Amitriptyline (brand name “Elavil”) is a drug derived from the chemical dibenzocycloheptadiene that was discovered and approved in the early 1960s for the treatment of major depression. It is formally classified as a tricyclic antidepressant (TCA) and functions principally via inhibiting the presynaptic reuptake of norepinephrine and serotonin. This effect of dual presynaptic reuptake inhibition is thought to improve one’s mood by increasing extracellular levels of aforementioned neurotransmitters, norepinephrine and serotonin.
Additionally, amitriptyline appears to act as a histaminergic receptor and mACh (muscarinic acetylcholine) receptor antagonist, as well as an inhibitor of sodium, calcium, and potassium channels. As a result of its ability to modulate an array of neurotransmitters, amitriptyline is often effective in treating a host of neurological conditions beyond just depression, including: anxiety disorders, migraines, neuropathic pain, and insomnia. Though it is clearly a time-tested antidepressant, many users report unwanted side effects.
Examples of common unwanted side effects associated with amitriptyline include: constipation, dry mouth, somnolence, urinary retention, and weight gain (Read: Amitriptyline & Weight Gain). When considering these side effects, along with the fact that amitriptyline may lose its antidepressant efficacy over an extended term of administration, it’s no wonder that some users discontinue treatment. Should you have decided to quit taking this drug, you may wonder how long amitriptyline stays in your system after your last dose.
How long does Amitriptyline stay in your system?
If you’ve recently discontinued this drug, you may be in for an unpleasant battle with amitriptyline withdrawal symptoms. These symptoms typically emerge as a result of your neurophysiology attempting to recalibrate itself back to functioning without the artificial modulation of critical neurotransmitters. Furthermore, it is important to note that some users may also report lingering side effects upon cessation of amitriptyline treatment.
The combination of withdrawal symptoms and possible lingering side effects may leave you confused, wondering how long it really takes to clear amitriptyline from systemic circulation. To determine how long amitriptyline is likely to stay in your system, it is necessary to examine its elimination half-life. The elimination half-life of amitriptyline is reportedly within the range of 10 to 50 hours, with the average being ~15 hours.
With this information we can estimate that it’ll likely take between 2.29 and 11.5 days to completely rid your system of amitriptyline. That said, in accordance with the reported average half-life of 15 hours, a majority of healthy adults with normative metabolisms should eliminate the drug in approximately 3.44 days following their final dose. However, just because amitriptyline may have been eliminated from your plasma does not automatically ensure that its metabolites were simultaneously cleared.
Amitriptyline is metabolized via oxidative N-demethylation to form the metabolite nortriptyline, which exhibits a longer elimination half-life than its parent (amitriptyline). The elimination half-life of nortriptyline ranges from 16 to 90 hours, suggesting that it will take between 3.67 and 20.63 days to fully clear from your system. This means that to fully eliminate 100% of amitriptyline (and its metabolites) it could take up to 21 days.
- Source: http://pubchem.ncbi.nlm.nih.gov/compound/amitriptyline
- Source: http://pubchem.ncbi.nlm.nih.gov/compound/nortriptyline
Variables that influence how long Amitriptyline stays in your system
It is important to realize that the speed by which you are able to metabolize and eliminate amitriptyline, along with its chief nortriptyline metabolites, will be dictated by a multitude of variables. It is these variables that dictate whether one individual is likely to clear amitriptyline at a faster or slower rate than average from his/her system. Notable variables to consider when contemplating how long amitriptyline is likely to linger in your system include: CYP450 isoenzyme function, individual factors, dosage, term of administration, and co-administered drugs.
CYP2D6 / CYP2C19 metabolism
Perhaps the most important determinant of amitriptyline elimination speed is that of CYP450 (cytochrome P450) allelic expression. Alleles associated with CYP450 genes, namely CYP2D6 and CYP2C19, are known to influence elimination of amitriptyline and its metabolites. Users of amitriptyline carrying one reduced and one non-functional CYP2D6 allele and/or 2 non-functional CYP2D6 alleles will fail to adequately metabolize amitriptyline.
Similarly, those carrying reduced and/or non-functional CYP2C19 alleles will also lack the ability to sufficiently metabolize amitriptyline. This will lead to increased plasma concentrations of amitriptyline and a prolonged elimination half-life. If you’ve taken a genetic test such as “GeneSight” and were noted as being a “poor metabolizer” and/or “intermediate metabolizer” of either CYP2D6 and/or CYP2C19 – amitriptyline may remain in your system for a much longer duration upon cessation.
