
IM 108
Nasal 200
Sublingual 400
Very well. the patient chooses his ROA (and by implication, in-clinic vs at-home administration) and we titrate to these doses which we’ve assumed for illustration. The difference in the cost of the ketamine is negligible because the price of the ketamine drug is low and the differences in quantity illustrated are modest.
The side-effects are not necessarily proportional to the therapeutic effects. They may vary quite independently.
Consider, for example, positive side-effects such as euphoria. A given patient’s experience of euphoria is apt to be acceptable, up to a point. Negative side-effects are another matter.
Annoying side-effects such as dissociation (feelings of being separated from one’s body or visual hallucinations) are apt to be in rough proportion to the therapeutic effects. That is, they won’t be much of an annoyance at very small doses. They are apt to increase as the patient is titrated toward his sweet-spot dose. Beyond that point, we need to be less concerned. We don’t want to titrate a patient beyond his sweet-spot dose.
Our attention should focus on serious adverse side-effects. These are organ damage to the urinary tract, liver, and possibly other organs such as the gall bladder.
While the brain gets only its fair share of access to the milligrams of ketamine we take in, the kidneys and liver must process every (or very nearly every) milligram. Our hypothetical patient’s organs must tolerate all the ketamine processed whether that’s 100, 108, 200, or 400 mg. And, they must process these quantities at the frequency of administration for the duration of ketamine therapy.
Fortunately, for the vast majority of patients, ketamine therapy for mental health is very well tolerated by the organs. Nevertheless, a very few patients report symptoms of ketamine cystitis. See: https://ketaminetherapyformentalhealth.com/ketamine-cystitis-bladder-harm/ for further discussion.
Any patient who knows s/he is vulnerable to cystitis should consider starting ketamine therapy using a higher bioavailable route of administration. Such a patient might already suffer from cystitis, in which case, ketamine therapy is probably ill-advised. Or, such a patient might have close blood relatives who suffer from cystitis. But if neither applies to your case, the lower quantities of ketamine administered via IV or IM are unlikely to be of much of an advantage. Your risk of serious adverse side effects is so low that bioavailability should not influence your decision on your choice of ROA.
So, if not bioavailability per se, which considerations might have a significant influence on your choice? Choice of ROA; and, consequently, choice of venue (in-clinic or at-home). These will include:
1. safety of the venue for your dosing experience;
2. whether one ROA is significantly more/less effective for you;
3. relative cost of an in-clinic provider vs. an at-home provider; and,
3. accessibility to a clinic.
Safety of Venue of Administration
Patients vary in their ability to self-administer ketamine. And patients will vary in their taste for professional supervision during dosing. A patient desperate for relief should seriously consider an in-clinic initial experience where the provider is apt to initiate titration at a higher dose and titrate more aggressively. And in such a protocol it’s more important to monitor a new patient for adverse reactions such as blood pressure rises, nausea, and emotional response. A clinic is apt to dose a new patient at 0.5 mg/kg which – for a 160 lbs patient – would be 36 mg.
Conversely, a patient dosing at home can initiate ketamine therapy at a lower dose and titrate gradually as slowly as s/he becomes comfortable with the experience. Joyous, the prominent very-low-dose at-home provider, will initiate a new patient with sublingual doses of 15 mg. For a 160 lbs patient, that’s a bioequivalent dose of about 0.05 mg/kg; i.e. 1/10th the bioequivalent dose that s/he might receive via IV or IM in a clinic. It is unreasonable to suppose that such a very-low-dose self-administered at-home is less safe than a typical starting IV or IM dose in-clinic.
We hasten to say that many at-home providers begin new patients with sublingual doses of 100 or 200 mg. For a 160 lbs patient, these deliver bioequivalent doses of 34 mg and 69 mg respectively. I.e., they are comparable to or larger than, the conventional initial dose in-clinic. Nevertheless, a cautious new patient is free to begin dosing at 1/2 or 1/4 the dose authorized by the provider, incrementing according to personal comfort level.
Rate of Uptake
Whether one ROA is significantly more/less effective for you probably has more to do with rate and duration of uptake than bioavailability per-se. To this point, we’ve said nothing about the rate-of-uptake of ketamine into the bloodstream; nor anything about the duration of administration. These phenomena are apt to be as important, or more important, as bioavailability.
Ketamine administered by IV is not, typically, delivered equally throughout the duration of the infusion. Suppose a 100 mg dose and a 50-minute duration of infusion, it’s not that the rate of administration is a continuous 2 mg/minute. In a research setting the administration is apt to be heavily front-loaded. Researchers want consistency in observing the rate of rise, and then fall, of the blood samples taken periodically during the infusion and thereafter. In a clinical setting, the infusion is apt to be started slowly, say 1 mg/minute for a few minutes and then 2 and 3 mg/minute up to a peak and then trailing off for the remainder of the session. Here, the view is to allow the patient to gradually come-up to a target level of blood concentration and then maintain that concentration for the remainder of the session.
