Drug Interactions: HIV Medications, Street Drugs and Methadone

A drug interaction is what happens when one drug that you take affects the way another drug you take works in your body. An interaction can affect your body's ability to break down one drug or both drugs. It can also affect the strength or effectiveness of one drug or both drugs. Drug interactions become more complicated -- and more likely to happen -- the more drugs you take. In many cases, interactions aren't a problem. There are lots of drugs that don't affect each other at all. But some medications should never be used together because they combine to create a toxic reaction. Such interactions are dangerous, even life threatening.

The liver breaks down and absorbs (metabolizes) antiretrovirals for HIV, methadone, alcohol, street drugs like cocaine and heroin, prescription and over-the-counter medications, herbs, vitamins -- the works. The liver has primary responsibility for drug metabolism, but the kidneys also play a role, mostly by eliminating drugs. Specific pathways of enzymes in the liver metabolize different drugs, but many drugs are metabolized by the same pathways. This is where interactions can occur.

The liver can only do so much work at one time. If you take two or more drugs at once, they can compete for the same enzymes in the liver in order to be broken down. This competition can affect the way the drugs are metabolized. One drug might be metabolized faster than usual, reducing levels of the drug in your blood and making it less effective. This could be a problem with a number of drugs. If your methadone levels are too low, for example, you could experience serious withdrawal symptoms. And if your anti-HIV drug is at low levels, it won't work as well and could allow your virus to become resistant to that drug and, perhaps, others as well.

Another kind of interaction can cause one of the drugs you're taking to be metabolized more slowly than usual. You could end up with a dangerously high dose of the drug in your system because it isn't being broken down and absorbed properly. In essence, this could cause an overdose and, depending on the drug, could be fatal.

It might be useful to think of the liver as a funnel -- or many funnels, some of them having funnels within them. If drug A and drug B compete with one another for the same funnel, for example, a number of possibilities could occur:

The levels of both Drug A and Drug B could increase in your system;
The levels of both Drug A and Drug B could decrease in your system;
Drug A levels could increase in your system and Drug B levels could decrease;
Drug A levels could decrease in your system and Drug B levels could increase;
Drug A levels could increase in your system and Drug B could remain at normal levels;
Drug A levels could decrease in your system and Drug B could remain at normal levels;
Drug A could remain at normal levels in your system and Drug B levels could decrease;
Drug A could remain at normal levels in your system and Drug B levels could increase; or
Both Drug A and Drug B could remain at normal levels in your system.

The more drugs you add to the mix, the more difficulty the funnels may have metabolizing them properly. There are many possible interactions -- some of them may not cause a problem, but others certainly could.

The following describes known and potential drug interactions that involve medications to treat HIV or prevent and treat opportunistic infections. Some of this information is based on studies that have been conducted in test tubes, animals, or people; some of it is based on case reports -- incidents that have actually happened to people; and some of the information is theoretical, based on what we know about how different drugs are metabolized -- which pathways they use and how they use them.

HIV Medications and Street/Recreational Drugs

There hasn't been much research on how illegal street drugs and HIV medications interact. Certainly, your best bet is not to use street drugs at all if you're taking HIV medications. But some interactions are known to be more dangerous than others.

It's difficult to study interactions between illegal drugs and antiretrovirals. Some people have a higher tolerance to some drugs than other people do. Also, there are too many different kinds of cuts put on drugs, especially heroin and cocaine, which are hardly ever pure. So laboratory tests using pure heroin or cocaine, for example, wouldn't necessarily tell us what might happen in your body with drugs bought on the street.

We have more information about interactions with prescription drugs that are used recreationally, But even then, some drugs that are available by prescription, when bought on the street, may be cut with other substances that could cause unexpected interactions with other drugs.

Alcohol

Videx (ddI) can increase the risk of pancreatitis, and so can chronic alcohol use. So if you're using alcohol regularly, inform your healthcare provider and consider alternatives to Videx. There are other nucleosides to choose from.
Alcohol increases Ziagen (abacavir) levels in your blood. A small study showed that consuming the equivalent of five alcoholic drinks with Ziagen resulted in up to a 41% increase in Ziagen levels. The increase isn't a good thing. Regular Ziagen dosing (300 mg every 12 hours) gives you enough of the drug to do the job. Increasing the amount won't fight HIV any better -- but it could increase your risk of side effects. Ziagen is also in the combination pills Trizivir and Epzicom.
Alcohol should not be used with Agenerase (amprenavir) oral solution (the liquid version) because it has propylene glycol in it, which can cause side effects when it's mixed with alcohol.
The protease inhibitor Reyataz (atazanavir) can increase levels of bilirubin in some people, which can cause jaundice (yellowing of the skin and whites of the eyes). If you start taking Reyataz, be sure to have liver function tests performed regularly, including checking bilirubin levels. People with liver disease, such as chronic hepatitis B or hepatitis C, or liver damage caused by alcohol use may be more likely to experience high bilirubin levels, but no differences have been reported so far in people with mild to moderate liver damage.
Occasional and light use of alcohol is not known to interact with other HIV medications, but regular, heavy alcohol use can damage your liver, which might make it more difficult for your liver to properly break down some anti-HIV drugs, particularly protease inhibitors and non-nucleosides. The result could be levels of these antiretrovirals that are too low to slow down HIV replication the way they're supposed to. That could result in a higher viral load, lower CD4 count, and the development of drug-resistant HIV. Liver damage can also work the opposite way, allowing some drugs to build up in your system, which could cause worse side effects or an overdose.
Since alcohol can cause dehydration, be sure to drink a lot of water to help your body deal better with any alcohol you drink.