Fortunately, only a small percentage of users (3% to 10%) will exhibit decreased CYP2D6 and/or CYP2C19 function as a result of their alleles. A majority of individuals (upwards of 70%) will metabolize amitriptyline normally and are hence classified as “extensive metabolizers.” In extensive metabolizers, elimination of amitriptyline and its metabolites should occur within 1 week post-discontinuation, rather than 3+ weeks post-cessation as may occur in a poor or intermediate metabolizer.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/1771652
Although allelic expression is likely the most prominent variable in regards to amitriptyline elimination speed, it is important to consider other factors that could alter its half-life. Assuming two extensive metabolizers simultaneously administered a single-dose of 75 mg, one individual would likely eliminate the amitriptyline from his/her system quicker than the other. In this example that assumes identical phenotypes, dosages, and simultaneous ingestion – differences in elimination speed may be derived from various interindividual factors including: age, body mass, hepatic function, metabolism, and renal function.
Age: It is understood that the elimination half-life of amitriptyline may be protracted in elderly patients (over the age of 65). This prolonged term of elimination is could be due to age-related physiologic changes such as: decreased concentrations of plasma proteins (resulting in distributional changes of amitriptyline and metabolites), declining hepatic function, and diminishing renal function. It is also necessary to state that elderly individuals are more likely to exhibit other health problems, leading to usage of medications that could interfere with amitriptyline metabolism.
One study documented that elimination half-life of amitriptyline among healthy elderly patients averaged 31 hours. This differs significantly from the average among healthy younger adults at ~15 hours. With this information we can estimate that elderly individuals are likely to take longer than 1 week to eliminate amitriptyline from their systems, whereas younger adults may take less than a week.
Other research suggests that elimination half-life of amitriptyline among elderly adults was 21.7 hours, whereas it was just 16.2 hours in younger adults. This suggests that it’ll likely take around 5 days to fully eliminate from the plasma of an elderly adult, but just 3.71 days for a younger adult. Though differences in elimination speed between “young” and “elderly” may not be of major clinical significance, they should be understood.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/2677125
- Source: http://www.ncbi.nlm.nih.gov/pubmed/6825390
Body mass + Fat (%): A user’s body mass and percentage of body fat may influence how long amitriptyline remains in systemic circulation upon discontinuation. It is understood that amitriptyline is highly lipophilic and up to 90% of a dose binds to plasma proteins in-vivo. It is also known that obese individuals with a high percentage of body fat exhibit altered levels of plasma proteins throughout the body, thereby altering amitriptyline’s volume of distribution throughout the body.
Altered distribution may initially lead to expedited elimination of amitriptyline among those with a high body mass index (relative to dosage). However, with frequent/long-term usage, amitriptyline’s lipophilic properties suggest that it is likely to accumulate in fat stores throughout the body. Since individuals with a high percentage of body fat have a greater quantity of fat stores, accumulation of amitriptyline may ensue, prolonging its elimination half-life and slowing the detoxification process.
Hepatic function: Medical literature suggests using tricyclic antidepressants like amitriptyline with caution among individuals with hepatic impairment. Typically, the greater the extent to which an individual is hepatically impaired, the longer he/she can expect to retain amitriptyline (and its metabolites) in systemic circulation. This is due to the fact that hepatic impairment interferes with expression of CYP2D6 and CYP2C19 isoenzymes in the liver.
This interference decreases the efficiency by which amitriptyline is metabolized in the liver, leading to abnormally high spikes in amitriptyline plasma concentrations. This in turn triggers adverse reactions because there’s a greater amount of unmetabolized amitriptyline circulating throughout a user’s system. For this reason, it is thought that individuals with hepatic
In essence, this interference prevents amitriptyline from getting efficiently metabolized and leads to abnormally high spikes in amitriptyline plasma concentrations. The high plasma concentrations and hepatic accumulation of amitriptyline generally trigger adverse reactions and/or side effects, while also prolonging its elimination speed. It is likely that certain individuals with severe forms of hepatic impairment may exhibit half-lives near 50 hours, the slower end of the spectrum.
Metabolism: When most professionals discuss an individual’s ability to metabolize drugs, they are referring to genetic variants that impact isoenzyme function; in the case of amitriptyline they would be referring to CYP2D6 and CYP2C19 function. That said, your basal metabolic rate (BMR) can also have a slight effect in how quickly you metabolize and excrete exogenous substances such as amitriptyline from your body. Your BMR is indicative of how much energy your body is burning in a resting state.
