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Antiretrovirals, Part III: Antiretrovirals and Drugs of Abuse

From the Department of Medicine, Walter Reed Army Medical Center; and the Uniformed Services University of the Health Sciences F. Edward Hebert School of Medicine, Bethesda, Md. (Drs. Wynn, Cozza, Zapor, and Wortmann). Dr. Armstrong is the Medical Director, Center for Geriatric Psychiatry, Tuality Forest Grove Hospital, Forest Grove, Ore., and Associate Clinical Professor of Psychiatry, Oregon Health Sciences University, Portland, Ore. Drs. Armstrong and Cozza are co-authors, along with Dr. Jessica R. Oesterheld, of the Concise Guide to Drug Interaction Principles for Medical Practice: Cytochrome P450s, UGTs, P-glycoproteins, 2nd edition. (American Psychiatric Publishing, Inc., 2003). Address all correspondence to Dr. Cozza, Psychiatrist, Infectious Disease Service, Ward 63, Department of Medicine, Walter Reed Army Medical Center, 6900 Georgia Ave., Washington, DC 20307-5001; kelly.cozza{at}na.amedd.army.mil (e-mail).
The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.

ABSTRACT

The third in a series reviewing the HIV/AIDS antiretroviral drugs, this report summarizes the interactions between antiretrovirals and common drugs of abuse. In an overview format for primary care physicians and psychiatrists, the metabolism and drug interactions in the context of antiretroviral therapy are presented for the following drugs of abuse: alcohol, benzodiazepines, cocaine, GHB (liquid X), ketamine (special K), LSD (acid), MDMA (Ecstasy), opiates, PCP (angel dust), and THC (marijuana).

Until recent times, the adverse health events associated with "recreational" drug use were limited to overdose and drug-related accidents or violence. With the advent of HIV/AIDS in the early 1980s, the recreational drug user’s risk of disease increased dramatically. No group was more at risk than injection drug users who shared needles. According to the Centers for Disease Control and Prevention and the Canadian Communicable Disease Report, roughly one-quarter to one-third of all new cases of HIV are associated with injection drug use. With this in mind, our colleagues at Walter Reed Army Medical Center’s Infectious Disease Service present this last of three installments reviewing the side effects and drug interactions associated with antiretroviral therapy. This multipart synopsis is intended to provide succinct information regarding potential side effects, toxicities, and drug interactions of the medications commonly used in the management of HIV-infected patients. The protease inhibitors were presented in Part I (Psychosomatics 2004; 45:262–270 [May-June issue]), and all other antiretrovirals were reviewed in Part II (Psychosomatics 2004; 45:524–535 [November-December issue]). This segment briefly reviews the interactions between antiretrovirals and common drugs of abuse and recreation. This article was researched through an extensive Medline/PubMed literature search with emphasis on the most recent human studies and case reports.

The introduction of highly active antiretroviral therapy into the regimen of HIV/AIDS treatment has substantially improved length and quality of life for many patients. Recreational drug use, however, poses a serious risk of potential drug-drug interactions with the life-saving medications of highly active antiretroviral therapy.

We will review antiretroviral medication interactions with the following substances of abuse: alcohol, benzodiazepines, cocaine, GHB (liquid X), ketamine (special K), LSD (acid), MDMA (Ecstasy), opiates, PCP (angel dust), and THC (marijuana).

ALCOHOL

Ethanol metabolism occurs primarily via alcohol dehydrogenase and subsequently aldehyde dehydrogenase.¹ Abacavir (Ziagen®) undergoes similar metabolism via alcohol dehydrogenase to a carboxylate derivative. Since both ethanol and abacavir use alcohol dehydrogenase, an interaction seems likely.² McDowell et al.³ studied this possible interaction in 25 HIV-positive patients randomly assigned to abacavir, ethanol, or the combination. Each patient underwent all three regimens with a 7-day washout period between. Concomitant administration resulted in a 41% increase in abacavir area under the concentration curve (AUC) and no change in ethanol.³ Though statistically significant, the abacavir level fell well within levels known to be safe. However, given this information, patients prescribed abacavir should be counseled against ethanol ingestion to avoid any potential complication.

