CATR: Welcome, Dr. dela Cruz. Tell us what you do.
Dr. dela Cruz: I’m an assistant professor at UT Southwestern Medical School where I’m the adult psychiatry residency associate program director, and I teach medical students, residents, and fellows. Clinically, I’m an outpatient addiction psychiatrist where I treat a variety of patients with substance use disorders, many with medical comorbidities.

CATR: Could you take us through the treatment of a patient with a stimulant use disorder from the beginning?
Dr. dela Cruz: Obviously, the first step is diagnosis. It is important to ask about the different stimulants someone might be using such as methamphetamine, cocaine, or prescription stimulants. Ask about over-the-counter medicine like pseudoephedrine as well as bath salts and designer hallucinogens with stimulant properties. It can take a lot of questions to be certain what a patient is using, and I encourage providers to know local patterns of drug use. Urine drug screens are helpful for diagnosis and tracking treatment response. I don’t use them for punishment, but as a way to determine if a treatment plan is working.

CATR: But urine drug screens don’t detect all stimulants.
Dr. dela Cruz: That’s right. Almost all include cocaine, which is detectable for 1–3 days and is straightforward because of its unique metabolic product benzoylecgonine, but other results require interpretation. Lots of medications like pseudoephedrine, phenylephrine, propranolol, and atenolol produce an amphetamine false positive. Even a confirmed positive amphetamine might mean prescribed amphetamine, lisdexamfetamine, or methamphetamine. Some, but not all, urine drug screens include a specific methamphetamine test. Methamphetamine is metabolized to amphetamine, so a patient who’s using meth will be positive for both; it doesn’t mean they are using multiple substances. Providers should get familiar with what their locally available screens test for.

CATR: What else should providers be paying attention to?
Dr. dela Cruz: A good skin exam is important, particularly for patients using intravenously. Subcutaneous injection and skin popping can lead to fat necrosis and cellulitis. There’s a rare vasculitis associated with cocaine use, due to an adulterant called levamisole, that looks like a nonhealing open wound. I would recommend a dermatology consult if this vasculitis is suspected. And of course, people who use stimulants, and particularly those who smoke them, can have extremely poor dental hygiene from dry mouth and bruxism.

CATR: What are some of the demographic differences that you see across the stimulant use disorders?
Dr. dela Cruz: In terms of prescription stimulants, I see a lot of students, even early-career professionals. These people use them to stay awake, work, or party on the weekend. According to DSM criteria, tolerance and withdrawal do not apply to people taking stimulants as prescribed. Intranasal cocaine is seen among this group as well. Only about 15% of people who use cocaine or stimulants develop a use disorder, so there is a group who use cocaine casually without developing an addiction (Wagner FA and Anthony JC, Neuropsychopharmacology 2002;26(4):479–488). Crack use is seen more in an older urban population. Methamphetamine started as a rural drug but has become closely associated with sex work. In the population of men who have sex with men (MSM), there is a high prevalence of methamphetamine, ecstasy (also known as MDMA, 3,4-methylenedioxymethamphetamine), and GHB (gamma hydroxybutyrate).

CATR: Do you always test patients with stimulant use disorders for transmissible infections?
Dr. dela Cruz: Consider screening patients using a question like, “Have there been times in which you’ve had unprotected sex or sex with partners for whom you didn’t know their STD status?” Intravenous drug use is also a risk factor, so ask about that. If there is concern, order a transmissible disease panel (HIV, hepatitis B and C, syphilis, gonorrhea, chlamydia) or consult the patient’s primary care provider. This is also an opportunity to consider pre-exposure prophylaxis (PrEP) for high-risk patients (Editor’s note: For more on prophylaxis, see our Q&A with Sandra Springer, MD, in CATR Nov/Dec 2019).

CATR: What are some practical differences to consider when treating patients with different stimulant use disorders: cocaine versus methamphetamine versus prescribed stimulants, for instance?
Dr. dela Cruz: The stimulants differ only slightly in their mechanisms, from a brain perspective. I wouldn’t expect big differences in terms of response to medications.