Individuals with a high BMR tend to burn more energy at rest, which also leads to faster elimination of drugs from systemic circulation. This is perhaps best evidenced from studies analyzing patients with hyperthyroidism, discovering that drugs are eliminated at a substantially quicker rate – in part due to higher BMR. Contrarily, lower-than-average BMR indicates that less energy is being used in a resting state, which may slightly increase elimination half-life of amitriptyline.
Renal function: If you exhibit impaired renal function, the elimination half-life of amitriptyline may be subject to alteration. Although research was unable to find significant differences between the elimination half-life of amitriptyline between healthy volunteers and those with renal impairment, they discovered major fluctuations in elimination half-life among those with renal impairment. This suggests that in general, those with renal impairment are no more likely to retain amitriptyline for a longer duration than those without impairment.
However, from an individual perspective, it was discovered that renal impairment resulted in major variations in elimination half-life. Furthermore, it is known that formation and circulation of various secondary metabolites differ among those with renal impairment compared to those with normative kidney function. Though it cannot be generalized that renal impairment increases time of amitriptyline retention, it may expedite or protract elimination of amitriptyline in certain individuals – likely contingent upon degree of renal impairment and other factors.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/4049459
- Source: http://www.ncbi.nlm.nih.gov/pubmed/3971655
Urinary pH: The pharmacokinetics of amitriptyline are dependent upon the user’s urinary pH. It is known that acidification of urinary pH can increase renal excretion of both amitriptyline and its nortriptyline metabolite. Research shows that when urine is made very acidic to a pH of “4,” renal excretion of amitriptyline and its nortriptyline metabolites may increase up to 1000-fold.
Therefore, it should be considered that the more acidic your urinary pH, the quicker you are likely to eliminate amitriptyline from systemic circulation. On the other hand, the more alkaline your pH (as evidenced by a higher number), the longer you may retain amitriptyline and its metabolites. Much of urinary pH is contingent upon dietary intake; those who eat acidic foods may eliminate amitriptyline faster than those on a highly alkaline diet.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/3015809
Dosage (High vs. Low)
The dosage of amitriptyline that you take may affect how long it stays in your system. If you were to take a dose of 75 mg, it would likely take less time to eliminate from systemic circulation than if you took a dosage of 300 mg. This is due to the fact that upon administration of a large dosage, isoenzymes (CYP2D6 and CYP2C19) within the liver are taxed to a greater extent than they would be at a low dose.
In other words, hepatic isoenzymes need to work harder to metabolize a greater load of an exogenous substance (in this case amitriptyline). Furthermore, upon metabolism of the larger dose, a greater amount of the parent drug circulates throughout the body along with increased levels of nortriptyline metabolites. The greater the quantity of amitriptyline (and metabolites) that enter plasma circulation, the greater the level of volume distribution and tissue accumulation can be expected (largely due to its lipophilicity).
Additionally, it is necessary to consider that higher doses yield a greater number of metabolites that accumulate in the kidneys to be excreted. A high number of these metabolites could interfere with the efficiency of renal excretion, possibly leading to reabsorption and recirculation throughout the body. The combination of hepatic burden, accumulation propensity, increased distribution, and possibly decreased renal efficiency may protract elimination among high-dose users.
Case studies suggest that high doses may be substantially increase elimination half-life of amitriptyline among those considered “poor metabolizers” (as a result of CYP2D6 or CYP2C19 expression). One such study documented a comatose female who overdosed and exhibited increases in amitriptyline plasma concentrations for 6 consecutive days, reaching a pinnacle on the sixth day. To put this in perspective, many individuals at normal doses would have completely eliminated the drug from systemic circulation when this woman had just attained peak plasma levels.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/21614669
Term of administration
The total term over which you’ve been taking amitriptyline may affect how long it stays in your system. Individuals that take amitriptyline for just 1 or 2 days are likely to eliminate the drug from systemic circulation quicker than those that have administered amitriptyline for between 3 and 8+ days. This is largely due to the fact that users of the drug for less than 3 days are unlikely to have attained steady state concentrations of amitriptyline in the plasma.
Steady state concentrations of amitriptyline are attained within the span of 3 to 8 days (for most users). If you’ve attained steady state plasma concentrations of the drug, expect to retain it in your system for longer than someone who hasn’t. Among a user that discontinued after just one or two doses (equivalent to 1 or 2 days) an insufficient amount of the drug will have accumulated in the plasma to prolong elimination half-life within the normal 10 to 50 hour range; single-dose users may exhibit half-lives of less than 10 hours.
