| Table 1. Potential and Documented Drug Interactions between Recreational Drugs and Antiretroviral Agents |
| Alcohol |
| Pharmacokinetics | Interactions | Significance | Comments |
| Principally metabolized by alcohol dehydrogenase, but acute use can lead to enzyme inhibition, and chronic use may induce activity of CYP2E1 and CYP3A . | With induction of CYP3A, alcohol may increase the metabolism of PIs and NNRTIs. Because a common metabolic pathway is used by abacavir, there is theoretical concern that alcohol may compete for metabolism, thus increasing abacavir serum concentrations. | Inducing metabolism of specific medications may result in subtherapeutic levels, predisposing to resistance and decreasing efficacy. | Although the possibility of CYP3A induction is of theoretical concern, there may be little or no actual interaction between alcohol and ARV agents. Alcohol abuse and concomitant use of hepatotoxic agents may increase the risk of early and severe liver damage. Additionally, chronic alcohol abuse in the presence of didanosine markedly increases the risk of pancreatitis. There is no evidence of increased risk of abacavir-related toxicity or hypersensitivity reaction. |
| Amphetamine Compounds (crystal methamphetamine) |
| Pharmacokinetics | Interactions | Significance | Comments |
Primarily metabolized by cytochrome P450 (CYP2D6). Under normal conditions, approximately 15% of a dose is eliminated renally, but as urine becomes more acidic, the proportion excreted renally may increase to 55%. | Inhibition of CYP2D6 can interfere significantly with hepatic metabolism of the amphetamine compound. Such inhibitors include:  | Ritonavir (increases amphetamine levels 2- to 3-fold) |  | | Delavirdine | | | Selective serotonin reuptake inhibitors (SSRIs) (primarily fluoxetine, fluvoxamine, sertraline, paroxetine) | |
| Inhibition of amphetamine metabolism leads to increased levels of the compound. Effects similar to those seen with large doses may be anticipated. Response is variable from patient to patient and may include intense exhilaration, euphoria, agitation, panic, angina, cardiovascular collapse, convulsions, and cerebral hemorrhage. Amphetamines do not have any significant effect on ARV agents. | Patients who are taking ritonavir or other potent CYP2D6 inhibitors should be strongly urged to avoid using amphetamine compound(s). |
| Amyl Nitrate (poppers) |
| Pharmacokinetics | Interactions | Significance | Comments |
| Completely and rapidly metabolized in the liver by first-pass mechanism. | Pharmacodynamic property of this agent creates rapid and systemwide vasodilation. Agents that also cause vasodilation may create an additive effect. The use of erectile dysfunction (ED) agents such as sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), and amyl nitrate may significantly decrease cardiac circulation. | Combinations of nitrates and ED agents can cause severe hypotension and may lead to loss of consciousness, ischemic angina, unstable angina, and myocardial infarction. | Nitrates and nitric oxide compounds are contraindicated with ED agents. Caution should be exercised with concomitant use of other vasodilators. |
| Benzodiazepines, Group I (alprazolam, clorazepate, clonazepam, diazepam, midazolam, triazolam) |
| Pharmacokinetics | Interactions | Significance | Comments |
| These agents are metabolized extensively in the liver by CYP3A4 isoenzymes. | Drugs inhibiting CYP3A4 could theoretically interfere with metabolism of these agents, causing a large increase in the area under the time-concentration curve (AUC). Ritonavir is the most potent CYP3A4 inhibitor. | Large increases in the AUC (>3-fold) of some of these compounds could have serious consequences, including sedation and respiratory depression. | Midazolam and triazolam are contraindicated for use with ritonavir; other PIs should be used with extreme caution. Other benzodiazepines may be administered safely with PIs, with close monitoring and dose adjustment. |
| Benzodiazepines, Group II (lorazepam, oxazepam, temazepam) |
| Pharmacokinetics | Interactions | Significance | Comments |
| These benzodiazepines are metabolized primarily by conjugation with glucuronic acid, which is mediated by glucuronosyltransferase enzymes. | Agents that increase glucuronosyltransferase enzyme activity may increase the metabolism of these compounds. Ritonavir may increase the metabolism of these drugs by this mechanism. | Concomitant use of these agents with ritonavir may decrease their therapeutic effectiveness. In patients who are abusing these agents, reduction in serum levels may cause symptoms of withdrawal, including: rebound insomnia, tremors, irritability, dysphoria, panic/paranoia, and convulsions. | Patients receiving these benzodiazepine agents for therapeutic purposes should be monitored for loss of effectiveness in the presence of ritonavir therapy. These benzodiazepine agents are likely to have less toxicity than the above (group I) agents. Patients who are known to be actively abusing these agents should be given an alternate PI or monitored for withdrawal. |
