To answer your questions about how long for both mirtazapine and lorazepam, see @Alex113 post, just above your post, above, and my response to @Alex113 , that you're quoting from here . I've re-posted that info for you above this.
I was asking about how long she was on each dose of mirtazapine. The answer you quoted is how long she was on the drug in general not each dose. I'm trying to understand whether she was, say, on 7 mg for 1 month and 15 mg for 2 months, or perhaps 7 mg for 2.5 months and 15 mg for 2 weeks. Different situations.
This is simply not the case, or, more accurately, diminishes the issues that benzos cause. And if you're 'dependent' on benzos, then you're heading towards tolerance withdrawal eventually, depending on your system. Some patients have more resistance to hitting tolerance withdrawal than others, other patients can hit tolerance withdrawal in a matter of weeks. And an unlucky few can it that in a week or two. It's a genetic crap-shoot.
I am in no way trying to diminish the seriousness of benzodiazepine dependence. They are terrible drugs with many serious side effects, and can cause serious physical and psychological dependence. However, I believe you are seriously overstating the 'tolerance withdrawal' phenomenon which is to my knowledge not guaranteed or even necessarily common. In fact, it would really help me if you could link me to a literature review or something which sheds some light on the phenomenon, because unless there is some data out there on the epidemiology or at least pathophysiology of it, then we are both basing our opinions on anecdote and have no reason to quibble much further about it other than to agree 'it could be a factor, who knows'.
I also want to reiterate that
@Alex113's sister has been using lorazepam for 2.5 years, at a dosage only slightly elevated (if at all) from typical introductory dosages. This indicates a degree of stability at that dosage that would stretch the plausibility of 'tolerance withdrawal' as an explanation. Not to mention the coincidence that it is supposedly happening at specifically at the same time she is first trying and subsequently reducing the dosage of a drug which has caused evident side effects.
Again, not accurate. The 'kindling' effect is something entirely different, and refers to rapid-onset tolerance withdrawal on a benzo, after previous experience with a different benzo which has already damaged or weakened your system.
There really is NO way to achieve what you call a ' .... steady state of the drug ...' because using benzos damages your system in a uniquely difficult way that absolutely requires increased doses to maintain a ' ...steady effect ...'., since by taking a benzo, you're slowly destroying your own ability to produce GABA, and burning down the GABA receptors in your system, so that the only source of the calming effect of GABA is through benzos. This is why withdrawal of any sort is so overwhelmingly horrible and difficult.
I think you should go and read a little more about kindling. It is not something that necessarily entails 'tolerance withdrawal', and most typically occurs during repeated instances of withdrawal from benzodiazepines (whether the same or different from prior use) or other GABAergic sedatives such as alcohol, barbiturates, etc. There are a host of physiological changes that happening during acute cold-turkey withdrawal from these drugs that, after repeated instances of withdrawal, in aggregate, sensitize neurons in a way that makes withdrawal more severe.
There is not a huge amount of literature on the phenomenon of 'tolerance withdrawal' that I've been able to find but I remember reading the theory that it is related to kindling that occurs on a small scale inter-dose. But again, as I said above, I can't find much information about 'tolerance withdrawal' in general so feel free to link me to something which substantiates anything about the subject.
The main challenges in achieving a steady state of benzodiazepine merely have to do with how quickly the body eliminates the drug and how often the patient can feasibly dose. Now, whether a steady state ameliorates the issues you are talking about is a somewhat different thing.
Tolerance to benzodiazepines is more tied to a reduction in GABA-A receptor expression than a reduction of GABA synthesis, as far as I know, but in any case these reductions are tied homeostatically to the increased efficacy of GABA at GABA-A receptors for a given steady state of benzodiazepine. Obviously there's still a liability in that the dosage could be interrupted, and also subtle biochemical changes in other aspects of the brain related to this new homeostasis, but not anything that drastically changes the excitatory/inhibitory balanace. Of course the situation is, in truth, more complicated anybody could sum up in 1 paragraph but I feel like this covers the main gist. This is a good literature review on mechanisms of benzodiazepine tolerance, if you care to investigate -
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321276/
Actually, it's just the reverse. Dosing inconsistently, as in only when you need it and in small amounts, avoids the destruction of your own GABA production and the retention of most, if not all, of your system's GABA receptors, and gives your brain time to rebalance after the interim and occasional use of a benzo.
People who abuse the drug usually do so in a desperate attempt to get relief from the effects of tolerance withdrawal, which are identical to cold-turkey withdrawal, tho slightly less in initial intensity.
This is a huge misconception - dosing inconsistently is the exact trigger for the kindling phenomenon, as is seen strikingly more often in, say, binge-drinkers who are dosing as inconsistently as possible, essentially withdrawing fully before their next dosage. Please go read even the Wikipedia article on kindling. It's true that you will get a homeostatic tolerance to any GABAergic sedative with consistent dosing, but aside from the general loss of receptor expression, there is less change than you might expect, compared with the essentially traumatic (physiologically, that is) experience of abrupt withdrawal which results in kindling. Someone who very gradually weans down from a single, even if prolonged, course of benzodiazepines stands a great chance of more-or-less full recovery in a way that someone with kindled neurons does not.