Acute alcohol ingestion can inhibit CYP 2D6 and 2C19, while long-term use can induce CYP 2E1 and 3A4.⁴ Thus, acutely, the metabolism of medications such as secondary tricyclics, beta-blockers, and some SSRIs can be inhibited, raising serum levels. With chronic use, medications like oral contraceptives, protease inhibitors, nonnucleoside reverse transcriptase inhibitors, and statins can become subtherapeutic.⁵ Patients should be counseled accordingly regarding the risks of ethanol ingestion while taking certain prescription medications.

Acetaminophen (Tylenol®) metabolism involves several pathways, including CYP 2E1. Typically only 5% of the metabolism of acetaminophen occurs via CYP 2E1. Oxidation of acetaminophen via CYP 2E1 results in the hepatotoxic compound N-acetyl-p-benzoquinoneimine (NAPQI). Usually formed in small amounts, NAPQI can be detoxified by conjugation with glutathione. High doses of acetaminophen (>10 g) or induction of CYP 2E1 causes the production of more NAPQI and exhausts glutathione stores resulting in hepatotoxicity.^6–8 Thus, with chronic alcohol use, doses of acetaminophen usually considered nontoxic can have toxic effects. HIV-infected patients who may be taking acetaminophen-containing compounds (over-the-counter or prescription) may produce an excessive toxic metabolite level if they are also ingesting potent CYP 2E1 inducers such as ethanol.

BENZODIAZEPINES

Benzodiazepines are not all alike, varying in half-life, potency, and metabolism. With regard to drug-drug interactions, benzodiazepines can be divided into two main groups on the basis of CYP 3A4 metabolism. The triazolobenzodiazepines, which include midazolam (Versed®), triazolam (Halcion®), and alprazolam (Xanax®), are dependent on CYP 3A4 for metabolism. Greenblatt et al.⁹ previously reported the effects of acute ritonavir (Norvir®) exposure during alprazolam therapy. During the initial treatment with ritonavir, alprazolam clearance decreased, which led to enhanced alprazolam effects. Frye et al.¹⁰ studied ritonavir effects on alprazolam AUC during coadministration. After 12 days of ritonavir therapy, alprazolam AUC was diminished. This discrepancy is likely due to ritonavir’s initial inhibition of CYP 3A4 followed by CYP 3A4 induction over time.¹¹ Inhibiting CYP 3A4 will cause midazolam, triazolam, and alprazolam levels to rise, leading to possible toxicities such as oversedation, while induction of CYP 3A4 will cause therapeutic failure of the triazolobenzodiazepines, including withdrawal symptoms or dose escalation. Common CYP 3A4 inhibitors include the protease inhibitors; the nonnucleoside reverse transcriptase inhibitors delavirdine (Rescriptor®) and efavirenz (Sustiva®); and the psychotropics nefazodone (Serzone®), paroxetine (Paxil®), and fluoxetine (Prozac®). Common CYP 3A4 inducers include carbamazepine (Tegretol®), phenytoin (Dilantin®), rifampin (Rifadin®), and phenobarbital (Phenob®) as well as nevirapine (Viramune®), a nonnucleoside reverse transcriptase inhibitor antiretroviral.

Other benzodiazepines, such as lorazepam (Ativan®), oxazepam (Serax®), temazepam (Restoril®), and diazepam (Valium®), are metabolized by a variety of enzymes, including uridine 5'-diphosphate glucuronosyltransferase (UGT) 1A1, 1A3, and 2B7, with minor contributions by CYP 3A4. This multienzyme approach limits the frequency of drug-drug interactions. No case reports were found in the literature regarding interactions with antiretrovirals and these benzodiazepines.

Flunitrazepam (Rohypnol®, "roofies") is a potent benzodiazepine not available in the United States but prescribed in Europe and Latin America. Common to the club scene, flunitrazepam can create a significant sense of euphoria and calm lending to its high abuse potential. Flunitrazepam is primarily metabolized by CYP 3A4 and 2C19. CYP 3A4 inhibitors such as ritonavir, paroxetine, and nefazodone will likely result in flunitrazepam toxicity, the effects of which include hypotension, confusion, visual disturbances, urinary retention, and aggressive behavior.¹² Flunitrazepam is also a potent inhibitor of UGT 1A1, 1A3, and 2B7.¹³ This potent inhibition may result in increased levels of UGT substrates such as other benzodiazepines, valproate, and certain opiates.

COCAINE

Intravenous drug use is a well-known risk factor for HIV transmission, but studies show that smoking free-base "crack" cocaine is also an independent risk factor for the transmission of HIV.^14–16 Given the high recidivism rates of cocaine use, an understanding of the impact of continued cocaine use on antiretroviral therapy is important to successful treatment practices.

