Ultimate Harm Reduction Guide to Drug Mixing

According to the CDC, drug poisoning deaths have more than doubled since 1999 and now surpass the number of deaths due to traffic fatalities. The total number of drug poisoning deaths in the U.S. was 43,982 in 2013. Increases in opioid overdose deaths have been a major contributing factor to the increase in overall drug poisoning deaths. The number of opioid overdose deaths has more than quadrupled since 1999. In 2013 there were 23,153 opioid overdose deaths – 16,235 involving opioid painkillers, 8,260 involving heroin/opium, and at least 1,342 involving a combination of the two.

…opioid overdoses are seldom due to opioid use alone; the majority are a result of mixing an opioid with some other drug.-Kenneth Anderson

However, as we shall discuss in detail below, opioid overdoses are seldom due to opioid use alone; the majority are a result of mixing an opioid with some other drug. The best way to avoid opioid overdose is not taking opioids; the next best thing is to avoid drug mixing entirely. If you insist on mixing drugs in spite of the inherent dangers, then it is imperative to take extra safety precautions to not die when mixing drugs.

The most important safety precautions include not using alone, limiting the amount of drugs you have available, sticking to less lethal combinations, using smaller amounts of each drug, using the least impairing drug first, and having the opioid overdose reversal drug Narcan (naloxone) on hand. When injecting drugs of unknown strength and purity such as street heroin, always start with small “tester” shots to gauge the strength of the drug before injecting a full dose. Likewise, when using a drug or drug combination for the first time, stick to tiny doses to gauge your innate tolerance first. Make sure your friends know which drug combinations you have taken. Have a plan for what to do if something goes wrong. Know about rescue breathing, the recovery position, and other aspects of opioid overdose response.

In case of overdose always call 911 even if you have administered Narcan (naloxone) to the overdose victim.

Twenty-two states and the District of Columbia have passed Good Samaritan laws to protect people from prosecution for calling 911. Don’t expect to be able to administer Narcan (naloxone) to yourself to reverse your own opioid overdose; most people lose consciousness without ever realizing they have overdosed. Narcan (naloxone) can only reverse overdoses where opioids are involved; however, it is always a good idea to administer Narcan (naloxone) if you suspect opioids might be involved or don’t know what drugs are involved because it can’t hurt. Narcan (naloxone) has no effect on non-opioid drugs such as stimulants, alcohol, or benzodiazepines, but it is harmless. In the case of polydrug overdoses involving opioids and other drugs, reversing the effects of the opioids with Narcan is usually sufficient to save the person’s life.

Narcan (naloxone) has no effect on non-opioid drugs such as stimulants, alcohol, or benzodiazepines, but it is harmless… reversing the effects of the opioids with Narcan is usually sufficient to save the person’s life.-Kenneth Anderson

It is also essential to know the purity of your drug; there are reports that more than half of what is sold as ecstasy is fake, and some drugs sold as ecstasy are highly dangerous. Get a drug testing kit from Amazon and make sure that the drug you take or mix is actually what it purports to be. Heroin laced with fentanyl is another deadly imposter.

Finally, be aware that it is impossible for anyone to give you a formula for how much of each drug is safe to mix with the other, because no one can know what your innate and acquired tolerance for each substance is, not to mention your innate and acquired tolerance for the combination itself.

Overdose and Synergy: When 1 + 1 = 5, 6, or 7

Breathing in humans is controlled by the Respiratory Control Center which is found in the hind brain. Some of the neurons comprising the Respiratory Control Center contain opioid receptors. Other neurons comprising the Respiratory Control Center contain GABA receptors. Opioids alone in large enough concentrations can overwhelm the opioid receptors in the Respiratory Control Center and lead to death by opioid overdose, which kills by stopping breathing. Likewise, GABA agonists such as alcohol or benzodiazepines (Xanax, Valium, Librium, Klonopin, Ativan, etc.) can overwhelm the GABA receptors and lead to death by alcohol poisoning or benzodiazepine poisoning, which also kill by stopping breathing. However, when poisoning occurs via ingestion of these drugs alone, large doses are required, and such poisonings occur far less frequently than do those which occur when these drugs are mixed together.