Amphetamines (Speed, Methamphetamine, Crystal Meth [Tina, Ice])

Norvir (ritonavir) -- at full dose or the much lower doses used to "boost" other protease inhibitors -- could increase amphetamine levels in the blood significantly. Kaletra, which contains a small amount of ritonavir, could have the same effect. This increase isn't a good thing. It could have serious consequences, including a faster heart rate and higher blood pressure, possibly even death. The other protease inhibitors and the rarely used non-nucleoside Rescriptor (delavirdine) could have less of an impact, but might still have some. There's no sure way to predict what might happen with these combinations.
Taking amphetamines and certain antidepressants called SSRIs (Prozac, Paxil, Luvox, or Zoloft) together could, at least hypothetically, lead to a condition called "serotonin syndrome," which can be life-threatening. When serotonin levels increase too much, confusion, agitation, coma, anxiety, and seizures can occur.

Cocaine (Coke, Blow, Crack)

There have been no reported interactions between cocaine and HIV medications.
You may have heard reports that cocaine significantly speeds up HIV reproduction in lab cultures. There have also been studies showing that mice infected with HIV and then injected with cocaine had significantly more virus and fewer CD4 cells than mice infected with HIV but no cocaine. This could certainly mean that cocaine use speeds up HIV disease progression in people, although what actually happens in the human body isn't clear.

Ecstasy (MDMA, X)

There was one death in England, which resulted from a single dose of Ecstasy taken with Norvir. Norvir slows down the liver enzyme that breaks down Ecstasy, so Ecstasy accumulates in your system, making it 5 to 10 times stronger. In addition, up to 10% of Caucasians (the figure for other populations isn't known) have a deficiency in this enzyme, which may be why some people could overdose on what would be a non-toxic dose for others. If you're taking any protease inhibitor or non-nucleoside, Ecstasy can be extremely dangerous. Of these, Norvir seems to be the most dangerous, while Viracept (nelfinavir), Viramune (nevirapine), and Sustiva (efavirenz) may be less so. But drug interactions in the test tube are sometimes opposite to those seen in the body, so, again, this is hard to predict.
If you do take Ecstasy with a protease inhibitor, wait as long as possible after taking the medication before taking the Ecstasy. And be sure to have someone with you who knows what you've done in case you have difficulties. It's really better not to mix these drugs! If you do, think about taking less Ecstasy than you might normally take -- maybe 25% of your usual amount. Be sure to take regular breaks from dancing and other physical activity, drink plenty of fluids, and avoid alcohol -- alcohol causes dehydration.
If you aren't dancing or exercising, however, don't drink large quantities of water after taking ecstasy. It's actually possible to fatally overdose on water this way, because Ecstasy can also slow the body's ability to expel water as urine. Basically, drink to quench your thirst.

GHB (Gamma-Hydroxy-Butyrate, Grievous Bodily Harm, Liquid X, G)

GHB is potentially dangerous with protease inhibitors, especially Norvir (full dose or lower doses), as well as the non-nucleosides Rescriptor and, possibly, Sustiva. And never mix GHB with alcohol.

Heroin (Dope, Smack, Brown, Junk, China White)

Some people who use heroin and are prescribed antiretrovirals for their HIV may be afraid to take their HIV medications regularly for fear that they'll interact with the heroin. There are no documented interactions between antiretrovirals and heroin, although there are some theoretical ones. If you're using heroin, it's probably fine -- and better for your health -- to take your anti-HIV medications as well.
Most protease inhibitors -- Norvir, Kaletra, Agenerase, Lexiva, and Viracept in particular -- as well as the non-nucleosides Rescriptor and Sustiva may reduce heroin levels, although this is only based on theoretical research about the way your body breaks down heroin and these particular drugs. If this is true, it could lead to withdrawal symptoms. You might need more frequent doses of heroin to avoid withdrawal -- one big dose won't last longer and could be an overdose. Be careful.
Some synthetics sold as heroin (fentanyl, alpha-methyl-fentanyl) are potent in tiny doses and could be deadly if combined with another drug.

Ketamine (Special K)

When combined with some anti-HIV medications, Special K can lead to "chemical hepatitis," inflammation of the liver that could require hospitalization. The inflammation usually goes away in several weeks, but anything that damages the liver can be a serious problem for people with HIV. Norvir, Kaletra, Viracept, Agenerase, Lexiva, Rescriptor, and Sustiva are the antiretrovirals with the greatest potential to cause ketamine toxicity.

LSD (Acid, Blotter)

No known interactions. But it's possible that some anti-HIV medications, especially Norvir, could lead to a longer or more intense trip than planned or desired.

Marijuana

According to one study, smoked marijuana slightly lowers levels of the protease inhibitors Crixivan and Viracept, although the decreased levels weren't enough to affect the antiretrovirals' activity. Protease inhibitors may also increase THC levels, the active ingredient in marijuana -- so smaller doses may make you more stoned. The same is true of the synthetic version, Marinol (dronabinol), which contains THC and is used to treat nausea and increase appetite. This interaction doesn't seem to be dangerous -- although you should consider it if you're planning on being coherent!
Sustiva makes many people feel at least somewhat disoriented. Using marijuana might heighten these feelings -- and not necessarily in a good way.

PCP (Angel Dust, Rocket Fuel)

Levels of PCP may increase due to interactions with protease inhibitors or the non-nucleosides, Rescriptor and, possibly, Sustiva. These interactions could cause PCP toxicity. If you're on anti-HIV medications and using PCP, think about using less PCP than you might otherwise to avoid a possible interaction.