Cocaine undergoes both N-demethylation and hydroxylation during its first pass metabolism. N-Demethylation of cocaine results in the active and hepatotoxic metabolite norcocaine, while hydroxylation produces inactive metabolites including benzoylecgonine and ecgonine methyl ester. Cocaine’s metabolism to norcocaine is primarily performed at CYP 3A4.^17,18 The inactive metabolites have little clinical impact outside of their use for forensic evaluations.^19–21

Scarce research exists directly measuring the impact of cocaine on antiretroviral therapy efficacy. However, extrapolating from the available data, a significant risk for cocaine toxicity exists. All protease inhibitors and many other antiretrovirals are CYP 3A4 inhibitors to some degree, with ritonavir, indinavir (Crixivan®), and efavirenz being potent inhibitors. Administration of a potent CYP 3A4 inhibitor with subsequent cocaine ingestion could result in a cocaine overdose. Cocaine overdose is potentially fatal due to rhabdomyolysis,²² arrhythmia, and cardiovascular collapse.²³ Other potent CYP 3A4 inhibitors include ketoconazole (Nizoral®), nefazodone, erythromycin, and clarithromycin (Biaxin®).

Norcocaine, the CYP 3A4 metabolite of cocaine, is a known hepatotoxic agent.^24,25 Antiretrovirals that induce CYP 3A4 activity, such as nevirapine, may shift the metabolism of cocaine from hydroxylation to N-demethylation and create a higher level of the potentially toxic metabolite.^26,27 Thus, drugs that inhibit or induce CYP 3A4 must be monitored in active cocaine users.

GHB (LIQUID X)

GHB (gamma hydroxybutyrate), a natural product of GABA metabolism,²⁸ was initially developed as an anesthetic in 1960.²⁹ Camacho et al.³⁰ found that over half of survey respondents in their HIV clinic reported GHB use. GHB metabolism and elimination remains poorly understood. The major route of elimination is via expired carbon dioxide during breathing. Although no human studies are available, animal models indicate first pass metabolism is mediated by the cytochrome P450 system, and inhibition of this system could result in GHB toxicity. Harrington et al.³¹ reported a case of GHB toxicity in an HIV-positive male subject being treated with ritonavir and saquinavir (Invirase®) who also regularly used MDMA (ecstasy). Having recently initiated highly active antiretroviral therapy, the HIV-positive male subject ingested his normal MDMA dose, which resulted in much longer effects than usual (29 hours). He attempted to counter the side effects of MDMA by taking a small dose (10 mg/kg) of GHB. Within 20 minutes he became unresponsive with a heart rate of 40 bpm; he required intubation for airway protection. After several hours of supportive measures, the patient regained consciousness and no longer required respiratory support. The authors concluded that the likely cause was protease inhibitor-mediated inhibition of P450 enzymes resulting in toxic levels of GHB and MDMA.

KETAMINE (SPECIAL K)

Ketamine, a derivative of PCP (phencyclidine hydrochloride), was developed for use as an anesthetic. Although its primary use is in veterinary medicine, recreational use has gained popularity in the "rave" scene.³² Ketamine is metabolized via N-demethylation by CYP 2B6 to norketamine and subsequently hydroxylated to inactive metabolites, which are excreted in urine.³³ CYP 3A4 and 2C9 appear to be involved in the metabolism of ketamine to a lesser extent. Limited animal data suggest that ketamine may be an inhibitor of CYP 3A4, although no human data are currently available.³⁴ In light of this information, patients should be counseled regarding the possibility of ketamine increasing side effects of antiretroviral treatment such as nausea, renal toxicity, hepatotoxicity, and weakness.

LSD (ACID)

LSD (lysergic acid diethylamide), more commonly known as acid, is a powerful hallucinogenic drug, altering many aspects of cognition.³⁵ The metabolism of LSD remains incompletely understood. LSD has multiple metabolites including N-desmethyl LSD (nor-LSD), 2-oxo-LSD, 2-oxo-3-hydroxy-LSD (OH-LSD), 13-hydroxy-LSD, and 14-hydroxy-LSD.³⁶ Of these metabolites, OH-LSD seems to be the major metabolite. In vitro studies using human liver microsomes and hepatocytes showed solid evidence of liver involvement in metabolism of LSD to OH-LSD.³⁷ Until we have more complete knowledge about the metabolism and effects of LSD on other medications, patients taking LSD concurrent with highly active antiretroviral therapy should be counseled regarding the possibility of unknown interactions.

