One other thing that has to be taken into account is the potential for Xanax withdrawal symptoms. Doctors almost always encourage a gradual tapering, which means you would slowly decrease the amount of Xanax being taken.
By doing this it allows the body time to naturally shift its own chemicals to the previous levels from before Xanax was being taken. Some of the possible withdrawal symptoms from suddenly stopping Xanax can be very serious:. Whether someone is taking Xanax with or without a prescription, the dangers of suddenly stopping are very real. Doctors should provide extensive information about possible interactions with other medications as well as what to do if tolerance increases.
Taking Xanax without a prescription is incredibly dangerous for several reasons, as we discussed above. This means a person who has decided to take Xanax without a prescription is walking into a scenario that can spin out of control at any moment. If a person thinks they should just stop taking Xanax and everything will be fine, as you just saw, they could end up experiencing horrible side effects.
Finding professional help and treatment for Xanax means taking many things into account , and staying safe during the whole process is one of the most important. Vertava Health has many locations throughout the United States that offer comprehensive and medically supervised detoxification detox.
The road to full recovery from addiction or mental health can have many stops. If a person needs to detox from Xanax then the first step may need to be detox. Questions About Treatment? Call now to be connected with one of our compassionate treatment specialists. As scary as it is to know, a person going through withdrawal from Xanax or another benzodiazepine can in fact experience horrible side effects, including death. The detox program for Xanax could last as short as two weeks or as long as eight, it really depends on many factors related to the individual in treatment, such as the length of their addiction and how much Xanax they were taking.
Along with that, Xanax withdrawal symptoms can in fact last for weeks or even months. The first withdrawal symptoms a person will experience when ceasing to take Xanax can last for anywhere between one and four days. More severe withdrawal symptoms, such as the ones experienced by a person who has been taking Xanax for much longer, could last anywhere from a couple of weeks to a month.
All of these reasons are why the medically supervised detox offered at a professional treatment center like Vertava Health is so important. Not only is medical staff available to help keep a person safe and comfortable during the process of detox, but qualified doctors are as well.
The combination of these therapies with medically supervised detox will help set up a successful recovery, one that is focused on long-term health and wellness, rather than simply fixing the current situation. The good news is there are people who will listen, who are always ready to talk and extend a hand to help guide someone through addiction and into long-term recovery. Finding a recovery program that is dedicated to helping overcome each obstacle may seem daunting.
Vertava Health is here to show you how strong you are and help you find the path through those obstacles, all the way to lifelong recovery. However, from the presented evidence it is difficult to conclude that benzodiazepines indeed produce a robust and reproducible tolerance for all side effects. It is clear however, that benzodiazepine tolerance is not a uniform process for all clinical effects and does not apply to all available benzodiazepines.
However, it is not known which factors predict whether a certain benzodiazepine possesses the potential to produce tolerance. Unfortunately, many studies address the physical dependence of benzodiazepines and their abuse potential, but do not specifically investigate tolerance. Decades of research into the molecular effects of long-term benzodiazepine treatment have already importantly advanced our understanding of tolerance and several excellent reviews on this topic have already been published [ 5 , 11 , 34 , 77 ].
The general assumption is that chronic benzodiazepine use leads to compensating changes in the central nervous system. This way, the GABA A receptor may become less responsive to the continuing acute effects of benzodiazepines, either as a result of adaptations in the GABA A receptor itself, intracellular mechanisms, or changes in other neurotransmitter systems, such as the glutamatergic system. Although adaptive processes probably play an important role, it is important to realize that the development of tolerance is not uniform for all its actions, and differences between preclinical and clinical tolerance development may exist.
Therefore, the possibility that not one but multiple adaptive mechanisms simultaneously coexist complicates research into benzodiazepine tolerance. Moreover, these adaptive changes could be limited to one or more specific brain areas. This makes it very challenging to single out one a priori unifying mechanism underlying tolerance. In support, a study in rats using 2-deoxyglucose quantitative autoradiography showed that during chronic diazepam treatment, heterogeneous tolerance to the diazepam-induced reduction of glucose utilization occurred in the brain, depending on treatment duration and brain region [ 6 ].