…when one dose of opioid is added to one dose of alcohol, it is not like two doses of opioid, or two doses alcohol; it is more like five doses of opioid or five doses of alcohol.-Kenneth Anderson

In other words, when one dose of opioid is added to one dose of alcohol, it is not like two doses of opioid, or two doses alcohol; it is more like five doses of opioid or five doses of alcohol. The opioids work to shut down the neurons with opioid receptors at the same time that the alcohol works to shut down the neurons with GABA receptors and the end result is that the entire Respiratory Control Center shuts down due to fairly low doses of each drug in the combination. When two drugs combined together have a far greater effect than either drug has alone, we call this effect synergy. Opioids are synergistic with alcohol. They are also synergistic with benzodiazepines.

Opioid Tolerance

Tolerance to opioids can develop rapidly over a short period of time with daily use. One can eventually wind up taking ten times the dose that would have killed one at the outset. Tolerance also drops very rapidly with abstinence; this is why if someone attempts to shoot the same dose of heroin after a 28-day rehab that they were shooting before, it will almost certainly kill them. Rehabs which say things like “Your disease is progressing even when you are not using” or “You will pick up again exactly where you left off” are responsible for the death of many clients. Sane rehabs teach overdose prevention and recommend maintenance therapy instead of drilling harmful slogans into clients’ heads.

So the same mix of drugs that might be safe for you might kill your friend, who is the same height and weight.-Kenneth Anderson

Researchers also speak about innate tolerance: everyone is born with different abilities to tolerate opioid drugs, or any drug for that matter. If you are a first time user then make your opioid dose very small because if you happen to be born with very low innate tolerance even a small dose could lead to respiratory arrest and kill you. There are huge individual differences in tolerance for different drugs. So the same mix of drugs that might be safe for you might kill your friend, who is the same height and weight. Finally there is such a thing as situational tolerance. Your tolerance for the drug will be lower in a new situation than when you are using in your usual situation. This has been proven even in rats; rats which were given their usual dose of opioids in a new situation died of overdose.

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Drug Mixing and Opioid Painkiller (Analgesic) Overdose

According to the New York City Department of Health 97 percent of drug overdose deaths in the city in 2012 involved drug mixing, and in 2013 this statistic was 94 percent. More than a quarter of overdose deaths in New York City involve mixing three drugs together, with the most common combination being heroin, cocaine, and alcohol. Figure 1 shows the most common lethal drug combinations found with non-medical painkiller use for the year 2011 in New York City. Since any number of drugs can be involved in a given death, these percentages add up to far more than 100 percent.

Relatively safe combinations with opioid painkillers are: marijuana, ecstasy, LSD, and mushrooms. Cocaine, alcohol, and benzodiazepines can be fatal when mixed with opioids.-Kenneth Anderson

Many areas in the U.S. do not record such precise information concerning drug mixing on death certificates as does New York City; however, it is reasonable to assume that 90 percent or more of drug overdoses throughout the U.S. also involve drug mixing. Relatively safe combinations with opioid painkillers are: marijuana, ecstasy, LSD, and mushrooms. Cocaine, alcohol, and benzodiazepines can be fatal when mixed with opioids. Moreover, since strong hallucinogens such as LSD can impair judgment it is safest to only have the intended dose of opioid on hand so as not to take more when impaired.

Many non-recreational medications can also have fatal interactions with opioids, so always check any medication you are taking for drug interactions on a reliable source such as drugs.com.

