Tox and Hound – Don’t Be A Goofball

by Dan Rusyniak

No doubt the plateau in opioid deaths in many towns across America has led to a collective sigh of relief. And to be sure, fewer people dying is a very good thing. But, like the game Whac-A-Mole™, as soon as one epidemic decreases, another emerges. In the mid ’90s to the early 2000s, it was the methamphetamine epidemic. After methamphetamine, it was the prescription opioid, heroin, and now synthetic opioid (i.e., fentanyl and derivatives) epidemics. Today’s new emerging problem is neither meth nor an opioid. It is both.

People using two illicit substances together is nothing new. The speedball, a combination of cocaine and heroin, after all, was behind the deaths of some of our, well certainly some of my, most beloved actors: e.g., John Belushi and Chris Farley. And while speedballs are commonly defined as the combination of cocaine and heroin, it can also be the name for the combination of any stimulant and sedative. One combination that I am particularly worried about is the intravenous combination of methamphetamine and heroin (or fentanyl) — The Goofball.^​1,2​

Not to get off track, but how do street drugs end up with their names? Goofball, for instance, had been a slang term for barbiturates and sedatives for years and then one day, poof, it is the name for methamphetamine and heroin. My best guess is that it is a play on the name speedball and since it involves methamphetamine, which causes more cognitive problems than cocaine, it came to be called goofball. But I digress. The reason I am worried about goofballs is that usage of this drug combination is on the rise. There is reason to believe, as I shall discuss, that goofballs, especially when they involve fentanyl, may be particularly deadly.

That methamphetamine use is on the rise is not news. In fact, methamphetamine use never really went away. Yes, more people used opioids in the last decade, but since 2011 the number of persons seeking treatment for methamphetamine use disorder has steadily increased.^​3​ With the prevalence of opioid-use disorder and amphetamine-use disorder where it is today, it was only a matter of time before we would see them merge. Data from a variety of western cities have confirmed this. In a recent sample of persons who inject drugs in the Denver area, 28% of them report injecting goofballs and 40% admit to using both drugs independently at different times.^​4​ This is similar to a recent survey in the greater Seattle area where approximately 50% of heterosexual men who use IV drugs used goofballs – a fivefold increase between 2009 and 2017.^​5​ This study also showed increases in goofball use among homosexual men (from 18 to 31%).^​5​ A survey in San Diego, has shown similar increases, and lastly, a national survey also demonstrated co-use increased from 19% in 2011 to 34% in 2017.^​3,6​ Although these studies asked participants about heroin use, it is also likely that many of those surveyed were using, both knowingly and unknowingly, fentanyl. The increase in co-use of fentanyl and methamphetamine is also supported by a 2018 cross-sectional analysis of urine drug screens sent by health professionals as part of routine care.^​7​ When compared to samples analyzed from 2013, there was a 798% increase in samples where both fentanyl and methamphetamine were present.^​7​ And, lastly, we are seeing evidence of increased usage in overdose deaths. While deaths from methamphetamine are increasing, the majority of these cases involved opioids as well.^​8,9​

These increases led me to the question of why? Why would someone want to use both a stimulant and a depressant?

One answer is that both drugs are everywhere. The rise of heroin use, its availability, and antecedent causes for use have been widely documented. The current opioid of choice in many US cities is fentanyl. As it turns out, manufacturing a highly potent opioid in a lab is far more profitable than growing plants. You don’t need to worry about rain, sun, pests, harvests, rival drug lords, etc. Collectively, this results in the widespread availability of low-cost fentanyl and is behind the growing number of fentanyl-related deaths in the US.^​10​ Meth is also everywhere. No longer concocted in trailers, basements, garages, or by high school chemistry teachers with lung cancer, the meth today is made in Mexico and is cheap and pure.^​6​ With both cheap and available, it is no surprise that the two drugs attributed to the largest number of overdose deaths are methamphetamine and fentanyl. These two drugs have, like our politics, split the country in half with deaths in the east attributed most commonly to fentanyl and those in the west to methamphetamine.