Whereas acute diazepam administration resulted in reductions in glucose utilization throughout the brain, 3 days of diazepam treatment led to tolerance in brain structures associated with sensory processing parietal cortex, auditory cortex, cochlear nucleus which was interpreted to correlate with reduced sedation.
After day diazepam treatment, tolerance to the depressant effect of diazepam on cerebral glucose occurred in the mamillary body, subiculum, and caudate nucleus, whereas changes in the frontal cortex approached significance. Of particular interest is the finding that none of the amygdaloid nuclei showed any blunting over time, in line with persistent anxiolytic effects of benzodiazepines.
Before taking a closer look at specific mechanisms that have been proposed to underlie benzodiazepine tolerance, it is important to note that pharmacokinetic factors probably do not play a major role in the development of tolerance [ 81 ]. In support, plasma levels after acute diazepam administration did not differ between chronically alprazolam-treated and untreated panic disorder patients, even though sedative and amnesic tolerance was observed [ 40 ].
The most obvious candidate to mediate the adaptive changes in cellular and synaptic function after chronic benzodiazepine treatment is the GABA A receptor. One explanation for a loss of benzodiazepine function is a loss in GABA A receptor allosteric coupling. Benzodiazepines are generally referred to as positive allosteric modulators PAMs because their binding alters the GABA A receptor conformation with an increased capacity to bind GABA, leading to increased channel opening frequency, increased chloride influx, and, consequently, to hyperpolarization.
In terms of tolerance development, it has been hypothesized that chronic treatment affects the benzodiazepines' capacity to pharmacologically enhance the GABA response i. The receptor uncoupling hypothesis is attractive as it does not assume any changes in subunit expression and ligand binding yet uses the knowledge on the specialized functions of the GABA A receptor and the different subunits.
However, the uncoupling process is an aspecific process as it can be induced by exposure to different classes of GABA A receptor modulators acting at different modulatory sites, such as neurosteroids and barbiturates [ 82 ]. Also, more recent indications for reduced allosteric coupling were found after chronic treatment using transfected cell lines that express GABA A receptors or in neurons [ 84 — 94 ].
The mechanisms underlying possible differences in coupling remain poorly understood. To our knowledge, no studies exist which have directly investigated GABA A receptor subunit composition after chronic exposure. GABA A receptors are phosphorylated by various protein kinases and dephosphorylated by phosphatases [ 95 ]. Dynamic functional alterations in GABA A receptor phosphorylation status may directly affect the inhibitory synaptic strength, with changes in channel openings or indirectly influence receptor trafficking.
However, the precise effects of phosphorylation on neuronal GABA A receptor function are complex, even though key residues within the intracellular loop of the GABA A receptor seem of particular importance.
Also, PKA activity was found to be directly involved in changed GABA A receptor functioning in hippocampal pyramidal cells following chronic flurazepam treatment [ 97 ]. Probably, phosphorylation patterns rather than individual sites are of importance, supported by the finding that mutation to one PKA phosphorylation site is not involved in tolerance [ 90 ]. Unfortunately, no chronic treatment was included in these studies. It remains to be seen whether changes in allosteric coupling are relevant to the development of tolerance in vivo.
Because benzodiazepine tolerance gradually develops over days to weeks, this would suggest that structural changes take place, whereas posttranslational compensation would be expected to be directly manifest. In support, uncoupling seems to develop rapidly, with the classical benzodiazepine chlordiazepoxide applied together with GABA stimulating the rate and extent of desensitization produced in a single neuron within several seconds [ 99 ].
Also, the observed uncoupling after chronic benzodiazepine treatment is rapidly reversed by a brief exposure in vivo to the benzodiazepine antagonist flumazenil [ 83 , 86 ].
The most straightforward hypothesis to explain impaired sensitivity after chronic benzodiazepine exposure would be a general downregulation of GABA A receptors throughout the brain.