Poppers (Amyl Nitrate or Butyl Nitrate)

Be sure not to use poppers if you take Viagra, Levitra, or Cialis. Poppers increase levels of these drugs, lowering your blood pressure enough to cause serious, even lethal, reactions (see below for more detail).

Ritalin (Methylphenidate)

There are no known interactions between Ritalin and any medications specific to HIV.

Sedatives and Tranquilizers

Interactions between barbiturates, benzodiazepines and antiretrovirals, especially the protease inhibitors and non-nucleosides, are tricky. There are many possible variables that could affect the interactions listed below, including other drugs that you might be taking.

Barbiturates (Barbs, Downers)

Barbiturates are rarely used on the street since they don't provide much of an attractive high or down. But if you are taking barbiturates, there are some things that could be helpful to know:
Combining a barbiturate -- Amytal (amobarbital), Nembutal (pentobarbital), or Seconal (secobarbital), for example -- with many of the protease inhibitors or non-nucleosides can lower levels of the anti-HIV medication. This interaction can reduce or eliminate the benefit of the anti-HIV drug and possibly cause HIV to develop resistance to the drug.
High doses of barbiturates can cause unconsciousness, even death.
The combination of barbiturates with alcohol or any other central nervous system depressant, including heroin, is extremely dangerous. Alcohol intensifies the sedative effect of the barbiturate, which can cause abnormally slow and shallow breathing, coma, and death. Even the normal dose of a barbiturate can be lethal if it's combined with alcohol.

Benzodiazepines (Bennies, Benzos, Downers)

Taking the sedatives Halcion (triazolam) or Versed (midazolam) with any of the available protease inhibitors or the non-nucleosides Rescriptor or Sustiva could lead to a very dangerous, even deadly interaction, raising Halcion or Versed levels so much that serious sedation could result, possibly stopping your breathing.
Taking Ambien (zolpidem) with full-dose Norvir could cause a similar reaction, but low-dose Norvir, which is usually prescribed now, doesn't seem to significantly increase Ambien levels.
Valium (diazepam) and Tranxene (clorazepate) levels can also increase when used with some of these same anti-HIV medications -- particularly Invirase, Fortovase, Norvir, Agenerase, and Lexiva -- but the interaction doesn't seem to be as severe or as potentially dangerous as that of Halcion or Versed.
Norvir may increase Klonopin (clonazepam) levels, while Viramune and Sustiva may decrease Klonopin levels, possibly leading to symptoms of benzodiazepine withdrawal.
Norvir slightly decreases Xanax (alprazolam) levels, while Invirase, Fortovase, Agenerase, Lexiva and Rescriptor increase Xanax levels. Except for Rescriptor, which greatly increases Xanax levels, the degree that these other antiretrovirals raise Xanax levels isn't clear.
Invirase, Fortovase, Agenerase, Lexiva and Rescriptor may increase Dalmane (flurazepam) levels as well, but not as significantly as with Halcion or Versed.
Physical dependence on benzos can develop. Withdrawal should be medically supervised because of the risk of seizures.
Combining benzodiazepines with alcohol can be life threatening. Alcohol intensifies the sedative effect of the benzodiazepam, which can lead to coma or death. Benzos can also interact with opiates such as heroin, methadone or OxyContin (oxycodone) to cause increased, possibly lethal sedation.

Bottom line: Mixing downs can be very dangerous. Mixing depressant drugs -- alcohol and opioids; alcohol and barbiturates; alcohol and benzodiazepines; or a combination of depressant drugs -- is the cause of most overdose deaths.

Viagra (Sildenafil), Levitra (Vardenafil), and Cialis (Tadalafil)

These three drugs, marketed to help with impotence (erectile dysfunction), are often used recreationally by men to help get and keep an erection. None of them increase sexual desire. Although these are prescription drugs, people often get them through friends, on the street, or through the Internet. This means that what looks like Viagra, for example, may be Viagra -- then again, it may not be. The three available medications have similar interactions with other drugs.
There has been at least one documented death caused by the interaction of a protease inhibitor and Viagra (sometimes called blue diamonds or Vitamin V). The man had a heart attack. Protease inhibitors increase the blood concentrations of Viagra, which raises the likelihood and severity of side effects -- extremely low blood pressure, dizziness, fainting, changes in your vision, and prolonged erection (meaning hours -- not a good thing). Norvir (ritonavir) increases Viagra concentrations the most, while Fortovase (soft-gel saquinavir) and Invirase (hard-gel saquinavir) seem to have the least effect on Viagra blood levels. Other medications that increase Viagra blood levels include the non-nucleoside Rescriptor, the antifungals Nizoral (ketoconazole) and Sporanox (itraconazole), and the antibiotic erythromycin.
Levitra and Cialis have similar interactions with these same drugs. Although not every drug has been studied with each of these medications to figure out every conceivable interaction, the way that they're broken down by the liver gives us a good idea of the possible interactions.
The usual dose of Viagra is 50 mg once a day (at most). The usual dose of both Levitra and Cialis is 10 mg, also once a day at most. Based on what's known and what can be assumed, take a lower dose of Viagra, Levitra, or Cialis -- and take it less often -- to avoid a possibly dangerous drug interaction if you're also taking one of the drugs listed above. Some examples:

If you're on a protease inhibitor, don't take more than one 25 mg dose of Viagra within a two-day period.

If you're on a protease inhibitor-containing regimen that doesn't include Norvir, the highest dose of Levitra should be 2.5 mg within a 24-hour period.

If you're taking Kaletra or Norvir (even at a low dose) as part of your regimen, the highest dose of Levitra should be 2.5 mg and it shouldn't be taken again for three days.

If you're taking erythromycin, don't take more than one 5 mg dose of Levitra in a 24-hour period.