MDMA (ECSTASY)

MDMA (3,4-methylenedioxymethamphetamine), also known as ecstasy or Adam, has gained increasing popularity since its arrival on the drug scene in the 1980s. Increasing use, particularly in adolescents, likely stems from the intense euphoric high and the misperception of limited adverse drug effects.^38–40 Both overdose and chronic use have serious medical complications that include life-threatening hyperthermia, seizures, acute renal failure, rhabdomyolysis, hyponatremia, and alteration of brain structure and function.^41–43

MDMA is metabolized via N-demethylation and oxidation at CYP 2D6 to 3,4-dihydroxymethamphetamine, with minor contributions from CYP 1A2, 2B6, and 3A4.^44,45 A smaller portion of MDMA is N-demethylated to 3,4-methylenedioxymethamphetamine at CYP 2D6 and 1A2.⁴⁶ Amphetamine and methamphetamine have a similar pattern of metabolism to MDMA.

Henry and Hill⁴⁷ reported a case of death resulting from the interaction of MDMA and ritonavir. An HIV-positive male subject on antiretroviral therapy that included ritonavir ingested approximately 180 mg of MDMA (a typical dose) while at a local bar. He had ingested similar quantities of MDMA before initiating antiretroviral therapy without ill effects. Within several hours, the man became tachypneic, tachycardic, hyperthermic, had a tonic-clonic seizure, and subsequently died. Postmortem studies showed an MDMA level about 10 times expected based on the estimated ingestion. In this case, inhibition of CYP 2D6 by ritonavir likely led to the overdose.

de la Torre et al.⁴⁸ conducted a study of 14 patients who were given varying doses of MDMA. Each of these patients was genotyped for CYP 2D6 activity. Of those patients who completed the study, there was significant variation in plasma levels, suggesting a nonlinear pharmacokinetic pattern to MDMA metabolism. There is also some suggestion of P-glycoprotein involvement.⁴⁹

Though the metabolism of MDMA and amphetamines is incompletely understood, the nonlinear pharmacokinetics, CYP 2D6 genetic variability, and possible P-glycoprotein effect place any patient taking a CYP 2D6 inhibitor at high risk for MDMA toxicity. Potent CYP 2D6 inhibitors include ritonavir, bupropion (Wellbutrin®), fluoxetine, paroxetine, and quinidine (Quinidex®).

OPIATES

A more detailed review of drug interactions involving opiates has been previously published in this space.^50,51

Narcotic analgesics can be grouped into synthetic compounds and those related to an alkaloid found in poppy seeds. The synthetic compounds include phenylpiperidines (e.g., meperidine [Demerol®] and fentanyl [Actiq®]) and pseudopiperidines (e.g., methadone [Dolophine®] and propoxyphene [Darvon®]). The alkaloid-related drugs include natural derivatives (e.g., heroin, morphine, and codeine) and semisynthetics (e.g., hydromorphone [Dilaudid®], oxymorphone [Numorphan®], oxycodone [OxyContin®], dihydrocodeine, and buprenorphine [Buprenex®]). This section will address each of these groups in turn.

Phenylpiperidines such as fentanyl and alfentanil (Alfenta®) are primarily metabolized through CYP 3A4, while meperidine undergoes a more complicated metabolism that is not yet fully understood. Meperidine undergoes both hydrolysis to meperidinic acid via liver carboxyl esterases and demethylation to normeperidine by microsomal liver enzymes. Piscitelli et al.⁵² found that ritonavir dosing in healthy subjects decreased meperidine AUC while increasing normeperidine, implying induction of metabolism. Although normeperidine has some pharmacologic activity, it is known to be CNS excitotoxic, increasing the risk of seizures. CYP 3A4 inhibitors and inducers both pose risks during meperidine therapy. Inhibitors may cause meperidine overdose while inducers may create more normeperidine and an increased risk of seizures. Fentanyl and alfentanil, primarily metabolized by CYP 3A4, pose a risk when coadministered with a CYP 3A4 inhibitor such as ritonavir, efavirenz, delavirdine, and nefazodone.