Heroin Overdose and Drug Mixing

People who use heroin are about six times more likely to die of an overdose than those using painkillers non-medically. Although heroin accounted for less than 6 percent of past year non-medical opioid use in 2013, it accounted for about 34 percent of opioid overdose deaths. One reason why heroin leads to more deaths than other opioid painkillers is that the Therapeutic Index for heroin is relatively low: about one third of that for morphine. The Therapeutic Index is obtained by dividing the effective half dose (ED50) by the lethal half dose (LD50). The Therapeutic Index for morphine is around 70 to 1; for heroin it is around 25 to 1. Since recreational doses are often much larger than therapeutic doses, Gable (2004) developed the notion of the Safety Ratio to discuss the dangers of recreational drug use. The Safety Ratio for heroin is about 6 to 1, which is very, very low.

People who use heroin are about six times more likely to die of an overdose than those using painkillers non-medically.-Kenneth Anderson

In addition to the low Safety Ratio, it is also very likely that heroin users tend to be much higher risk takers than non-medical painkiller users. This is suggested by the fact that few non-medical painkiller users transition to heroin, which, although generally cheaper and easier to obtain than painkillers on the black market, retains its status as a shunned and frightening drug. Additionally, those who transition to heroin are frequently already dependent on opioid painkillers, which helps account for the high dependence rates found among heroin users (63.7 percent) compared to non-medical painkiller users (13.4 percent) (NSDUH 2013).

Although it is quite easy to overdose on heroin alone, the vast majority of heroin overdoses are caused by mixing heroin with another drug, as is the case with painkillers. The usual culprits are: benzodiazepines, alcohol, cocaine, and other opioids. The New York City Department of Health reported that 36 percent of heroin overdose deaths in 2013 also involved benzodiazepines.

Strang (2003) found significantly increased risk of death by overdose following discharge by patients who successfully completed a 28-day abstinence-based rehab program.-Kenneth Anderson

Other major risk factors for heroin overdose are release from incarceration and abstinence-only residential drug treatment. Binswanger (2007) reports that inmates have 129 times the risk of death from drug overdose in the first two weeks after release from prison as the general public due to the fact that tolerance has dropped severely as a result of abstinence from opioids while incarcerated. Strang (2003) found significantly increased risk of death by overdose following discharge by patients who successfully completed a 28-day abstinence-based rehab program.

As with other opioids, combining heroin with depressants such as alcohol or benzodiazepines has a synergistic effect on respiration which can lead to death. Because of the low Therapeutic Index of heroin even smaller amounts of these substances can be deadly when combined with heroin than when combined with other opioids. It is safest to avoid these combinations entirely, but if you choose to mix heroin with depressants then please be careful to follow the safety precautions we mentioned earlier in this article.

Heroin and Cocaine: A Deadly Combination

When heroin is injected together with cocaine the combination is known as a “speedball.” This is a very dangerous combination resulting in a large number of deaths each year. Mechanisms of death for speedballs are poorly understood; hypotheses include opioid overdoses when cocaine wears off and cocaine poisoning resulting in heart attacks and arrhythmias. Further research is called for on this topic.The Harm Reduction Coalition offers the following hypotheses concerning the toxicity of speedballs: 1) the body has to process more drugs, 2) the stimulant causes the body to use more oxygen while the depressant reduces the breathing rate, and 3) people who speedball usually inject more frequently with less time between shots than people using only heroin.Of all possible opioid/stimulant combinations, the mixture of heroin and cocaine is probably the most dangerous. Risk can be lowered by substituting a longer half-life stimulant such as amphetamine or methamphetamine for the cocaine, or an opioid with a higher therapeutic index such as morphine for the heroin, but these combos can be fatal as well, so it is important to follow the safety precautions mentioned in the introduction when using these combinations.

Only about 15 percent of heroin overdose deaths are the stereotype “needle in the arm” deaths; the overdose generally happens over the course of 1 to 3 hours. The breathing grows shallower and shallower as the opioids have a stronger and stronger effect on the respiratory center in the brain. The person becomes unresponsive and begins to turn blue. So the fact that someone did not die immediately after shooting up is NOT evidence that they are safe; they need observation for several hours thereafter.