Additionally, it is necessary to consider that long-term users of amitriptyline are likely to have built up tolerance to the effects of low doses. After an extended term of daily administration, an individual’s neurophysiology will no longer be responsive to the low dose, which in turn may lead to an upward titration in dosing. As a result of the increased likelihood of higher doses in long-term users, we can surmise that they’d be more likely to retain the drug for a longer duration, primarily based on increases in dosing and possibly tissue accumulation of metabolites.
If you co-ingested any drugs (or supplements) along with amitriptyline, there’s a chance that its metabolism may be altered. Alterations in metabolism as a result of co-administered drugs can radically increase and/or decrease elimination half-life of amitriptyline depending on how they affect CYP450 enzyme function. Since amitriptyline is principally metabolized via CYP2D6 and CYP2C19 isoenzymes, any drug that serves to inhibit or induce function will alter the half-life of amitriptyline.
A CYP2D6 or CYP2C19 inhibitor is known to interfere with isoenzyme function, leading to poorer metabolism of amitriptyline. In the event that an agent prevents optimal metabolism of amitriptyline, its plasma concentrations, distribution, and half-life will be increased. Examples of some notable CYP2D6 inhibitors include: Bupropion, Cinacalcet, Fluoxetine, Paroxetine, Quinidine, and Ritonavir. Examples of CYP2C19 inhibitors include: Chloramphenicol, Fluoxetine, Fluvoxamine, and Moclobemide.
Should you have co-ingested any aforementioned inhibitors (especially Fluoxetine which potently inhibits both), amitriptyline is likely to remain in your system for much longer than average. On the other hand, certain co-administered agents may expedite the metabolism and elimination of amitriptyline. These drugs act as CYP2D6 and CYP2C19 inducers or enhance isoenzymatic function to bolster metabolism.
Examples of CYP2D6 inducers include: Dexamethasone, Glutethimide, Promethazine, and Rifampicin. Some common CYP2C19 inducers include: Artemisinin Aspirin, Carbamazepine Norethisterone Prednisone, and Rifampicin. Should you have co-administered any of the aforementioned inducers, expect elimination half-life of amitriptyline to decrease.
Note: The degree to which a CYP2D6 or CYP2C19 inhibitor/inducer affects elimination half-life of amitriptyline may depend upon the potency of the specific agent, as well as the dosage at which it was administered.
Amitriptyline: Absorption, Metabolism, Excretion (Details)
Following oral administration, amitriptyline is efficiently absorbed by the gastrointestinal (GI) tract. It is subject to first-pass hepatic metabolism, facilitated by CYP450 (cytochrome P450) enzymes, primarily CYP2D6 and CYP2C19. It is these isoenzymes (CYP2D6 and CYP2C19) that convert amitriptyline to its pharmacologically active metabolite “nortriptyline” via oxidative N-demethylation. Other isoenzymes such as CYP1A2, CYP3A4, and CYP2C9 play minor roles in the N-demethylation process.
In addition, CYP2D6 is the sole isoenzyme responsible for conversion of amitriptyline to its other notable metabolite 10-OH-amitriptyline (10-hydroxy-amitriptyline); this conversion occurs via hydroxylation. CYP2D6 further converts the metabolite nortriptyline to form 10-OH-nortriptyline (10-hydroxy-nortriptyline) – which is also pharmacologically active. After amitriptyline is extensively metabolized, it is approximately 30% to 60% bioavailable (some sources estimate ~45%).
Up to 95% of an amitriptyline dose is bound to plasma proteins, and its volume of distribution is estimated at 19 liters per kilogram (L/kg). Peak plasma concentrations of amitriptyline are attained approximately 3 hours post-ingestion. Plasma concentrations of amitriptyline are subject to alteration based on a user’s pH. The greater the acidity (lower pH) of the user, the higher the level of unbound amitriptyline; vice-versa also applies (higher pH equals lower unbound amitriptyline).
Amitriptyline is highly lipophilic, suggesting that repeated administration may lead to accumulation within bodily tissues and fat stores. There is significant interindividual variation in plasma elimination half-life of amitriptyline ranging from 10 to 50 hours. Most healthy adults exhibit an amitriptyline half-life of 15 hours, indicating that it’ll take less than 4 days to eliminate it from systemic circulation.