Already earlier in Section 2. If receptor internalization simply downregulates GABA A receptor density, then a priori regional differentiation would be expected based on receptor distribution. The processes that control the assembly, membrane trafficking, and synaptic accumulation of GABA A receptors are complex for review, see [ ].
In short, GABA A receptors are assembled from individual subunits out of the endoplasmic reticulum within minutes after their translation, with amino acid sequences in the N-terminus influencing the GABA A receptor subtype Figure 2. Ultimately, clathrin-dependent endocytosis occurs after receptor dephosphorylation, after which degradation or recycling may ensue Figure 2. If prolonged activation of the GABA system leads to receptor downregulation, then this could be established by interfering at multiple steps of the dynamic GABA A receptor life cycle.
These include decreased subunit mRNA transcription, subunit degradation in the endoplasmic reticulum e. The finding that the protein synthesis inhibitor cycloheximide and the RNA synthesis inhibitor actinomycin D blocked the effects of chronic diazepam exposure in recombinant cells expressing GABA A receptors indicates that GABA A receptor synthesis is of at least some importance [ 87 ].
Unassembled GABA A receptor subunits that are to be targeted for ER-associated degradation are ubiquitinated and degraded in the proteasome. GABA A receptors are inserted at extrasynaptic sites and can diffuse along the plasma membrane in and out of synaptic domains. At synapses they are stabilized by an interaction with the scaffolding protein Gephyrin.
GABA A receptors are delivered by a clathrin-mediated pathway to early endosomes where they can be targeted for degradation in the lysosome or for recycling upon binding of Huntington-associated protein HAP1.
Reprinted by permission from Elsevier, reprinted from [ ]. Up to now, a plethora of studies have tried to address whether chronic benzodiazepine treatment indeed affects GABA A receptor expression and thus benzodiazepine binding sites using compounds with different subtype selectivity profiles at different doses and varying treatment duration.
A recent excellent review summarized all data on the regulation of GABA A receptor subunit after chronic benzodiazepine treatment that was mostly studied in rats [ ]. It is beyond the scope of this review to repeat the meticulous work laid down in this paper. This paper confirms that both for mRNA and protein subunit levels, the available evidence leads to a divergent and sometimes conflicting picture, although the majority of the studies essentially do not show any significant difference in subunit expression [ ].
Furthermore, a lack of consistency appears for subunit changes in different specific brain areas. Moreover, the length and method of chronic treatment seem relevant since differences in GABA A receptor subunit mRNA levels after chronic diazepam treatment in rats can depend on whether diazepam is administered as daily systemic injections or via osmotic minipumps [ ].
Binding studies also generally report no changes in benzodiazepine binding after chronic treatment [ 92 , 93 , ]. Thus, a general central downregulation or even consistent region-specific changes in GABA A receptor expression after chronic benzodiazepine use are not supported by the literature. Even though methodological differences e. Moreover, molecular results are often not combined with behavioral tests, preventing a direct correlation between behavioral tolerance and molecular changes.
Clinical studies applying in vivo binding or postmortem GABA A receptor expression after chronic benzodiazepine treatment are to the knowledge of the authors lacking.
Changes in rates of GABA A receptor endocytosis, receptor membrane insertion, intracellular trafficking, and association with helper GABA A receptor-associated proteins could still play a role, leading to a reduction in membrane surface receptors without affecting overall subunit protein expression e.
Another interesting suggestion is that a possible loss of synaptic function after chronic exposure could be due to a shift to a perisynaptic or even an extrasynaptic localization of GABA A receptors, away from clustering of GABA A receptors at synapses Figure 2 [ ].
At least in alcohol research, such dynamic changes in plasticity at inhibitory synapses have been shown [ ]. Moreover, it cannot be excluded that particular subunits play a role in the development of tolerance after chronic treatment in the absence a direct up- or downregulation.
Moreover, only tolerance to the sedative effects of diazepam was reported. Thus, it may still be possible that tolerance to other benzodiazepine effects is mediated by other subunits. From the previous sections, we conclude that compensatory changes solely arising from the GABA system may at most partially explain the tolerance arising following chronic treatment with benzodiazepines.
