CATR: Start by giving us an overview of psychostimulants.

Dr. Hurley: There are three major categories of stimulants that are misused: 1) prescription stimulants, 2) illicitly manufactured stimulants, and 3) cocaine. Prescription psychostimulants, which are approved for the treatment of ADHD and misused when taken without a prescription or outside the dosing guidelines provided by a prescription, include methylphenidate and medications based on amphetamines. Illicitly manufactured methamphetamine is a major driver of increasing overdose deaths in recent years. The prevalence, especially of methamphetamine and cocaine, varies greatly by geography, with methamphetamines being by far the most common agent in the Midwest and West Coast of the United States and cocaine being more prevalent in the Northeast.

CATR: What are some of the pharmacological differences between these agents? 

Dr. Hurley: Stimulants all work by increasing dopamine neurotransmission in the brain. There are many amphetamine and amphetamine-derived medications used for ADHD treatment like lisdexamfetamine, dextroamphetamine, and amphetamine salts. These agents all work by increasing the release of dopamine and norepinephrine as well as blocking their reuptake, though time of onset and duration of action varies. Lisdexamfetamine is a prodrug that metabolizes to amphetamine, so it works slower while amphetamine salts are much faster. Extended-release formulations of course will have longer half-lives. Methamphetamine is lipophilic, which means it absorbs into the brain very quickly, so the time of onset is very short and its effects are much longer than prescription amphetamine medications. Methylphenidate has a similar mechanism of action to cocaine, which inhibits dopamine reuptake out of the synaptic cleft. However, cocaine has a stronger effect, where the magnitude of the perceived reward with cocaine is going to be greater. Also, cocaine is absorbed very quickly, much more so than methylphenidate.

CATR: Other than mechanism of action, how do cocaine and methamphetamine compare?

Dr. Hurley: The biggest difference is how long they last. Cocaine lasts around 20 or 30 minutes. There is some variation between people, and the effects of injection or smoking tend to be shorter-lived than insufflation. But cocaine effects are generally brief. When somebody uses cocaine, they typically use several times in succession, maybe over the course of an evening or a day. Methamphetamine, on the other hand, lasts 12–15 hours after use—much longer. And when people use multiple times, that can result in half a week or more of not sleeping, not eating. In an emergency setting, cocaine intoxication might resolve in an hour or two, which is not the case with methamphetamine.

CATR: Is the time of duration related to the prevalence or severity of adverse effects? 

Dr. Hurley: I think so. The longer half-life is a big reason why we are seeing such high rates of hemorrhagic stroke and heart attacks with methamphetamines, as well as drug-induced psychiatric issues, particularly psychosis. Do people still have those consequences with cocaine? Sure. I’m not saying cocaine is safe, but longer-acting stimulants have greater adverse effects on someone’s health and function.

CATR: You mentioned that methamphetamines are a major driver of increasing overdose deaths. Why is that?

Dr. Hurley: This is the fourth wave of the overdose epidemic. In the third wave, prior to 2019 or so, we were already seeing many overdose deaths from fentanyl. But now we’re seeing deaths from sedatives and stimulants piled on top of this already high overdose rate. (Editor’s note: For more on the waves of the overdose epidemic, see our Q&A with Dr. Ciccarone in CATR Jul/Aug/Sep 2023.) As I mentioned, stimulants can certainly cause death on their own, usually by causing a cardiovascular event, but a lot of stimulant-related mortality comes from inadvertent exposure to fentanyl. Fentanyl is now being found in illicit stimulants and sedatives, usually without the knowledge of whoever is buying the drug, and there is something about the combination of these drugs that is particularly risky and dangerous.

CATR: How common is it to find fentanyl in stimulants or other nonopioid drugs? 

Dr. Hurley: The short answer is that we don’t know. But to optimize safety, we operate with the assumption that all methamphetamine and cocaine has fentanyl in it. Of course, this isn’t true, and paradoxically, if it were true, the situation would be safer—stimulant users would have opioid tolerance, and we could treat everyone as though they had an opioid use disorder (OUD). And we’ve got treatments for OUD! So, it’s not just the presence of fentanyl that is the riskiest part of using illicit stimulants; it’s the unreliability of whether a drug contains fentanyl. A recent article examining drug seizure data found that the prevalence of fentanyl in methamphetamine and powdered cocaine was 12%–15%. But there was incredible variability between geographies.

CATR: Can you outline the treatment options for stimulant use disorder (StimUD)? 

Dr. Hurley: Treatments for StimUD can be thought of in terms of the traditional biopsychosocial model. We have medications, various manualized psychotherapies, and—specific to StimUD—we have contingency management, which produces the most robust response. (Editor’s note: For more on contingency management, see our interview with Dr. DePhilippis in this issue.) And while we don’t have any FDA-approved medications, there are some effective off-label agents. Topiramate, naltrexone, bupropion, and mirtazapine all have evidence behind them. The combination of injectable naltrexone and high-dose bupropion seems to be particularly promising for methamphetamines (Trivedi MH et al, NEJM 2021;384:140–153).

CATR: What about prescribing stimulant medications to treat patients using cocaine or methamphetamines?