If you're taking 200 mg of Nizoral a day, your dose of Levitra shouldn't be more than 5 mg in one day; and if you're taking 400 mg of Nizoral a day, your dose of Levitra shouldn't be more than 2.5 mg in one day.

If you're taking Norvir (including low-dose Norvir), Nizoral, or Sporanox, your dose of Cialis should be 10 mg no more than once in three days.

Grapefruit juice could increase levels of Cialis in your blood, so avoid it if you take that drug.

Levitra can decrease levels of the protease inhibitor Crixivan, so if you're taking Crixivan three times a day (which is rare), it would be safer to use Viagra or Cialis at lower doses than usually recommended.

Warnings

Using poppers (amyl nitrate or butyl nitrate) with Viagra, Levitra, or Cialis can cause a severe decrease in blood pressure -- low enough to cause you to fall down or faint, perhaps hurting yourself. Even more serious reactions due to the drop in blood pressure include stroke, heart attack, and death.
If you take one of these drugs and have an erection that lasts for more than four hours, go to the emergency room. If you don't get treated, this can result in the permanent loss of erectile function.
Combining Cialis with significant amounts of alcohol can increase the side effects of Cialis, perhaps to a dangerous degree. Combining alcohol with Viagra or Levitra doesn't seem to have the same effect.
If you have liver damage due to viral hepatitis, alcohol use, or for any other reason, be careful if you use any of these drugs. If you have mild to moderate liver damage, use a low dose (25 mg of Viagra, 5-10 mg of Levitra, or no more than 10 mg of Cialis). Higher doses could cause serious side effects. We don't know what happens if someone with severe liver damage takes one of these drugs. If you're on a protease inhibitor and have liver damage, your safest bet is not to use them at all -- in that situation, there would be a lot going on at once and unpredictable things could happen.
If you have kidney damage and plan to use one of these drugs, either take Levitra (which kidney damage doesn't seem to affect) or a low dose of Viagra (25 mg) or Cialis (5 mg).

Levitra and Cialis are relatively new compared to Viagra, which has been on the market since 1998. As more people use these drugs and further studies are conducted, we'll learn more about their safety and other possible interactions.

HIV Medications and Methadone

The same liver enzymes that metabolize methadone break down many medications for HIV and drugs that prevent and treat opportunistic infections. So these drugs can cause changes in the way you respond to your methadone dose. Some can increase the effects of methadone; others can decrease it. Methadone can have an effect on the strength of some anti-HIV drugs, too.

It's best to tell both your HIV healthcare provider and the provider at your methadone clinic about all the medications you're taking. But if you don't share the information, at least know the drugs that you're on. Most of the important methadone-medication interactions decrease the effect of the methadone. If your dose isn't comfortable for you, it isn't "addictive behavior" to want one that is.

People considering detoxing from methadone should be aware that this might not be a good idea for some people with HIV, particularly if your CD4 count is low. Methadone-maintained people have fewer hospitalizations and are more likely to receive anti-HIV medications than many heroin users who aren't on methadone. When lowering your methadone dose it may be safest to go slowly and wait until you've adjusted to each decrease before moving on to the next one.

The following are some of the known drug interactions with methadone. There may be others. This area, like most involving drug users, hasn't been thoroughly studied -- although, because methadone is legal, the information about possible drug interactions is more complete and there's more of it compared to that for illegal drugs. If you start a new medication and find that your methadone dose isn't "holding" you or that it makes you feel drowsy or over-medicated, talk to the provider at your clinic. If they refuse to adjust your methadone to meet your needs, ask your HIV care provider to discuss it with them. You shouldn't have to suffer because of ignorance about drug interactions from some clinic staff.

Drugs That May Make Methadone Stronger (More Potent)

Many medications can increase methadone levels to varying degrees. In most cases, the increase is minimal and might not have any noticeable effect. But if the increase is substantial enough, you could become over-medicated, although this is rare.
Diflucan (fluconazole), used to treat fungal infections, can raise methadone levels in the blood by up to 35%. In one study of this effect, no symptoms of overdose were reported in the thirteen people who took Diflucan with methadone. Nizoral (ketoconazole), another anti-fungal, can have a similar effect.
The antidepressants amitriptyline (Elavil and generic versions) and fluvoxamine (various brand names including Luvox) can also increase the amount of methadone in your system. Fluvoxamine can raise methadone levels by anywhere from 20% to 100%. An increase above 30-50% could make you dangerously over-medicated. Then, if you stop taking fluvoxamine and your methadone levels suddenly go down again, you could suffer symptoms of withdrawal.
Using anti-anxiety medications such as Valium (diazepam), Xanax (alprazolam), or Halcion (triazolam) with methadone can have a "synergistic" effect -- you can become more sedated than each individual drug would cause (1+1 = 3).
Tagamet (cimetidine), used to treat ulcers and acid reflux (heartburn), can slightly increase methadone levels, as can urinary alkalinizers (Bicitra, Polycitra) used to treat gout and kidney stones.
Rescriptor (delavirdine), the rarely used non-nucleoside, increases methadone levels slightly but, for most people, the increase isn't enough to require a decrease in their methadone dose.
Grapefruit juice could slightly increase methadone levels in the blood, but the effect doesn't seem to be significant.
Cipro (ciprofloxacin), an oral antibiotic sometimes used to treat MAC (Mycobacterium avium Complex), bacterial pneumonia, and many common bacterial infections, can cause significant increases in methadone levels. This increase could possibly lead to serious sedation and even overdose for some people.