That's the half-life of actually metabolizing both the drug itself, and its inactive ingredients. It's effective half-life as an anxiolitic is more like 4 to 5 hours, decreasing rapidly from that point. This is why lorazepam is prescribed with at least 2, usually 3, and more occasionally 4, doses a day. It's also what makes it one of the more dangerous benzos, along with Xanax, which is much worse, and is even shorter in effect, though its onset is faster.
I think you are misunderstanding the concept of 'half-life'. A drug's half-life is, by definition, the time it takes for its concentration to be halved, which can be further specified in terms of its concentration in the blood, or a certain tissue, or say based on the amount of drug metabolites excreted totally, etc. This is, in most cases and in this case specifically, essentially unrelated to the inactive ingredients of the drug - an oral dosage of lorazepam powder, say, is not going to result in pharmacodynamics different from the drug in pill form. The whole thing breaks down pretty rapidly in the stomach, and there is little change to the rest of the ADME (absorption/distribution/metabolism/excretion).
It is also pointless to use 'half-life' in reference to the drug's subjective effects, as half-life is, by definition, quantitative. What you are calling lorazepam's 'effective half life as an anxiolytic' is what most people would just call the drug's duration. The subjective duration of a drug may be extremely different from its biological half-life. For a habitual user of cannabis, e.g., the half life of THC is like a week, but obviously the subjective duration of a single dosage of cannabis for that user would probably be a only a couple of hours (depending on the size of the dosage, of course).
So while the subjective effects of lorazepam may not be very long, and I would imagine this is especially so in tolerant users, this is only indirectly related to the drug concentration and half-life, which is an objective phenomenon, and importantly, the one that fundamentally affects the biological processes that underlie tolerance and withdrawal.
Also, for the record, 12 hours is usually considered a 'moderate' length half-life. There are many benzos with shorter half lives, such as midazolam, triazolam, brotizolam, alprazolam (slightly shorter), etc. Though some of those are not typically prescribed in a regimen for this exact reason.
Nor did I say that it did. I said that it might be triggering a problem with serotonin
And while Kratom doesn't usually cause serotonin syndrome on its own, it can be a strong contributory factor.
Along with it's action on opioid receptors, it acts on the release of serotonin and norepinephraine at lower doses, and produces opioid and benzodiazepine-like sedative effects like pain relief, relaxation, and a mild euphoria, which is one of the reasons that it's being looked at more closely for the relief of depression and anxiety.
Kratom inhibits a broad spectrum of the CYP450 hepatic isozyme system, inhibiting CYP2C9, CYP2D6, and the most prevalent and utilized pathway, CYP3A, with the most potent pathway being the CYP2D6, which is the least-traveled in benzo metabolizing.
Because of kratom’s affinity for serotonin and norepinephrine receptors, it stands to reason that it’s a solid player in serotonin syndrome, particularly when coupled with other drugs that affect serotonin.
Again @Alex113 , I think your sister is on a difficult-to-manage cocktail of drugs, some of them fighting with each other, others potentiating each other, and all-in-all, making for potential problems down the road. And I still believe that what she's experiencing now seems a lot like tolerance withdrawal from the lorazepam, which will most likely only get more severe.
The effect of kratom alkaloids on serotonin is de minimis. I have not seen any research which really shows it to significantly release or inhibitor the reuptake of serotonin, and the only interaction with the serotonin system by mitragynine appears to be as a 5-HT2A antagonist, an action which, as I mentioned before, is actually somewhat protective against serotonin syndrome.
I think a lot of the confusion on this point is due to this one paper which described kratom's antinociceptive properties as involving "both descending noradrenergic and serotonergic systems" (
https://www.sciencedirect.com/science/article/abs/pii/S0014299996007145). However, this was suggested on the basis of behavior changes in kratom-dosed mice after subsequently being treated with cyproheptadine, reserpine, idazoxan, etc., all drugs either selective for norepinephrine or with effects so broad that they are almost meaningless. If anything, these results to me suggest an effect on norepinephrine, but in no way necessarily on serotonin without other evidence. It's actually a good paper, and perhaps is a good guidepost to future directions in kratom research, but the mere mention of serotonin had people suddenly declaring it was definitively involved. Almost every article or paper I've seen repeating that ends up pointing back to this one paper.
Perhaps people are also eager to swallow the serotonin myth because of kratom's unusual effects. It is clearly different from other opioids, being particularly benign or wholesome in comparison, and it is not entirely clear why. I think some of this probably has to do with norepinephrine, but I think a lot of these differences are due to the lack of beta-arrestin recruitment, which has been shown to modify opioid effects to a great degree in other drugs.
All of that, and of course, the aforementioned possibility that kratom can contribute to serotonin syndrome in that it effects drug metabolism, but again, this does not seem to be a factor in this case. I have not seen a single case of serotonin syndrome in the literature which could not be attributed to this specific interaction or where serotonin syndrome seemed a likely outcome regardless of kratom usage.
For this case, maybe there is an additive effect between kratom and mirtazapine in their matching 5-HT2A antagonism, or adrenergic effects, but neither of these are much related to serotonin syndrome.
I think we could probably rule out serotonin syndrome entirely on the basis of symptoms, at this point. If
@Alex113's sister does not have some significant configuration of fever, pupil dilation, sweating, overactive reflexes, nausea/diarrhea, etc., then there is no need to discuss further, I think.