Novice users account for about 17 percent of heroin overdose deaths. Most OD deaths are experienced users. Just because you used a drug or drug combination without dying before does not necessarily mean it won’t kill you the next time. The more dangerous the drug or drug combination, the more important it is to observe safety precautions every time you use it. Tolerance changes constantly due to a multitude of factors: your general health, whether you are tired or hungry, medications you may be taking, time since last drug use, and even the environment you are in.

Methadone, Buprenorphine, and Drug Mixing

…people on methadone maintenance who combine their methadone with benzodiazepines, alcohol, cocaine, or other opioids are at risk for fatal overdose.-Kenneth Anderson

People on methadone maintenance or buprenorphine are at lower risk for overdose than those actively using heroin only. One study found that methadone maintenance reduces death rates by as much as 75 percent. Preliminary studies (Weiss et al. 2011; Potter et al. 2013) suggest that methadone and buprenorphine maintenance are also beneficial for people with Opioid Painkiller Use Disorder; however, the effects of maintenance on overdose death risk for this population have apparently not yet been studied. However, people on methadone maintenance who combine their methadone with benzodiazepines, alcohol, cocaine, or other opioids are at risk for fatal overdose. The New York City Department of Health found benzodiazepine mixing in 58 percent of deaths involving methadone in 2013.

Relatively safe drug combinations with methadone are the same as with other opioids: marijuana, ecstasy, LSD, and mushrooms. It is unfortunate that some clinics will punish clients for testing positive for THC since this is about the safest combination that there is. So check your clinic’s rules before using cannabis. If you use alcohol keep it very moderate. Large doses of alcohol with methadone are quite deadly. It is an unfortunate fact that many people on methadone maintenance use Xanax or another benzodiazepine to give the methadone a “kick” since this so often results in death. Marijuana is by far the safest choice if a need for intoxication is to be filled.

Dangers of Pre-Mixed Opioid Painkillers

A number of opioid painkiller pills consist of a mixture of an opioid painkiller with a non-opioid painkiller such as aspirin, ibuprofen or acetaminophen. Although aspirin and ibuprofen are relatively harmless, acetaminophen is highly toxic to the liver and can cause liver failure in large doses. Acetaminophen is sold under the brand name Tylenol and causes several hundred deaths and over 70,000 emergency room visits each year in the U.S. People rapidly develop tolerance to opioids and many daily users eventually wind up taking ten times the dose which could have initially killed them. However, people do not develop any tolerance at all to acetaminophen.

Often the dose of a painkiller required to get an experienced opioid user high contains enough acetaminophen to kill him/her dead. Acetaminophen overdose is not instantaneous; it manifests itself over a period of 24 to 96 hours. Taking more than 4 grams of acetaminophen in a day can be toxic to a healthy person; if acetaminophen is taken by someone with liver damage or if it is mixed with alcohol the toxic dose is much lower.

Commonly prescribed opioid/acetaminophen combinations are given in Table 1. The most commonly encountered brand names have been bolded. Do not assume this table is exhaustive; always check any new drug you take on drugs.com or in the PDR.

Stimulant Mixing and Stimulant Overdose

Stimulant overdoses are one of the most dangerous overdoses because there is no antidote. Pulp Fiction was only a movie; in reality you will not be able to inject adrenaline into someone’s heart to reverse their cocaine overdose; stimulant overdose requires treatment in the hospital. Effects of stimulant overdose can include: stroke, heart attack, arrhythmia, dehydration, panic attack, and extreme paranoia. Mixing stimulants together greatly increases the odds of overdose. The CDC reports 4,944 deaths due to cocaine in 2013 and another 3,627 due to other psychostimulants.