Glutamate is an excitatory neurotransmitter acting on glutamate receptors. Together with the GABA system, they constitute the two fast-acting and opposing neurotransmitter systems that can modulate synaptic plasticity. In support, close neuroanatomical connections exist between GABAergic and glutamatergic neurons [ , ]. Therefore, it is not surprising that as these two opposing and fast-acting neurotransmitter systems form a delicate balance, chronic increased activation of the GABAergic system during benzodiazepine treatment may pertubate glutamatergic transmission.
The basis of benzodiazepine tolerance could then lie in sensitization of the glutamatergic system—a putative process that could account for the withdrawal symptoms after chronic benzodiazepine discontinuation [ 5 , ]. Such sensitization is reminiscent to adaptive glutamatergic processes as seen in kindling experiments, although it should be noted that kindling only occurs with intermittent and not after continuous treatment [ ]. Glutamatergic sensitization could thus play a role in the development of tolerance as well as withdrawal symptoms upon cessation of treatment.
Glutamatergic changes after benzodiazepine withdrawal will not be discussed here, but there are indications that the glutamatergic system plays a role in withdrawal states with accompanying increases in anxiety and seizure activity for review see [ 5 ]. However, glutamate receptor mRNA and protein changes may be dynamic during withdrawal, with unchanged levels during the early phase of withdrawal but changes occurring several days later [ ].
This consequently complicates the interpretation of withdrawal studies and their significance for our understanding of benzodiazepine tolerance. Similar to the GABAergic system, the glutamate system is diverse and complex, generally being divided into ionotropic and metabotropic receptor types.
Three classes of the ionotropic glutamate receptor occur in het central nervous system: the NMDA receptor N-methyl-D-aspartate , the AMPA receptor alpha-aminohydroxymethylisoxazolepropionic acid , and the kainate receptor for a recent review see [ ]. AMPA receptors are widespread heterotetrameric ligand-gated ion channels composed of four types of subunits GluR 1—4 , and are crucial to long-term synaptic plasticity such as long-term potentiation for review see [ ].
Relevant to this review, a study showed that AMPA receptor desensitization was caused by a rupture of a domain interface which allowed the ion channel to close, providing a simple yet elegant explanation [ ]. Several studies have addressed the compensatory glutamate sensitization hypothesis during chronic benzodiazepine exposure to account for the development of tolerance as reviewed by [ 5 , ].
In rodents, the development of tolerance to the sedative effects of the classical benzodiazepines diazepam and chlordiazepoxide was prevented by coadministration of the NMDA receptor antagonists CPP, dizocilpine, MK, and ketamine [ — ]. Also, lorazepam-induced tolerance to its acute anticonvulsant effects was partially prevented with simultaneous CPP treatment [ ]. In contrast, the development of tolerance to the anxiolytic effects of diazepam in a social interaction test was not blocked by concomitant administration of dizocilpine [ ].
This suggests that the mechanism underlying tolerance to the anxiolytic effects of diazepam is different from that underlying tolerance to the sedative effects.
However, another study showed decreases in hippocampal NR 2B subunits after chronic flurazepam treatment, even though the total amount of NMDA receptors was unchanged [ ]. In support, after long-term but not acute lorazepam treatment, no differences were found in the affinity or density of NMDA receptors, even though increased in vitro glutamate release and NMDA-induced cGMP efflux in the hippocampus was reported [ ].
Together, these data suggest that NMDA-dependent mechanisms contribute to the development of benzodiazepine tolerance. However, as anxiolytic tolerance was not blocked by NMDA receptor antagonism, the NMDA system could also play a differential role in tolerance depending on the specific behavioral effects [ ].
Even though the AMPA receptor antagonist GYKI did not affect the development of tolerance to the sedative effects of diazepam [ ], changes in AMPA receptor subunits have been reported to be altered after long-term benzodiazepine exposure [ ]. Specifically, significant reductions of mGLuR1 cortex and amygdala and mGluR2 mRNA amygdala were reported in rats treated chronically with diazepam, even though the effects were complex and dependent on treatment route subcutaneous or intraperitoneal injections.