However, the half-life of primary metabolite nortriptyline, and secondary metabolite 10-OH-nortripytline range from 16 to 90 hours, usually exceeding that of the parent drug (amitriptyline). On average, the elimination half-life of nortriptyline is estimated to be 25 hours, meaning it’ll take around 5.73 days to eliminate from your plasma. After metabolites are distributed, they undergo additional conjugation and are excreted via renal pathways.
A majority of an amitriptyline dose will be excreted as conjugated and unconjugated metabolites via the urine. As a result of extensive hepatic metabolism, less than 5% of a dose appears in the urine as unchanged amitriptyline. Additionally, a substantial portion of an amitriptyline dose is excreted via biliary pathways. Most individuals will have eliminated amitriptyline (and metabolites) from systemic circulation within 1 to 2 weeks after discontinuation. In extreme cases, full elimination could take up to 21 days.
- Source: http://pubchem.ncbi.nlm.nih.gov/compound/amitriptyline
- Source: http://www.ncbi.nlm.nih.gov/pubmed/3893842
- Source: https://books.google.com/books/about/Therapeutic_Drugs.html?id=woaQSQAACAAJ
- Source: http://www.ncbi.nlm.nih.gov/pubmed/4742811
Tips to clear Amitriptyline from your system
If you’ve recently discontinued amitriptyline, realize that in less than 21 days, it’ll be fully out of your system. Although you may want to detoxify from amitriptyline and clear it from your system as soon as possible, a longer elimination half-life may be advantageous in that it may make it easier to cope with discontinuation symptoms. Below are some suggestions for individuals that want to ensure that amitriptyline (and its metabolites) are out of their systems. Prior to implementing any of the suggestions, discuss their safety and alleged efficacy with a medical professional.
- Activated charcoal: One way to ensure that amitriptyline is fully out of your system is to administer activated charcoal. Should any unmetabolized amitriptyline linger within your liver and/or remain unmetabolized, activated charcoal will bind to it via adsorption, efficiently shuttling it out of your body. Activated charcoal not only decreases amitriptyline absorption by 99% when administered within 5 minutes of amitriptyline, it is able to reduce amitriptyline’s half-life by up to 20% (and nortriptyline metabolites by 35%) when administered 6-hours post amitriptyline ingestion. Furthermore, this supplement will bind to any endotoxins that may have accumulated throughout treatment. (Source: http://www.ncbi.nlm.nih.gov/pubmed/3015809)
- Calcium-d-glucarate: Due to the fact that amitriptyline is subject to urinary excretion, supplementation with calcium-d-glucarate may expedite the process. Calcium-d-glucarate functions by forcing the elimination of accumulated molecules in kidney detoxification pathways. This will likely lead to a faster, more efficient urinary excretion of amitriptyline metabolites and expedite overall detoxification.
- Urinary pH: It is well-documented that urinary pH can affect urinary excretion of amitriptyline metabolites significantly. Some studies have determined that renal excretion is increased by 1000-fold when a user’s urinary pH is highly acidic (at a level of “4”). Individuals with highly alkaline urine may be likely to reabsorb some of the metabolites prior to elimination, resulting in a prolonged elimination half-life. To ensure the fastest detoxification speed, you may want to consider eating more acidic foods. Don’t go overboard though, as this can lead to acidosis. (Source: http://www.ncbi.nlm.nih.gov/pubmed/3015809)
- Exercise: If you’ve been taking amitriptyline for a long-term and/or are overweight, there’s a chance that it may have accumulated to a significant extent in bodily tissues (e.g. fat stores). This is accumulation occurs as a result of amitriptyline’s lipophilicity a.k.a. fat solubility. Getting exercise as a means of burning body fat may force accumulated amitriptyline from out of these fat stores, which in turn may expedite detoxification.
How long has Amitriptyline stayed in your system after stopping?
If you’ve stopped taking amitriptyline, how long did it take before you felt as if you were fully “detoxified?” In other words, how long do you think the drug and its metabolites lingered in your plasma after your final dose. Do you think that you eliminated amitriptyline and nortriptyline metabolites faster than usual (in less than 4 days)?
Or do you think you’re your elimination took considerably longer than usual (nearly 21 days)? In your comment, provide evidence to support your speculation of a faster and/or slower elimination of amitriptyline. Evidence may include things such as: CYP2D6 or CYP2C19 metabolism, your age, dosage, term of administration, and whether you co-ingested other drugs.