Other Dangerous Combinations: Alcohol and Benzos, Alcohol and Cocaine, Prescription Medications

Alcohol and benzodiazepines both exert their effects on GABA receptors; however, they each target different subtypes of receptors which makes their combined effects synergistic rather than merely additive. In other words, people who mix alcohol and benzodiazepines together are at greater risk of overdose than people who use either one alone because they combine synergistically. The CDC reports that alcohol was involved in 21.4 percent of benzodiazepine related deaths in 2010.

…people who mix alcohol and benzodiazepines together are at greater risk of overdose than people who use either one alone because they combine synergistically.-Kenneth Anderson

There are also other reasons why the combination of benzodiazepines with alcohol is more dangerous than either alone. Although it is quite possible to ingest a lethal dose of alcohBol (BAC 0.3 ~ 0.6), in the vast majority of cases the person who has drank a potentially lethal dose vomits it back up before absorbing it into the bloodstream. There is always a competition between the irritated stomach which wants to throw up and the gag reflex in the brain which is being suppressed by the alcohol. Usually the stomach wins and the result is vomit instead of overdose death. However, benzodiazepines don’t irritate the stomach lining, so it is far less likely that the lethal combination of alcohol and benzodiazepines will be vomited out and far more likely that it will result in death. The alcohol benzodiazepine combo is not very good for recreational purposes either, tending simply to lead to rapid blackouts.

Although the combination of alcohol and cocaine is far less toxic than the other combinations we have discussed above, it is more toxic than either alcohol or cocaine alone, and reasonable caution should be exercised when consuming this combination. Pennings, Leccese, and Wolff (2002) note that the combination of alcohol and cocaine can have greater-than-additive effects on heart rate, concomitant with up to 30 percent increased blood cocaine levels. This combination also leads to the formation of cocaethylene by the liver, which may potentiate the cardiotoxic effects of cocaine or alcohol alone. Data also suggest that the combination can potentiate the tendency towards violent thoughts and threats, which may lead to an increase of violent behaviors.

…the combination of alcohol and cocaine can have greater-than-additive effects on heart rate, concomitant with up to 30 percent increased blood cocaine levels.-Pennings, Leccese, and Wolff (2002)

Many prescription medications can be deadly when combined with alcohol, recreational drugs, or even other prescription medications. Any time you get a new medication always check for drug interactions with alcohol, recreational drugs, or your other prescriptions on drugs.com or in the PDR before taking it.

Conclusion

• • Remember, just because a particular combo didn’t kill you the first time you used it doesn’t mean it won’t kill you down the road. Case studies and anecdotal evidence from overdoses reversed with Narcan (naloxone) suggest that most people use a drug or a drug combination many times before having a fatal overdose.

• • Narcan (naloxone) usually is sufficient to reverse the overdose even when drug mixing is involved because there usually isn’t enough alcohol or other drugs involved to kill on their own after the opioid has been neutralized; however, calling 911 is always a good idea – especially if you have good Samaritan laws in your state.

• Can you reverse your own opioid overdose with Narcan (naloxone)? Although this may happen on extremely rare occasions, the reality is that this is unlikely. Most people who overdose become unconscious before they are aware that they are overdosing; it is like drifting off into sleep. This is why it is so imperative to have a friend nearby who can administer the Narcan (naloxone) in case of overdose and call 911.

• It is impossible for anyone to give you a formula for how much of each drug is safe to mix with the other because no one can know what your innate and acquired tolerances for each substance is, not to mention your innate and acquired tolerance for the combination. The best we can tell you is which drugs do not interact, and which interact less with each other.

• Education is needed in the school system so that kids who find a bottle of painkillers in grandma’s medicine cabinet will know better than to wash them down with a bottle of booze or mix them with the bottle of Xanax that was sitting next to them.

• Tripsit has a reference chart of safe and dangerous drug combinations which can be found here.

• For information about obtaining Narcan (naloxone) please contact The Harm Reduction Coalition.

Thanks to Michelle Shears Whitman for consultation on this article.