A genetic approach with GluR 1 knockout mice showed that after subchronic flurazepam treatment, these mice developed a reduced and incomplete tolerance to the muscle relaxation and sedative effects of flurazepam, even though acute flurazepam effects were comparable between knockout and wild-type mice [ ].
With regard to glutamatergic kainate receptors, we found no pharmacological or genetic studies investigating the development of tolerance. Together, the evidence does not support a universal and replicable glutamatergic component, even though there are indications that NMDA receptor blockade can prevent tolerance to at least some behavioral benzodiazepine effects.
However, molecular data are diverse and sometimes inconsistent, which are reminiscent of the molecular changes in the GABA system after chronic benzodiazepine treatment see Section 4. Although the hypothesis that downstream signaling events adjust in response to chronic exposure to benzodiazepines seems plausible, a surprising paucity of data exist in this field.
In addition, changes in intracellularly located cAMP-response-element-binding protein CREB or calcium, vital in various second messenger systems, could be altered, and prolonged GABA concentrations in a neuronal culture have been shown to affect voltage-gated calcium channels [ ]. However, until further studies provide additional proof for chronic benzodiazepine-induced downstream intracellular changes, the evidence that this process plays a role is inconclusive.
Neurotrophic proteins support neuronal survival, synaptic growth, and differentiation throughout the brain via tyrosine kinase receptors Trk and, with lower affinity, via p75 receptors p75NTRs [ ]. Since they act as potent factors in regulating fast synaptic inhibition, adaptations leading to tolerance following chronic benzodiazepine treatment could in part be mediated via these neurotrophic factors.
This reduced immunoreactivity was hypothesized to be caused by a reduction in GABA A receptor surface expression and was accompanied by reduced postsynaptic responses with the direct GABA A receptor agonist muscimol [ ]. Interestingly, all these proposed mechanisms were already discussed in this paper.
Thus, neurotrophin-induced changes may not be an independent mechanism, but be a player in a causal chain of events. Again, to our knowledge, no studies exist on the effects of chronic benzodiazepine treatment on neurotrophic expression and functionality. There is ample evidence that the serotonin, dopamine, and acetylcholine receptor systems can modulate the GABA A receptor functionality [ — ] Figure 3.
Functional crosstalk between G-protein coupled receptors GPCRs which are present in the serotonin, dopamine, acetylcholine system and GABA A receptors is facilitated through multiple protein kinases and scaffold proteins. Finally, the functional effects of phosphorylation are diverse and range from inhibitions to enhancements of GABA A receptor activity, dependent upon the receptor subunit composition.
Reprinted by permission from Elsevier, reprinted from [ 95 ]. However, studies investigating the role of the serotonin, dopamine, and acetylcholine system in response to chronic benzodiazepine treatment are scarce. Another study showed that chronic diazepam treatment resulted not only in diazepam tolerance but also in a very modest reduced efficacy of the 5-HT 1A receptor agonist 8-OH-DPAT to induce flat body posture and forepaw treading [ ].
In contrast, only acute but not chronic diazepam treatment decreased basal extracellular dopamine levels in rats, even though both acute and chronic treatment regimens could reverse the stress-induced rise of cortical dopamine levels [ ].
There is ample and convincing evidence that neurosteroids are endogenous allosteric regulators that interact with GABA A receptors to modulate both tonic extrasynaptic and phasic synaptic inhibition for reviews, see [ , ].
In light of the plasticity-inducing actions of neurosteroids on inhibitory signaling, long-term enhancement of the GABA system with benzodiazepines may in turn evoke changes in the neurosteroids system such as changes in neurosteroid synthesis and metabolism, although classical benzodiazepines may differ in their potency to cause such changes [ ].
In support, ovariectomy attenuated the development of tolerance to the anticonvulsant actions of diazepam [ ]. Moreover, co-administration of the neurosteroids allopregnanolone or pregnenolone but not dehydroepiandrosterone prevented the development of tolerance after chronic treatment with either triazolam and diazepam [ ]. Adding to the complexity of the putative involvement of neurosteroids in benzodiazepine tolerance, factors such as GABA A receptor subunit composition, phosphorylation mechanisms, and extra synaptic localization—which are all factors that were already found to be involved in tolerance development—influence the specific dynamics of neurosteroid activity.