| Caffeine |
| Pharmacokinetics | Interactions | Significance | Comments |
| Thought to be extensively metabolized by the CYP1A2 enzyme group. Minor pathways include CYP2D6 and CYP3A4. | Drugs most likely to affect the metabolism of caffeine include those that inhibit its major metabolizing isoenzymes: ciprofloxacin (and potentially other fluoroquinolones) and macrolide antibiotics. | Elevations in caffeine levels may result in accentuated effects: increased blood pressure, increased central nervous system stimulation, tremors, and atrial dysrhythmias. CYP3A4 inhibitors such as ritonavir potentially elevate caffeine levels, but this is unlikely as it involves a very minor pathway in caffeine metabolism. | Recommend decreasing caffeine intake while concomitantly using agents that inhibit CYP1A2. No documented interaction between caffeine and PIs has been reported. |
| Cocaine |
| Pharmacokinetics | Interactions | Significance | Comments |
Primarily metabolized by tissue and plasma enzymes. Small amount (10%) is metabolized by P450 enzymes (CYP3A3/4, CYP2B1) to hepatotoxic metabolite. Cocaine may induce some P450 enzymes with chronic use, and inhibit others with acute use. The isoenzymes involved are not related to ARV drug metabolism. | Potential interaction with: | Protease inhibitors (PIs) | | | Nonnucleoside reverse transcriptase inhibitors (NNRTIs) (nevirapine, efavirenz) | | | Macrolide antibiotics (erythromycin, clarithromycin) | |
| Both inhibition and induction of P450 enzymes can lead to increased effects or toxicities of cocaine because of increased levels of the drug or active metabolites. However, given the minor role these enzymes play in overall cocaine metabolism, clinical significance is unlikely. Cocaine is unlikely to have any significant effects on ARV agents. | Monitor for increased cocaine effects and hepatotoxicity. Cocaine is also a known immunotoxic agent, significantly decreasing CD4+ cell production by as much as 3- to 4-fold, and increasing the rate of HIV reproduction up to 20-fold. |
| Ecstasy (X, MDMA) and GHB (gamma hydroxybutyrate) |
| Pharmacokinetics | Interactions | Significance | Comments |
Ecstasy is an amphetamine-like compound that has similar metabolism as amphetamine compounds, with the major portion metabolized by CYP2D6. GHB is also thought to be metabolized through the CYP2D6 isoenzyme. | Inhibition of CYP2D6 is likely to impair detoxification of ecstasy and GHB because of large increases in serum levels. Such inhibitors include: | Ritonavir (increases ecstasy levels by 5- to 10-fold) | | | Delavirdine | | | SSRIs | |
| At least 2 deaths from the combination of ritonavir and ecstasy have been reported. Ritonavir can increase the risk of life-threatening adverse effects from ecstasy (eg, heatstroke and dehydration) and GHB (eg, seizures, bradycardia, respiratory depression, loss of consciousness). Dehydration effects of these medications could increase the risk of renal stones in patients taking indinavir. | Strongly recommend avoiding the combination of ecstasy or GHB with ritonavir or other potent CYP2D6 inhibitors. Recent research has shown that ecstasy affects serotonin levels and can increase the potential for depression and anxiety disorders in individuals at risk. At least 68 deaths have been attributed to the combination of ecstasy and alcohol. |
| Heroin, Morphine, Hydromorphone, and Codeine |
| Pharmacokinetics | Interactions | Significance | Comments |
Morphine and hydromorphone are extensively metabolized to glucuronides, mediated by glucuronosyltrans-ferases. Codeine is mainly metabolized by glucuronidation, but minor pathways include a process mediated by CYP2D6. Heroin is converted to morphine in the blood rapidly and is metabolized similarly. | Plasma concentrations of all these agents may be decreased by agents that increase the activity of glucuronosyltransferases (eg, ritonavir). In the presence of ritonavir, heroin serum concentrations are reduced by as much as 50%. Administration of codeine with a CYP 2D6 inhibitor may inhibit the bioactivation of codeine into morphine. | Decreased levels of all these agents may result in loss of therapeutic effect when administered with ritonavir. Patients abusing these agents who add ritonavir may develop withdrawal symptoms, including lacrimation, rhinorrhea, irritability, tachycardia, elevated blood pressure, chills, flushing, sweating, seizures, myalgias, and arthralgias. There is also potential for an increase in a glucuronide metabolite, which is 45 times more potent than the parent compound. This increase in active metabolite could offset the above-described decreases in parent opiates. | Patients taking these agents with ritonavir or a CYP2D6 inhibitor (of codeine) should be monitored either for loss of therapeutic effect (in the case of prescribed opiates) or for withdrawal symptoms. |
| Ketamine (Special K) |