Drugs With Mixed or Contradictory Effects

Agenerase (amprenavir), a protease inhibitor, significantly decreases methadone levels. Methadone decreases levels of Agenerase, as well, so this combination makes both drugs less effective. It's probably best not to take a combination that includes Agenerase if you're on methadone.
Soon after the protease inhibitors Norvir (ritonavir) and Crixivan (indinavir) were approved, in vitro (laboratory) studies were conducted to see what affect these antiretrovirals might have on methadone. These test tube studies showed that both drugs increased the potency of methadone. But in the body, Norvir seems to have the opposite effect. It can decrease methadone blood levels by as much as one third and may require a slight increase in your methadone dose to avoid symptoms of withdrawal. A more recent study looking at the interaction between low-dose Norvir and methadone found that Norvir slightly and insignificantly increased methadone levels. If you're taking full- or low-dose Norvir and your methadone isn't holding you, report it and ask for a raise in your methadone dose.
Although Crixivan increases methadone levels in the test tube, it doesn't affect methadone in the body.
Alcohol, mixed with methadone, can increase sedation at first and later cause methadone to be metabolized quicker. After the effects of the alcohol wear off, you could feel withdrawal symptoms, possibly leading to relapse.

Drugs That Make Methadone Weaker (Less Potent)

Sustiva (efavirenz) and Viramune (nevirapine), two non-nucleosides, are the antiretrovirals that reduce methadone levels the most -- possibly giving you the feeling that your anti-HIV meds are "eating" your methadone.
Sustiva significantly reduces methadone levels in your blood. Based on small studies, the reduction varies a lot from person to person. Some have as much as a 50% reduction in methadone levels. Withdrawal signs and symptoms usually occur after seven days of starting Sustiva. Your methadone dose may need to be raised gradually -- 5-10 mg daily -- in order to be effective. In one study, the average increase in methadone dose required to avoid withdrawal symptoms was about 20%. Communicate with your provider!
Viramune may also require an increase in your methadone dose. As with Sustiva, your methadone dose may need to be raised 5-10 mg daily to be effective after starting a combination that includes Viramune. In one study, almost one-third of the people on Viramune required an increase in their methadone dose. A very small study showed similar results, with some people experiencing serious withdrawal symptoms one to two weeks after starting Viramune.
After measuring methadone levels in the blood of people taking either Sustiva or Viramune, a group of researchers in Ireland and England suggested that methadone doses might need to be increased in increments of 10 mg 8-10 days after starting either non-nucleoside.
Kaletra (lopinavir/ritonavir), a protease inhibitor, reduces methadone levels significantly enough to require an increase in some people's methadone dose to avoid withdrawal. The reduced methadone levels are caused by the lopinavir in Kaletra rather than by the small amount of ritonavir Kaletra contains.
Other antiretrovirals can also reduce methadone levels, including Ziagen (abacavir), Viracept (nelfinavir), Agenerase (see above), and Lexiva (fosamprenavir). Methadone dose increases might be necessary for some people, but probably not for most. The extent of these interactions varies from person to person and could depend on your methadone dose.
Rifampin (used to treat tuberculosis) can significantly decrease the length of time methadone stays in your system. Methadone doses may need to be raised significantly in order to remain effective for some people who are also taking Rifampin. If you're taking Rifampin, be sure to report it to your clinic. And if you feel like you're having withdrawal symptoms, talk to your provider about increasing your methadone dose.
The anti-seizure medications Tegretol (carbamazepine), Dilantin (phenytoin), and Phenobarbital can also weaken methadone's effects.
Doses of Vitamin C high enough to make the urine more acidic can reduce methadone levels and effects. So be careful not to overdo the Vitamin C!

Drugs That Methadone Makes Weaker

Methadone seems to decrease the absorption of Zerit (d4T, stavudine) and the buffered tablet version of Videx (ddI, didanosine) -- the decrease in Videx levels is quite significant, but the decrease in Zerit levels isn't. If you're on methadone, the amount of Videx getting into your system may not be enough to do its job. The low levels of Videx could also potentially lead to development of resistance.
Instead of increasing the daily dose of Videx buffered tablets, it's probably best to switch to Videx EC, the enteric-coated formulation of the drug. Methadone doesn't seem to interact with Videx EC.
Neither Videx nor Zerit seem to decrease the effect of methadone.

Drugs That Methadone Makes Stronger

Retrovir (AZT) levels in the blood can be increased by as much as 40% when it's taken with methadone. This means that if you take less AZT than someone who isn't on methadone, you may get the same anti-HIV effect, although routine dose reductions aren't recommended. If you're having bad side effects from AZT, this could be due to this interaction -- you may have too much AZT in your system. These increased side effects can be similar to opiate withdrawal (nausea, vomiting, headaches, etc.), so it can be hard to tell what's going on. Lowering your AZT dose may be in order, but don't lower it on your own. If you're taking AZT (or Combivir or Trizivir, both of which contain AZT), work closely with your healthcare provider to get the maximum benefit of your antiretrovirals, avoid developing drug-resistant HIV, and deal with possible side effects.

James Learned is Director of Treatment Education at ACRIA and Editor of ACRIA Update.

Maia Szalavitz is the co-author of Recovery Options: The Complete Guide: How You and Your Loved Ones Can Understand and Treat Alcohol and Other Drug Problems (Wiley, 2000).

Thanks to Carlos Santiago and Constance T. Chang for their research assistance.