Injections are, of necessity, bolus. That is, each injection enters the muscle within a second or two and then work their way into the bloodstream. To even-out the uptake, typically the nurse will split the dose into two injections separated by 10 – 15 minutes.
Nasal sprays are typically administered in multiples in each nostril, with each spray separated by a few minutes at the patient’s discretion. If the patient self-administers the multiple sprays in quick succession the rate of uptake will be rapid and intense. Conversely, if each spray (or pair of sprays) is separated by several minutes the rate of uptake will be slow and the peak will be substantially attenuated.
Sublingual self-administration is typically a slow process while the troche or RDT dissolves. At first, the concentration of ketamine in the saliva is high and absorption is relatively rapid (compared to later in the hold period). As the first milligrams of ketamine are absorbed the saliva concentration drops and subsequent absorption slows. Likewise for rectal administration.
Published curves for ketamine concentrations in the bloodstream by the various ROAs look roughly similar. A rapid rise to a peak and then a precipitous plunge at first and a gradual tapering off. IV and IM show higher and more rapid peaks compared to the other ROAs.
Let’s assume that conventional wisdom is correct; i.e., IV and IM are more effective than the other ROAs. If this is so, is it attributable to superior bioavailability? Or, is it more so the marked spike in blood concentration at the initiation of the dosing? We don’t know which of these two phenomena is more important. And, ultimately, it doesn’t matter much because the decision-making process will be the same. If-and-to-the-extent that IV and IM are more effective than the other ROAs, then they are superior. Ignoring all other considerations including cost, and accessibility among others.
Duration of Administration
Mental health patients typically are administered ketamine by IV over a 40 – 60 minute period. Pain patients are often administered ketamine for several hours. A few pain protocols administer ketamine continuously for multiple days. Does the duration of administration matter? Likely, it does. And if so, is a longer (or shorter) duration of administration a unique advantage of the IV ROA?
If a given quantity of ketamine is to be administered over a shorter/longer period of time IV has the obvious advantage of facilitating any desired rate and duration of uptake. Conversely, injections are intrinsically bolus; the best that can be done is to administer a series of injections at, say, 10 minute intervals. In either case, extending the duration of administration of these two in-clinic ROAs increases the provider’s cost and the price paid by the patient.
The annoying side-effects of ketamine therapy (dissociation, nausea, etc.) can be mitigated to some extent by extending the duration of administration. A hundred milligrams administered over 2 hours is apt to produce milder symptoms than administering that same quantity over a single hour. Whether a longer period of administration is more or less effective can only be determined by each patient through experience.
The lesser bioavailable ROAs also are amenable to patient experiments with shorter/longer durations of administration. A patient can space successive nasal sprays by one, two, three minutes or even longer. A patient can split doses of lozenges into halves or quarters and take them into the mouth in intervals of 10 or 15 minutes. The rectal ROA is more awkward and might require prescribing suppositories of lower doses and greater quantities.
Cost
Racemic ketamine is off-patent, manufactured in enormous quantities, and is relatively cheap. A ketamine clinic is not likely to charge less for a smaller quantity of ketamine administered via IV or IM. Many compounding pharmacies don’t charge more for lozenges of higher potency, nor even for larger quantities of lozenges per month in an order.
The major cost difference among the various ROAs is not the quantity of ketamine per dose. It’s the place of administration. Professional administration in-clinic is expensive. The provider has to cover the cost of the clinic overhead and personnel to administer and supervise you while under their care. These costs are eliminated (or substantially mitigated) by self-administration at-home.
So, one question the patient needs to grapple with is the cost vs. benefit of the in-clinic ROAs compared to self-administration at-home via racemic nasal sprays, lozenges, or suppositories. Cost vs. benefit is certainly not the only consideration, but it will be important to most patients.
Accessibility
Many patients don’t live close to an affordable ketamine clinic or don’t have viable transportation to/from the clinic during hours when the clinic is open. The in-clinic alternative simply isn’t viable for these patients.
Summary
There certainly are several advantages to the in-clinic IV and IM ROAs for ketamine therapy. According to each individual patient’s circumstances, these advantages may be compelling, especially for the initial phase of ketamine therapy. Nevertheless, there are also cost, accessability and other disadvantages to in-clinic IV and IM administration. See the several articles under the menu item “Treatment Information” for a thorough discussion of the various ROAs and In-Clinic vs At-Home venues.
The most important considerations for each patient are:
1. which venue and ROA works for his/her symptoms?; and
2. which venue and ROA is affordable and accessible for his/her circumstances?
While better bioavailability is one consideration, for most patients it’s not apt to be the deciding factor. Most patients respond well to the less bioavailable ROAs and can cope with at-home self-administration.