Bioavailability

Bioavailability means: How much drug reaches the target organ?  We can’t hope to develop this complex pharmacological phenomenon here fully.  Nevertheless, it is very important for two small minorities of patients using ketamine therapy:

• Those who are vulnerable to urinary tract indications, particularly cystitis; and,

• Those who respond to ketamine via one ROA but not others

Every ketamine user must know these two considerations to remain alert to their potential manifestation and respond effectively.

First, let’s dismiss a couple of non-considerations.  Ketamine is so cheap and safe that higher doses could easily overcome low bioavailable ROAs.  A patient who responds to 33 mg of IV ketamine with 100% bioavailability could just as well take 125 mg of sublingual (SL) ketamine with the low bioavailability of that ROA.  Even a patient who responds to 100 mg of IV could just as well take 400 mg of SL ketamine.  Cost and side effects wouldn’t be worth discussing in most cases.

The primary consideration is the risk of potentially serious side effects from ketamine therapy.  As we will discuss elsewhere in greater depth, ketamine irritates the urinary tract, particularly the bladder.  Using ketamine regularly in low doses (applicable to mental health therapy) increases the patient’s risk of ketamine cystitis.  Very nearly every substance has some potential for some adverse severe side-effects. (Drinking too much water can be lethal.) Ketamine’s most noteworthy risk is cystitis. Nevertheless, considering the severity of a patient’s otherwise treatment-resistant mental illness, this risk is very low and well worth taking. Moreover, even if ketamine irritates your bladder, if you respond promptly to the symptoms and suspend ketamine therapy, the bladder heals within a month. There is no permanent damage to your urinary tract. (But, of course, you still have your mental illness.) See https://ketaminetherapyformentalhealth.com/ketamine-cystitis-bladder-harm/ for a more thorough discussion of ketamine cystitis.

Accordingly, a patient who has good reason to anticipate urinary tract issues (e.g., personal or family history)  should seriously consider beginning a course of ketamine treatment by the highly bioavailable IV or IM ROAs at a very low dose in the vicinity of 33 mg, thereby avoiding exposure to doses in the vicinity of 125 mg using less bioavailable ROAs.  (Such a patient might titrate up to 66 mg IV, but that’s better than titrating up to 250 mg SL.) Any patient using the less bioavailable ROAs (SL/PR/PV/nasal) who begins to develop urinary symptoms should promptly suspend ketamine therapy for a month and consider the more bioavailable IM or IV ROAs.

The secondary consideration is that each patient responds differently to ketamine and its metabolites.  As ketamine is used, the body converts this molecule into metabolites, having different bio-therapeutic effects.  It’s beyond the scope of this site to attempt to explain the pharmacology.  It suffices to point out that a few patients who do not respond to ketamine via one ROA might nevertheless respond to ketamine via a different ROA.  

A likely variable in play is the “cocktail” of metabolites generated by each ROA.  This cocktail is a complex aspect of the bioavailability topic.  When this phenomenon manifests, it is typical that a patient who failed to respond to SL/PR/PV/nasal ROAs might respond to IV.  Moreover, we’ve seen several reports of patients who failed IV administrations but tried IM and responded successfully.  

Estimates of bioavailability we have seen quoted are given in the table below:

We urge you not to take the lower bioavailability figures seriously.  E.g., do not think that:

• if 25 mg of IV is the ideal therapeutic value for you, then you should expect that 100% / 25% = 4, and therefore 100 mg of SL ketamine should be equally effective;  nor that
• if 100% / 30% = 3.33, then 25 * 3.33 = 83 mg of sublingual ketamine might be equally effective.  

These are very crude figures, and the metabolite cocktail might have a more significant impact than the gross quantity of ketamine dosed.  

Numerous considerations will drive your choice of ROA.  If a personal/family history of urinary tract issues is an applicable consideration, then by all means, seriously consider IV/IM/SC ROAs.  If you seem to be developing urinary tract symptoms, pursue the available IV/IM/SC alternatives.  This is the most important thing to understand about bioavailability.

Your choices among nasal/PR/PV/SL will probably be more significantly influenced by taste/saliva/usage-preferences rather than guessing about your bioavailability in the ranges quoted.  

If you do not respond to ketamine via one ROA – at what your prescriber deems a likely adequate dose – try alternative ROAs.

Some differences in the metabolite cocktail may trigger your brain to respond.

In summary, here is your decision path as it concerns bioavailability:

• Are there any personal/family urinary issues?
• If ‘Yes,’ then first consider alternatives to ketamine therapy
• If ‘No,’ then proceed with the choice of in-clinic vs. at-home ROAs
• If you choose among IV/IM/SC ROAs, remain alert for potential urinary symptoms and notify your provider promptly if they appear
• If you choose a nasal/PR/PV/SC ROA, then upon the appearance of urinary symptoms, consider switching to IV/IM/SC
• In the event of urinary symptoms, suspend ketamine treatments for a month. Allow your bladder to heal. Then, resume with lower dose quantities and less frequent dosing with a higher bioavailability ROA.