Select Primary and Secondary References

Booker B, et al. Lack of effect of methadone (MET) on the pharmacokinetics (PK) of delavirdine (DLV) and N-delavirdine (N-DLV) [abstract #A-490]. 41st Interscience Conference on Antimicrobial Agents and Chemotherapy; 2001 December 16-19; Chicago, Illinois.
Agenerase (amprenavir) label.
Alderman CP, Frith PA. Fluvoxamine-methadone interaction. Aust NZ J Psychiatry 1999 Feb;33(1):99-101.
Altice FL, Cooney E, Friedland GH; Nevirapine induced methadone withdrawal: implications for antiretroviral treatment of opiate dependent HIV infected patients. Conf Retroviruses Opportunistic Infect 1999 Jan 31-Feb 4; 6th:137 (abstract no. 372).
Altice FL, Friedland GH, Cooney EL. Nevirapine induced opiate withdrawal among injection drug users with HIV infection receiving methadone. AIDS. 1999;13:957-962.
Antoniou T, Tseng AL. Interactions between recreational drugs and antiretroviral agents. Ann Pharmacother. 2002 Oct;36(10):1598-1613.
Ativan (lorazepam) label.
Ayres WA, et al. The bogus drug: Three methyl & alpha methyl fentanyl sold as "China White". J Psychoactive Drugs. 1981 Jan-Mar;13(1):91-3.
Bagasra O, Pomerantz RJ. Human immunodeficiency virus type 1 replication in peripheral blood mononuclear cells in the presence of cocaine. J Infect Dis. 1993 Nov;168(5):1157-64.
Baker R, et al. Ritonavir and ecstasy. BETA 1997 Mar 5.
Barry M, Gibbons S, Back D, Mulcahy F. Protease inhibitors in patients with HIV disease. Clinically important pharmacokinetic considerations. Clin Pharmacokinet. 1997 Mar;32(3):194-209.
Bart P-A, et al. Methadone blood concentrations are decreased by administration of abacavir plus amprenavir. Ther Drug Monit 2001;23:553-555.
Bart PA, et al. Ther Drug Monit 2001;23:553-555.
Bertschy G, Baumann P, Eap CB, Buettig D. Probable metabolic interaction between methadone and fluvoxamine in addict patients. Ther Drug Monit 1994 Feb;16(1):42-5.
Bochner F. Drug interactions with methadone: pharmacokinetics. In Hummeniuk induction and stabilisation of patients onto methadone. Monograph Series 39, Canbera: Commonwealth of Australia; 2000: 93-110.
Bornheim LM, et al. Characterization of cannabidiol-mediated cytochrome P450 inactivation. Biochem Pharmacol. 1993 Mar 24;45(6):1323-31.
Bornheim LM, et al. Human hepatic microsomal metabolism of delta 1-tetrahydrocannabinol. Drug Metab Dispos. 1992 Mar-Apr;20(2):241-6..
Burrows DL, Hagardorn AN, Harlan GC, et al. A fatal drug interaction between oxycodone and clonazepam. J Forensic Sci. 2003 May;48(3):683-6.
Chrisman CR. Protease inhibitor-drug interactions: proceed with caution, J Critical Illness 2003; 18(4):185-188.
Cialis (tadalafil) label.
Clarke S, et al. Absence of opioid withdrawal symptoms in patients receiving methadone and the protease inhibitor lopinavir-ritonavir, Clin Infect Dis 2002;34:1143-5.
Clarke SM, et al. Pharmacokinetic interactions of nevirapine and methadone and guidelines for use of nevirapine to treat injection drug users, Clin Infect Dis 2001;33:1595-7.
Clarke SM, et al. The pharmacokinetics of methadone in HIV-positive patients receiving the non-nucleoside reverse transcriptase inhibitor efavirenz, Br J Clin Pharmacol 2001;51:213-7.
Cobb M, et al. The effect of fluconazole on the clinical pharmokinetics of methadone. Clinical Pharmaco Ther 1998;63;655-622.
Crixivan (indinavir) label.
Crowley JR, et al. Mechanism-based inactivation of rat liver cytochrome P4502B1 by phencyclidine and its oxidative product, the iminium ion, Drug Metab Dispos 1995 Aug; 23(8):786-93.
Dalmane (flurazepam) label.
De la Torre R, et al. Non-linear pharmacokinetics of MDMA ("ecstasy") in humans. Br J Clin Pharmacol. 2000 Feb; 49(2):104-9.
DeMaria Jr. PA, Methadone drug interactions. Journal of Maintenance in the Addictions 2003; 2(3):69-74.
DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, October 29, 2004.
Eap CB, et al. Interindividual variability of the clinical pharmacokinetics of methadone: implication for the treatment of opioid dependence. Clin Pharmacokinet 2002;41(14):1153-1193.
Faragon J and Piliero P, Drug Interactions Associated With HAART: Focus on Treatments for Addiction and Recreational Drugs, AIDS Reader 13(9):433-450, 2003.
Forney RB & Hughes FW. Meprobamate, ethanol or meprobamate-ethanol combinations on performance of human subjects under delayed autofeedback (DAF), Journal of Psychology 1964 57:431-436.
Fortovase (saquinavir SGC) label.
Friedland G, Rainey P, Jatlow P, et al. Pharmacokinetics (pK) of didanosine (ddI) from encapsulated enteric coated bead formulation (EC) versus chewable tablet formulation (EC) in patients (pts) on chronic methadone therapy. XIV International AIDS Conference; July 7-12, 2002; Barcelona, Spain. Abstract TuPeB4548.
Geletko SM, et al. Decreased methadone effect after ritonavir initiation. Pharmacotherapy 2000;20:93-4.