Another reason someone might use goofballs is that co-administration of an opioid and a stimulant is more rewarding than either alone. Rats, for instance, will work harder to get an injection of heroin combined with either cocaine or methamphetamine than the stimulant alone.^​11,12​ Similarly, the simultaneous administration of cocaine and heroin causes a synergistic increase in the release of dopamine in brain areas involved in reward.^​11​ Despite this, there has not been convincing evidence that co-administration of stimulants and opioids causes a unique subjective experience.^​13​ Rather, it seems to cause a combination of both experiences at the same time.^​6​

Self-treatment of negative effects of drug use is another proposed reason persons might use both a stimulant and a sedative. Amphetamines, for instance, can cause severe sleep disturbances. Sedatives can counteract these effects. This is why military pilots used “Go pills” (e.g., amphetamines) to stay awake during long flights and “no-go pills” (e.g., zolpidem) to sleep when they returned.^​14​ Goofball users do the same. Because they are frequently homeless, or housing unstable, heroin use puts them at risk of being robbed if they lose consciousness on the street. This is why some persons with opioid use disorder now combine their heroin with methamphetamine. It allows them to stay awake during the evening hours when they are more likely to be victims of crime or arrested by the police.^​4,5​

One might assume that co-injecting methamphetamine with heroin, or now fentanyl, would be safer than injecting the opioid alone. After all, the physiologic effects of these drugs would seem to balance each other. Opioids cause hypothermia, sedation, and respiratory depression while amphetamines cause hyperthermia, wakefulness, and respiratory stimulation. If that was true, we would expect that persons who use goofballs would be less likely to overdose. Unfortunately, the opposite seems true. In surveys, goofball users were more likely to have overdosed than study participants who used heroin alone.^​1,4,5​

Why would that be? Possibly it is just an association. For instance, persons using two intravenous drugs may have riskier drug use patterns. Another possibility is that the combination of the two drugs actually increases their toxic effects. At least in animal studies, this has been demonstrated. In both mouse and rat studies, the co-injection of methamphetamine and morphine results in increased locomotion, increased body temperature and increased lethality.^{​15–18​} The mechanism behind the increased lethality is not completely clear. As noted above, the combined use of opioids and methamphetamine increased body temperature in rodents. Whether this might have a similar effect in humans is not known. There are at least two cases in which hyperthermia was posited as the cause of death in someone simultaneously injecting methamphetamine and heroin. These cases, however, were based on post mortem temperature being higher than anticipated for the ambient temperature.^​19​ Hyperthermic effects from goofballs may be further exacerbated when the opioid is fentanyl. Fentanyl, when used with other serotonergic agents can evoke serotonin syndrome.^​20​ Since methamphetamine can increase serotonin release, it is not hard to envision how a goofball containing meth and fentanyl could induce fatal hyperthermia.^​21​ And as we’ve previously discussed, with stimulants temperature is related to mortality.

It would seem that opioids may increase the hyperthermic effects of amphetamine, but what about the respiratory depressant effects of the opioid? In one controlled study of human volunteers, IV amphetamine (0.215 mg/kg) antagonized the respiratory depressant effects of a low dose of morphine (0.15 mg/kg).^​22​ At higher doses of morphine (0.3 mg/kg) this dose of amphetamine was no longer able to prevent respiratory depression. In rodents, cocaine attenuates the respiratory depressant effects of morphine.^​23​ However, these controlled studies only evaluated morphine. Whether similar effects would translate to persons using methamphetamine and heroin, or fentanyl, is not known. But at least the data suggest that this combination of drugs won’t worsen respiratory depression, right?. Well, not so fast. Fentanyl is unique among the opioids in its ability to cause muscle rigidity of the chest wall, diaphragm, and larynx. Physicians have known about this syndrome, known as “wooden chest syndrome”, since the 1970s.^​24​ It can occur at any dose of fentanyl and is associated with rapid injection.^​25​ In fact, some researchers have speculated that wooden chest syndrome may be the cause of some fentanyl-related deaths. In one forensic study, half of the deaths suspected to be from fentanyl detected no metabolites.^​26​ Since fentanyl metabolites show up rapidly after intravenous injection, their absence in autopsy suggests a rapid death.^​27​ The kind of death you might see when your larynx, chest wall, and diaphragm are unable to move. In the same study, they report two cases where paramedics describe the patient’s chest as unable to expand with ventilation.^​26​ But to be clear, the notion that a proportion of the increasing numbers of deaths from fentanyl are due to wooden chest, while intriguing, is still speculative. The mechanisms underlying fentanyl-induced wooden chest syndrome are not completely elucidated but researchers believe it involves increased activity in central noradrenergic neurotransmission.^​25​ This is, in part, because, along with being a weak serotonin reuptake inhibitor, fentanyl is a norepinephrine reuptake inhibitor.^​28​ Do you know what else increases norepinephrine levels? That’s right, methamphetamine.^​29​ Although there are no studies to date looking at this interaction, there is a real theoretical risk that using goofballs containing fentanyl will increase the risk of dying from wooden chest syndrome.

So while it is good to celebrate the reduced number of deaths from opioids, we would be wise to prepare for the increased use, complications, and likely deaths from the combined use of methamphetamine and fentanyl. To do otherwise would be naive, silly, and stupid. Ironically, the very definition of a goofball.