Pseudopiperidines include methadone and propoxyphene. Methadone is primarily metabolized by CYP 3A4 with minor contributions from CYP 2D6, 2C9, 2E1, and 1A2.⁵³ Given methadone’s frequent use in pain management and heroin addiction, several case reports and studies regarding interactions exist in the literature. Lopinavir/ritonavir (Kaletra®), ritonavir, nevirapine (Viramune®), and efavirenz have all been reported to cause opiate withdrawal when given in combination with methadone.^54–58 The mechanism for causing opiate withdrawal may be potent induction of a more minor enzyme such as CYP 2C9 as well as induction of CYP 3A4. Methadone may also inhibit CYP 3A4 and UGT 2B7, but these are in vitro data.^59,60 Further research in this area is still needed. A prudent clinical approach may be to obtain a trough methadone level and assess opiate withdrawal symptoms prior to initiating a new antiretroviral, then provide close observation in conjunction with teaching during the initial weeks after addition of cytochrome-inducing antiretrovirals.⁶¹

Alkaloid-related natural derivatives of poppy seeds include heroin, morphine, and codeine. Heroin, an illegal and very potent natural derivative, is metabolized primarily by plasma and liver esterases to 6-monoacetylmorphine and morphine, respectively, and has little interaction with the CYP 450 system. Morphine is metabolized by UGT 2B7 and 1A3. This metabolism results in three products: 3-conjugate morphine (M3G), 6-conjugate morphine (M6G), and 3/6-conjugate morphine (M3/6G). UGT 2B7 primarily produces M6G while UGT 1A3 produces M3G, even though there is likely some overlap as well as production of M3/M6G by both enzymes. Drugs that induce or inhibit UGT enzymes could alter analgesic efficacy causing breakthrough pain or opiate overdose.⁶² Similarly, codeine is primarily metabolized by UGT 2B7 with minor contribution by P450 2D6 (<5% to morphine) and 3A4 (10% to norcodeine). Codeine’s primary metabolite is codeine-6-glucuronide, which has been hypothesized to be responsible for codeine’s effective analgesia. In this case, drugs that inhibit or induce UGT 2B7 would be a concern when determining codeine dose.^63,64 For a listing of medications that affect UGTs, see http://www.mhc.com//Cytochromes//UGT//UGTTable.HTML.

Alkaloid-related semisynthetics include hydromorphone, oxymorphone, dihydrocodeine, hydrocodone, oxycodone, and buprenorphine. Hydromorphone, oxymorphone, and dihydrocodeine are potent analgesics primarily metabolized by UGT 2B7 and 1A3 with minor contribution from CYP 2D6. UGT metabolism produces hydromorphone-3-glucuronide (H3G), oxymorphone-6-glucuronide (O6G), and dihydrocodeine-6-glucuronide (DHC6G), respectively. H3G is a known CNS excitotoxin, while the potency and side effects of O6G and DHC6G are still being researched. Inhibition or induction of UGT enzymes may greatly impact analgesic efficacy or side effects, whereas inhibition or induction of CYP 2D6 seems to have little impact on overall efficacy or side effects of these medications.^65,66

Alternately, the semisynthetic opiates hydrocodone, oxycodone, and buprenorphine primarily use the P450 system. Hydrocodone, itself not a potent analgesic, is metabolized by CYP 2D6 and 3A4 to hydromorphone and normorphone respectively. Oxycodone is a potent analgesic in its own right, metabolized via CYP 2D6 to oxymorphone, whose metabolism is described above. Inhibition of CYP 2D6 by medications such as ritonavir or paroxetine would likely decrease hydrocodone’s analgesia while having little impact on oxycodone’s efficacy. Conversely, induction would likely result in hydrocodone toxicity from its active metabolite hydromorphone, while oxycodone’s conversion to an active metabolite would cause less variation in analgesia.

Buprenorphine is a mixed µ agonist/antagonist whose primary metabolism occurs via CYP 3A4 with metabolites being further conjugated by UGTs. Buprenorphine’s reliance on CYP 3A4 for metabolism increases the likelihood of drug-drug interactions with CYP 3A4 inducers or inhibitors.⁶⁷ Common CYP 3A4 inhibitors include the protease inhibitors ritonavir, lopinavir/ritonavir, and indinavir; the nonnucleoside reverse transcriptase inhibitors delavirdine and efavirenz; and the psychotropics nefazodone, paroxetine, and fluoxetine. Common CYP 3A4 inducers include carbamazepine, phenytoin, rifampin, and phenobarbital.⁵¹

PCP (ANGEL DUST)

PCP (phencyclidine) was originally designed by Parke-Davis in the 1950s as an anesthetic agent. Even though it never reached market due to significant side effects, PCP gained popularity as a drug of abuse in the 1960s and 1970s. While still not completely understood, PCP’s metabolism seems to be mediated primarily by CYP 3A4.⁶⁸ Although we have found no case reports, it is likely that patients receiving potent CYP 3A4 inhibitors while on PCP would increase their risk for PCP toxicity. Potent CYP 3A4 inhibitors include indinavir, ritonavir, efavirenz, ketoconazole, and nefazodone.