Girre, C, et al. Detection of blood benzodiazepines in injured people. Relationship with alcoholism. Drug and Alcohol Dependence 1998;21(1):61-65.
Gourevitch MN. Interactions between HIV-related medications and methadone: an overview, Mt. Sinai J Med 2001; 68(3):227-228.
Greenblatt DJ, et al. Differential impairment of triazolam and zolpidem clearance by ritonavir. Acquir Immune Defic Syndr. 2000 Jun 1;24(2):129-36.
Greenblatt DJ, et al. Differential impairment of triazolam and zolpidem clearance by ritonavir, J Acquir Immune Defic Syndr 2000; 24:129-36.
Guibert A, et. al. In vitro effect of HIV protease inhibitors on methadone metabolism (Abstract A-58). 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, September 28-October 1, 1997.
Halcion (triazolam) label.
Harrington RD, et al. Life-threatening interactions between HIV-1 protease inhibitors and the illicit drugs MDMA and gamma-hydroxybutyrate, Arch Intern Med 1999 Oct 11;159(18):2221-4
Haverkos HW, et al. Health hazards of nitrite inhalants. Am J Med. 1988 Mar;84(3 Pt 1):479-82.
Heelon MW, Meade LB. Methadone withdrawal when starting an antiretroviral regimen including nevirapine. Pharmacotherapy. 1999;19:471-472.
Hendrix C, et al. Pharmacokinetic (PK) and pharmacodynamic (PD) evaluation of methadone (MD) enantiomers following co-administration with amprenavir (APV) in opioid-dependent subjects [abstract #1649] 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2000 September 17-20.
Henry JA, et al. Fatal interaction between ritonavir and MDMA. Lancet 1998;352:1751-2.
Herrlin K, et al. Methadone, ciprofloxacin, and adverse drug reactions. Lancet. 2000 Dec 16;356(9247):2069-70.
Hollister LE. Interactions between alcohol and benzodiazepines. Recent Dev Alcohol. 1990;8:233-9.
Hsu A, et al. Ritonavir: Clinical pharmacokinetics and interactions with other anti-HIV agents. Clin Pharmacokinet 1998; 35:275-91.
Hsyu PH, Lillibridge JH, et al. Pharmacokinetic (PK) and pharmacodynamic (PD) interactions between nelfinavir and methadone. Conf Retroviruses Opportunistic Infect 2000 Jan 30-Feb 2; 7:91 (abstract no. 87).
Inoue T, et al. Effects of inducers and/or inhibitors on metabolism of lysergic acid diethylamide in rat liver microsomes, Xenobiotica 1980 Dec;10(12):913-20.
Invirase (saquinavir HGC) label.
Jones C. Suspicious death related to gamma-hydroxybutyrate (GHB) toxicity, J Clin Forensic Med 2001 Jun; 8(2):74-6.
Jung F, et al. Diazepam metabolism by cDNA-expressed human 2C P450s: identification of P4502C18 and P4502C19 as low K(M) diazepam N-demethylases. Drug Metab Dispos, 1997 Feb; 25(2):133-9.
Kaletra (lopinavir/ritonavir) label.
Kalvik A, et al. Help for heroin dependence: what pharmacists need to know about methadone maintenance therapy. Pharmacy Practice 1996; 12(10):43-54.
Kharasch ED, et al. Influence of hepatic and intestinal cytochrome P4503A activity on the acute disposition and effects of oral transmucosal fentanyl citrate. Anesthesiology. 2004 Sep;101(3):729-37.
Klonopin (clonazepam) label.
Kosel BW, Aweeka FT, Benowitz NL, et al. The effects of cannabinoids on the pharmacokinetics of indinavir and nelfinavir. AIDS. 2002;16:543-550.
Kreek MJ, et al. Rifampin-induced methadone withdrawal. N Engl J Med 1976; 294:1104-1106.
Kreek MJ. Drug interactions with methadone in humans. In: Braude MC, Ginzburg HM (eds). Strategies for Research on the interactions of Drugs of Abuse, NIDA Research Monograph 68. 1986:193-225.
Kreth K, et al. Identification of the human cytochromes P450 involved in the oxidative metabolism of "Ecstasy"-related drugs. Biochem Pharmacol 2000;15:1563-71.
Kronbach T, et al. Oxidation of midazolam and triazolam by human liver cytochrome P450IIIA4. Mol Pharmacol 1989 Jul; 36(1):89-96.
Laurenzana EM, et al. Metabolism of phencyclidine by human liver microsomes, Drug Metab Dispos. 1997 May; 25(5):557-63.
Levitra (vardenafil) label.
Levy RH, et al. (eds), Metabolic Drug Interactions, Philadelphia, PA: Lippincott Williams & Wilkins; 2000.
Lexiva (fosamprenavir) label.
Lim ML, et al. A two-way drug interaction between lopinavir/ritonavir and phenytoin [abstract #535], 10th Conference on Retroviruses and Opportunistic Infections; 2003 February 10-14; Boston, Massachusetts.
Lin LY, et al. Cytochrome P4502D isozymes catalyze the 4-hydroxylation of methamphetamine enantiomers. Drug Metab Dispos 1995;23:610-614.
Lin LY, et al. Oxidation of methamphetamine and methylenedioxymethamphetamine by CYP2D6. Drug Metab Dispos 1997;25:1059-1064.
Maroldo L, Manocchio S, et al. Lack of effect of nelfinavir mesylate on maintenance methadone dose requirement (abstract WePeB4120) Presented at: XIII international AIDS Conference, Durban, South Africa, July 9-14, 2000; 60.
McCance-Katz EF, et al. Methadone effects on zidovudine disposition (AIDS Clinical Trials Group 262). J Acquir Immune Defic Syndr Hum Retrovirol. 1998 Aug 15;18(5):435-43.
McCance-Katz EF, et al. Modified directly observed therapy (MDOT) for injection drug users with HIV disease, Am J Addict. 2002;11(4):271-278.