From our review of the literature on the various mechanisms that may underlie benzodiazepine tolerance, it occurs that there is a considerable variance in the published data. The heterogeneity of the data lies in the application of different methodologies, species, treatment regimens, and benzodiazepines. However, in vivo pharmacodynamic potency and pharmacokinetic half-life differences could greatly impact on tolerance processes [ 7 ].
Surprisingly, chlordiazepoxide did not lead to any precipitated seizures, even though a comparable GABA A receptor occupancy was obtained. Therefore, the assumption that classical benzodiazepines act as a homogeneous class probably complicates the interpretation of the current literature.
Altogether, it appears that none of the proposed putative mechanisms can sufficiently explain tolerance development.
Thus, multiple mechanisms may synergistically coexist, or an additional yet undiscovered mechanism may be present. However, the complex and adaptive nature of the GABA system and the existing heterogeneous literature on benzodiazepine tolerance suggest that one unifying tolerance mechanism may be a vast oversimplication.
In any case, the proposed tolerance mechanisms are not completely independent, exemplified by the fact that neurotrophic factors and neurosteroids are influenced by GABA A receptor composition and phosphorylation status, which are themselves proposed to be involved in benzodiazepine tolerance.
Unfortunately, the present literature does not consistently support a clear recommendation in terms of a pharmacological GABA A receptor profile e.
Here, we will review the evidence for tolerance development with novel GABA A receptor subtype selective compounds that provide the direct opportunity to evaluate their roles in tolerance. With the development of subunit-selective benzodiazepines, it has become possible to dissect the different effects of classical benzodiazepines see Section 2.
Still, if novel drugs possess reduced propensity to lead to tolerance development, this will be greatly welcomed from a clinical perspective. Continuing efficacy with these drugs would advance the clinical use of drugs acting at the GABA A receptor benzodiazepine site. Unfortunately, not many studies have directly addressed tolerance development using these novel compounds.
In addition to studies directly assessing tolerance, several studies have investigated the precipitated withdrawal after sub chronic treatment with subtype-selective compounds. However, because these studies do not specifically address tolerance development, the rather general conclusion from these studies is that partial or selective modulation of the GABA A receptor results in a reduced liability for physical dependence.
Thus, it is important to note that, even though zolpidem does not seem to engender any obvious tolerance development, zolpidem can lead to withdrawal symptoms that are comparable to those seen after chronic classical benzodiazepine treatment [ 29 , 77 ]. Thus, tolerance and withdrawal symptoms may constitute separate entities in benzodiazepine dependence. In support, one study demonstrated that marked withdrawal symptoms appeared upon abrupt discontinuation of chronic clorazepate treatment in dogs, even though tolerance was present to a rather limited extent [ ].
This would constitute a significant improvement over currently used benzodiazepines, even though the anxiolytic profile of these compounds remains to be determined [ ], and abuse liability may still be present [ 8 ]. However, interpretations should be made with caution since chronic treatment with nonselective partial positive allosteric modulators such as bretazenil did neither result in anticonvulsant tolerance [ 54 , 59 , 60 ] nor in FGprecipitated seizures [ ].
These studies implicate that the potency of classical and subtype-selective compounds, in addition to or despite subtype selectivity, may also be of importance in the development of tolerance.
In addition to a specific efficacy profile, tolerance development may also depend on a compound's affinity at certain GABA A receptor subtypes. This way, tolerance processes may be different with affinity-selective compounds such as zolpidem compared to efficacy-selective compounds such as TPA However, based on the currently available evidence, no definite conclusions can be drawn regarding the subtype involved in tolerance.