| Pharmacokinetics | Interactions | Significance | Comments |
Undergoes extensive demethylation and hydroxylation in the liver, possibly via CYP3A4, and is excreted in the urine. Ketamine is structurally similar to phencyclidine and may undergo similar metabolism. | CYP 3A4 inhibitors could inhibit the metabolism of ketamine, resulting in elevated serum concentrations of the compound. A wide range of CYP3A4 inhibitors can play a significant role in interactions with ketamine, including: | Protease inhibitors | | | Macrolide antibiotics | | | Delavirdine | |
| Ketamine has a reported wide margin of safety; however, elevated serum concentrations could result in increased heart rate, increased blood pressure, or respiratory depression. Chronic use of ketamine in the presence of ritonavir may increase ketamine concentrations and the potential for hepatotoxicity and drug-induced hepatitis. | Caution should be exercised with concomitant use of ketamine and agents that are CYP3A4 inhibitors. Two cases of drug-induced hepatitis have been reported in patients concomitantly using ketamine and ritonavir. Ketamine is often added to other illegal psychoactive substances such as ecstasy, marijuana, and others. |
| LSD, Mescaline, Psilocin, and Methyltryptamine |
| Pharmacokinetics | Interactions | Significance | Comments |
Information about P450 metabolism is not available. LSD is structurally similar to serotonin and thus may be metabolized similarly. This means that LSD might be eliminated by the enzymes monoamine oxidase (MAO), aldehyde dehydrogenase, and alcohol dehydrogenase. Mescaline, psilocin, and dimethyltryptamine may have similar metabolic pathways. | Based on the postulated metabolism of LSD, MAO inhibitors could cause serious interactions by decreasing LSD metabolism and increasing serum levels. Because the metabolism of both abacavir and LSD involves alcohol dehydrogenase, it is possible that levels of either drug may be affected by the other; the clinical significance of any possible interactions is unknown. | Possible adverse effects of increased serum levels of LSD include respiratory insufficiency, acute anxiety, fear, vascular spasm, and potentially fatal malignant hyperthermia. The clinical significance of this possible interaction is unknown. | Because no data confirm these interactions in humans, the clinical significance of combining LSD with MAO inhibitors or abacavir is unknown. |
| Phencyclidine (PCP) |
| Pharmacokinetics | Interactions | Significance | Comments |
PCP is mainly metabolized in the liver, mediated by CYP2C11. It is also speculated that PCP may inhibit CYP2B1. | Given the potential bidirectional effect on P450 enzymes, it is difficult to predict significant drug interactions. | The effects of PCP or PIs may increase with concomitant use. The clinical significance of this potential interaction is unknown. | No case reports have described interactions between PCP and P450 inhibitors. Caution should be exercised if combining PCP with ritonavir because of possible increased effects of both PCP and PIs. |
| Tetrahydrocannabinol (THC, marijuana, hashish, and hashish oil) |
| Pharmacokinetics | Interactions | Significance | Comments |
| Rapidly metabolized in the liver to an active metabolite (11-hydroxyl THC), which is then converted to inactive metabolites and excreted in the urine and stool. Levels of the active metabolite vary with route of administration. The oral route produces more of the active metabolite than either the intravenous or inhaled route. P450 isoenzymes are thought to be important in THC metabolism (CYP3A3/4, 2C9, 2C6). | Inhibiting agents that affect CYP3A3/4 could affect THC metabolism, thus increasing parent compound THC levels: | PIs | | | Macrolide antibiotics | | | Delavirdine | |
Inducing agents of the same isoenzymes could reduce THC levels: | Efavirenz, nevirapine | | | Rifampicin compounds | |
Fluconazole is an inhibitor of 2C9 and potentially increases THC levels. Clinical trials of THC in patients taking nelfinavir and indinavir suggested no change in THC levels, but some decrease in nelfinavir and indinavir levels. It is possible that more potent CYP3A3/4 inhibitors (eg, ritonavir) may change THC levels significantly. | Inhibition of selected isoenzymes may increase THC levels, producing higher parent THC levels but a lower amount of the active THC metabolite. The net effect on THC pharmacology is unknown. Symptoms of higher THC levels include frank hallucinations, delusions, paranoia, altered time sense, anxiety, panic, orthostatic hypotension, and increased heart rate. In the same way, medications that induce CYP3A4, 2C9 and 2C6 may increase or decrease THC effects. The clinical significance of changes in nelfinavir and unboosted indinavir with THC is unknown. | Recommend close monitoring of response to THC in patients who also take inhibitors and inducers of THC metabolism. To date, no clinically significant effects have been reported, despite widespread concomitant use of these agents. |