Studies suggest that PCP inhibits CYP 2B6 activity in vitro.⁶⁹ Though most medications are metabolized through other enzymes, several medications, including bupropion and efavirenz,⁷⁰ are CYP 2B6 substrates, and coadministration could lead to high plasma levels of the medication.

THC (MARIJUANA)

THC (tetrahydrocannabinol), the psychotropic component of Cannabis sativa, comprises several active chemical structures and metabolites. ⁸-THC and ⁹-THC content may be as high as 10% in certain varieties of marijuana.^{70 8}-THC undergoes metabolism to 7-hydroxy-⁸-THC and subsequently 7-oxo-⁸-THC, both of which are active metabolites. ⁹-THC undergoes similar metabolism to the active structures 8-hydroxy-⁹-THC and subsequently 8-oxo-⁹-THC. The primary means of metabolism for both ⁸-THC and ⁹-THC and their metabolites is via CYP3A4, with a more modest role by CYP2C9.^71–73

Limited in vivo research is currently available. Kosel et al.⁷⁴ studied the effects of cannabinoids on indinavir and nelfinavir. Sixty-two patients who were stable on regimens of indinavir or nelfinavir (Viracept®) were studied in a randomized placebo controlled trial of smoked marijuana and dronabinol (Marinol®). No clinically significant changes in plasma levels of either antiretroviral occurred. Similarly, Abrams et al.⁷⁵ studied smoked THC and dronabinol in 67 HIV patients receiving antiretroviral therapy. No significant interactions were noted that would warrant dose adjustment of antiretroviral therapy in the context of smoked THC or dronabinol.

Whether smoked or ingested, THC can be a useful therapy for HIV-associated wasting and other antiretroviral side effects such as gastrointestinal distress.⁷⁶ As understanding of THC use in the HIV population increases, it is possible that more patients will be offered this effective treatment. Although there is no current evidence that THC has a detrimental effect on antiretroviral therapy, the metabolism of THC through CYP 3A4 may be altered by antiretroviral therapy. Potent CYP 3A4 inhibitor administration may result in greater effect and longer duration of THC, and patients should be counseled concerning this possible interaction. Patients should also be counseled that daily smoked THC ingestion might result in CYP 1A2 induction (as is seen with the polyaromatic hydrocarbons [PAHs] of tobacco smoke).

SUMMARY

The complexities of HIV/AIDS treatment can be frustrating for both patient and clinician. The difficulties with side effects, adherence, and drug-drug interactions hamper the goal of effective therapy. These interactions have been summarized in Parts I and II of this series on antiretrovirals. Table 1 in this third installment reviews important sites of metabolism and potential interactions of drugs of abuse. Triazolobenzodiazepines (triazolam [Halcion®], alprazolam [Xanax®], and midazolam [Versed®]) are dependent on CYP 3A4 for metabolism and potent CYP 3A4 inhibitors such as ritonavir may cause significant toxicity, resulting in prolonged sedation and effect. MDMA use while taking ritonavir may also result in deadly consequences due to inhibition of MDMA metabolism via CYP 3A4. Methadone withdrawal, although not life threatening, can occur when a cytochrome-inducing antiretroviral such as nevirapine or ritonavir is initiated.

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TABLE 1. Summary of Metabolism and Major Potential Interactions With HIV/AIDS Treatment Regimens for the Drugs of Abuse

Open lines of communication and counseling about potential drug-drug interactions are also vital to effective HIV/AIDS therapy. The stigma surrounding drugs of abuse may result in patients failing to report or reporting reduced use of these substances. Inquiring about substances of abuse in order to ensure the safety of patients and to assist in preventing drug-drug interactions fosters trust and may provide opportunity for further treatment of both HIV and substance abuse or dependence.

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