McCance-Katz EF, et al. The protease inhibitor lopinavir-ritonavir may produce opiate withdrawal in methadone-maintained patients. Clin Infect Dis. 2003 Aug 15;37(4):476-82.
McCance-Katz EF, Rainey PM, Smith P, et al. Drug interactions between opioids and antiretroviral medications: interaction between methadone, LAAM, and nelfinavir. Am J Addict. 2004 Mar-Apr;13(2):163-80.
McCance-Katz, EF, et al. Letter to the Editor: Decrease in Methadone Levels With Nelfinavir Mesylate. Am J Psychiatry 157:481, March 2000.
McDowell JA, et al. Pharmacokinetic interaction of abacavir (1592U89) and ethanol in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother. 2000 Jun;44(6):1686-90.
Medline Plus, U.S. National Library of Medicine and the National Institutes of Health.
Mills KC. Serotonin syndrome. Am Fam Physician. 1995 Oct;52(5):1475-82.
Mirken B. Danger: possibly fatal interactions between ritonavir and "ecstasy," some other psychoactive drugs. AIDS Treat News. 1997 Feb 21;(No 265):5.
Moolchan ET, et al. Therapeutic drug monitoring in methadone maintenance: choosing a matrix. J Addict Dis 2001;20(2):55-73.
Nilsson MI, et al. Effect of urinary pH on the disposition of methadone in man. Eur J Clin Pharm 1982; 22: 337-342.
Norvir (ritonavir) label.
Ono S, et al. Human liver microsomal diazepam metabolism using cDNA-expressed cytochrome P450s: role of CYP2B6, 2C19 and the 3A subfamily. Xenobiotica 1996 Nov; 26(11):1155-66.
Otero MJ, Fuertes A, Sanchez R, et al. Nevirapine-induced withdrawal symptoms in HIV patients on methadone maintenance programme: an alert. AIDS. 1999 May 28;13(8):1004-5.
Palkama VJ, et al. Effect of saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam. Clin Pharmacol Ther 1999 Jul; 66(1):33-9.
Peterson PK, et al. Cocaine potentiates HIV-1 replication in human peripheral blood mononuclear cell cocultures. Involvement of transforming growth factor-beta. J Immunol. 1991 Jan1; 146(1): 81-4.
Physicians' Desk Reference (PDR) entry for Rifadin (rifampin capsules).
Pinzani V, Faucherre V, Peyriere H, et al. Methadone withdrawal symptoms with nevirapine and efavirenz. Ann Pharmacother. 2000;34:405-407.
Preston, A. The Methadone Briefing. London: ISDD, 1996. (out of print) See online version.
Quinn DI, et al. Pharmacokinetic and pharmacodynamic principles of illicit drug use and treatment of illicit drug users. Clin Pharmacokinet. 1997; 33(5):344-400.
Rainey PM, et al. Interaction of methadone with didanosine and stavudine. J Acquir Immune Defic Syndr 2000; 24(3):241-248; The 6th CROI - Conf Retroviruses Opportunistic Infect 1999 Jan 31-Feb 4; 6th:137 (abstract no. 371).
Rescriptor (delavirdine) label.
Retrovir (zidovudine, AZT) label.
Reyataz (atazanavir) label.
Richelson E. Pharmacokinetic drug interactions of new antidepressants: a review of the effects on metabolism of other drugs. Mayo Clin Proc. 1997; 72:835-847.
Roth MD, et al. Cocaine enhances Human Immunodeficiency Virus Replication in a Model of Severe Combined Immunodeficient Mice Implanted with Human Peripheral Blood Luekocytes. J Infect Dis. 2002 Mar 1;185(5):701-5.
Sellers E, et al. The pharmacokinetics of abacavir and methadone following coadministration, CNAA1012 (abstract 663) Presented at 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, September 26-28, 1999:25.
Shelnutt SR, et al. Phencyclidine metabolite irreversible binding in the rat: gonadal steroid regulation and CYP2C11, J Pharmacol Exp Ther. 1996 Apr; 277(1):292-8.
Staszewski S. Nevirapine/didanosine/lamivudine once daily in HIV-1-infected intravenous drug users. Antivir Ther. 1998;3 Suppl 4:55-6.
Stocker H, et al. Nevirapine significantly reduces the levels of racemic methadone and (R)-methadone in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. 2004 Nov;48(11):4148-53.
Strang J (chair), Drug Misuse and Dependence -- Guidelines on Clinical Management, The Scottish Office Department of Health. Welsh Office and the Department of Health and Social Services: Norwich, UK; 1999.
Sustiva (efavirenz) label.
Tanaka E. Toxicological interactions between alcohol and benzodiazepines. J Toxicol Clin Toxicol. 2002;40(1):69-75.
U.S. Drug Enforcement Administration: Benzodiazepines.
Valium (diazepam) label.
Versed (midazolam HCI Injection) package insert.
Viagra (sildenafil) label.
Videx (didanosine, ddI) label.
Viracept (nelfinavir) label.
Viramune (nevirapine) label.
Whitfield RM, et al. The impact of ethanol and Marinol/marijuana usage on HIV+/AIDS patients undergoing azidothymidine, azidothymidine/dideoxycytidine, or dideoxyinosine therapy. Alcohol Clin Exp Res 1997 Feb;21(1):122-7.
Yanagihara Y, et al. Involvement of CYP2B6 in n-demethylation of ketamine in human liver microsomes, Drug Metab Dispos 2001 Jun; 29(6):887-90.
Zerit (stavudine, d4T) label.
Ziagen (abacavir) label.

Back to the ACRIA Update Spring 2005 contents page.