Dr. Hurley: That can be a thorny issue. There is some evidence for this practice, specifically methylphenidate for cocaine use and mixed amphetamine salts for methamphetamine (www.asam.org/quality-care/clinical-guidelines). The pharmacologic rationale is pretty straightforward: We’re replacing a dangerous unregulated drug with a safer prescription medication. So, you might ask, “If methadone works for OUD, shouldn’t any psychostimulant work for StimUD?” And while it’s the same underlying principle, it’s not that simple in practice. First, prescription stimulants are not benign and can be addictive themselves. And while they can be helpful, they simply aren’t as successful for treating StimUD as buprenorphine and methadone are for OUD. But they can be helpful when used for the right patient with careful monitoring. We recommend that patients start with nonstimulant medications. If those don’t work, the stance of the American Society of Addiction Medicine (ASAM) and the American Academy of Addiction Psychiatry (AAAP) is that if a clinician is going to use a psychostimulant outside of its FDA-approved indication to treat StimUD, that clinician should be a board-certified addiction physician or in direct consultation with someone who is.

CATR: It’s unfortunate this approach doesn’t work.

Dr. Hurley: Things would be easier if it did. It’s clear that opioid agonists are the best treatment for OUD, but that doesn’t translate so cleanly with other addictions. However, that invites us to think about the addiction more comprehensively. Medications can help, but really our task is to figure out how to support patients as they navigate their lives. That means collaborating with patients to explore issues at home—do they have a support network? Do they have a safe place to live? What about work? Can I connect them with supportive employment, vocational rehab, peer support groups? If they are committed to abstinence, how do we continue to support that goal? But even if they aren’t committed to abstinence, we have tools to help these patients too. That is what the harm reduction movement is about.

CATR: How can we apply harm reduction principles to StimUD?

Dr. Hurley: Think about the classic harm reduction maxim: “Meet people where they’re at.” Do they have proper medical care? If not, think about the medical consequences of chronic stimulant use. Begin with modifiable cardiovascular risk factors like cholesterol and blood pressure. Don’t shy away from monitoring your patient’s cardiovascular risks through routine bloodwork and prescribing antihypertensives and statins. First-line treatment for these conditions is straightforward, and we can always consult with a primary care, cardiology, and/or medical toxicologist colleague when we have any questions about cardiovascular risk factor management. Dental issues related to dry mouth are also common with ongoing psychostimulant use. Ask your patients about their teeth, look into their mouth if they are reporting issues, and if at all possible, refer them to a dentist.

CATR: What are some other harm reduction tools that you would recommend?

Dr. Hurley: There is a lot of focus in the harm reduction community around route of administration. It is safer to smoke a drug versus inject a drug because it is easier to titrate drug use when smoking. Injection is also associated with infections that result in abscesses or other soft tissue infections, potentially advancing to sepsis. So, clinicians should encourage that switch. But even if somebody is injecting, connect them to syringe service programs so they have access to sterile injection equipment. We already discussed how fentanyl is now being found in illicitly sold cocaine, methamphetamines, stimulant pills, and sedative pills. People who purchase nonopioid drugs from the street are at particular risk if they get an accidental fentanyl exposure because they don’t have opioid tolerance. Anyone using these drugs should be offered fentanyl testing supplies, and I would argue that anyone using any category of intoxicants should be offered naloxone. Overdose rates are so high and such a threat to public health that universal naloxone access is a crucial public health strategy. So, I’ll prescribe naloxone for patients being seen for “only” cannabis or alcohol use. 

CATR: How can patients get their hands on harm reduction supplies?

Dr. Hurley: Naloxone is now over the counter, or it can be prescribed. Depending on where you are practicing, you may have access to local or state resources that can get harm reduction supplies to patients. But even if those aren’t available, there are places online where patients can go to get harm reduction materials. 

CATR: What resources would you recommend for clinicians interested in learning more?

Dr. Hurley: The ASAM and the AAAP have come together to publish a clinical guidance document that describes what clinicians should know about treating StimUD (www.asam.org/quality-care/clinical-guidelines). It’s fairly comprehensive, so that is usually where I refer people first. For those interested in psychotherapy, I recommend looking up The Matrix Manual, which is a free resource put out by the Substance Abuse and Mental Health Services Administration that outlines how to do cognitive behavioral therapy for StimUD (www.tinyurl.com/zb7fkfwj).

CATR: Any closing thoughts?

Dr. Hurley: I’ll close with one final point. There was a huge cocaine epidemic in the 1980s—we saw huge rates of cocaine use in the United States—and then the rates went down. They didn’t go down because everyone died; they went down because many people were able to stop using. We are seeing a reemergence of stimulant use, largely driven by methamphetamines. Rates are going up. We are in a scary situation. But we can’t forget that people do recover. About 75% of people with SUD at some point in their lives are able to recover (Jones CM et al, Drug Alcohol Depend 2020;214:108169). We have tools to help with that recovery: contingency management, cognitive behavioral therapy, high-intensity outpatient treatment, residential treatment, off-label medications. Stimulant use is challenging and can be dangerous, but it is not untreatable. Recovery is possible, and we owe it to our patients to offer the most effective, evidence-based tools at our disposal.

CATR: Thank you for your time, Dr. Hurley.