Also, it is not possible to distinguish tolerance processes in selective binding affinity and selective activation efficacy. In the present paper, we summarized the rather inconsistent data regarding changes in several neurotransmitter systems to explain the development of tolerance. Specifically, we addressed possible changes at the level of i the GABA A receptor subunit expression and receptor coupling , ii intracellular changes stemming from transcriptional and neurotrophic factors, iii ionotropic glutamate receptors, iv other neurotransmitters serotonin, dopamine, and acetylcholine systems , and v the neurosteroid system.
From the large variance in the studies, it appears that either different simultaneous tolerance mechanisms occur depending on the benzodiazepine effect, or that one tolerance-inducing mechanism depends on the activated GABA A receptor subtypes. This is not unlikely, given that tolerance is a heterogeneous process that occurs at different rates for the various effects and also depends on the profile of the subtype selective benzodiazepine. Adaptations could then occur on different time scales depending on the receptor subtype and brain region involved.
In line with this hypothesis, tolerance develops relatively quickly for the sedative and anticonvulsant actions of benzodiazepines, whereas tolerance to anxiolytic and amnesic effects most probably do not develop at all. It is intriguing that anxiolytic effects of classical benzodiazepines may not decline during prolonged treatment. In addition to subtype selectivity, additional factors may be important for a subtype-selective benzodiazepine to cause tolerance, including GABA A receptor potency efficacy and in vivo receptor occupancy over time.
An important question is how the development of tolerance of benzodiazepines could be reduced. One interesting suggestion could be—rather than intermittent use that can be defined by an individual—to develop benzodiazepine dosing schedules with varying daily doses including placebos.
This could result in continued clinical efficacy obviously depending on the indication and utilize the placebo effect. In conclusion, the development of tolerance following chronic benzodiazepine treatment is a complex process in which multiple processes may simultaneously act to cause varying rates of tolerance depending on the studied effect and the administered drug.
There is no convincing evidence that subtype-selective compounds acting at the benzodiazepine site lead to tolerance at a level comparable to classical benzodiazepines.
If this is indeed the case, one consequence may be that such subtype-selective compounds are unlikely to engender clinical tolerance, which would be a clinically significant improvement over classical benzodiazepines.
National Center for Biotechnology Information , U. Journal List Adv Pharmacol Sci v. Adv Pharmacol Sci. Published online Mar Christiaan H. Author information Article notes Copyright and License information Disclaimer. Vinkers: ln. Vinkers and B. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
This article has been cited by other articles in PMC. Abstract Despite decades of basic and clinical research, our understanding of how benzodiazepines tend to lose their efficacy over time tolerance is at least incomplete. In high doses, however, it has the potential to be abused and can lead to dependence addiction. Xanax is taken by mouth and is readily absorbed into the bloodstream. You should start feeling the effects of Xanax in under an hour.
The medication reaches peak concentrations in the bloodstream in one to two hours following ingestion. People who take Xanax will often build up a tolerance. For these people, it may take longer to feel the sedative effects of Xanax or the sedation may not feel as strong. One way to find out how long a drug will last in the body is to measure its half-life.
The half-life is the time it takes for half of the drug to be eliminated from the body. Xanax has an average half-life of roughly 11 hours in healthy adults. In other words, it takes 11 hours for the average healthy person to eliminate half of the dose of Xanax. Studies have shown that the half-life of Xanax ranges from 6. It takes several half-lives to fully eliminate a drug.
For most people, Xanax will fully clear their body within two to four days. This is why you may be prescribed Xanax up to three times per day. The half-life of Xanax is higher in elderly people. Studies have found that the average half-life is For obese individuals, it may be more difficult for your body to break down Xanax. The half-life of Xanax in people who are obese is higher than average.
It ranged between 9. Studies have found that the half-life of Xanax is increased by 25 percent in Asians compared to Caucasians. A higher basal metabolic rate may decrease the time it takes for Xanax to leave the body. People who exercise regularly or have faster metabolisms may be able to excrete Xanax faster than people who are sedentary.
It takes longer for people with alcoholic liver disease to break down, or metabolize, Xanax. On average, the half-life of Xanax in people with this liver problem is Each tablet of Xanax contains 0. In general, higher doses will take longer for your body to fully metabolize.
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