CATR: And what are some of the medications that you’ve found to be most helpful for patients with stimulant use disorders?
Dr. dela Cruz: There are no FDA-approved treatments, but work is being done in the field. I was lucky to be part of the recent ADAPT-2 trial looking at the efficacy of the combination of 450 mg bupropion daily and 380 mg extended-release naltrexone every 3 weeks in patients with methamphetamine use disorder (Trivedi MH et al, N Engl J Med 2021;384(2):140–153). It’s important to note that the naltrexone is given by deep intramuscular injection. The combination was more likely than placebo to decrease use and more likely to help patients achieve and maintain sobriety. Although the overall treatment response was relatively low (13.6% in the treatment group vs 2.5% in the placebo group), this trial is particularly clinically relevant because we evaluated the ability of the medications to help patients who are actively using decrease or stop, whereas many studies are relapse prevention trials. Mirtazapine is another good option. A recent trial by Phillip Coffin looked at mirtazapine in MSM (Coffin PO et al, JAMA Psych 2020;77(3):246–255) and found that mirtazapine 30 mg decreased methamphetamine use. So right now, my go-tos are mirtazapine or the combination of naltrexone and bupropion.

CATR: How would you evaluate the appropriateness of these medication options?
Dr. dela Cruz: Most psychiatrists are comfortable prescribing 30 mg of mirtazapine. Naltrexone and bupropion were well tolerated. You want to get a good seizure history before starting bupropion, especially since stimulants can predispose patients to seizures. Naltrexone can cause liver inflammation and should not be started in patients with transaminases more than 5 times the upper limit of normal or bilirubin elevation. Patients should have a platelet count 150 or higher because the medication is delivered by injection and there is concern that naltrexone could suppress platelets.

CATR: What about other medications like topiramate, n-acetylcysteine, disulfiram, or modafinil?
Dr. dela Cruz: There is lots of interest, but the data are mixed. There might be a role for lisdexamfetamine, which has been shown to decrease cocaine cravings (Mooney ME et al, Drug Alcohol Depend 2015;153:94–103). Other ­studies are ongoing, but doses are high in some of these protocols, up to 250 mg (Ezard N et al, BMJ Open 2018;8(7):e020723). Side effects included diarrhea, headaches, and anxiety. Modafinil has potential, but again, the data are mixed (Sangroula D et al, Subst Use Misuse 2017;52(10):1292–1306).

CATR: So it sounds like bupropion in combination with naltrexone, and mirtazapine are the top tier; perhaps modafinil and lisdexamfetamine are second line; and all the rest are third line.
Dr. dela Cruz: Yes. Keep in mind that the study investigated intramuscular naltrexone, so you have to have the capability to store and administer injections. For someone who’s misusing prescription stimulants, I would favor lisdexamfetamine or modafinil as a way to stabilize them on a safe dose of prescribed medication, which they are taking anyway.

CATR: What about particular psychotherapeutic techniques?
Dr. dela Cruz: We need to acknowledge with our patients why it is that they use substances in the first place. I always ask, “What do you think the substance helps you with?” Surprisingly, many clinicians don’t ask that. The answer to that simple question can be very revealing and help with treatment planning. For instance, you might discover symptoms that a patient is trying to treat, and a treatment plan will only succeed if these symptoms are addressed. A common answer is that stimulants help with social anxiety.

CATR: What’s your response to that?
Dr. dela Cruz: I say, “Well, how are we going to create a treatment plan that lets you have social activities in a safe way and doesn’t involve illicit drug use?” That can help set goals and allow for a therapeutic conversation, which should be balanced by motivational interviewing in which we examine the ways that drug use is harmful. If the patient does not reveal a particular motivation to change, I often ask, “What are your friends or family worried about?” and follow it up with, “Do you think those concerns have validity?” This can create that bit of cognitive dissonance we’re looking for in motivational interviewing to help the patient acknowledge negative effects of substance use (Editor’s note: For more on motivational interviewing, see our Q&A with Carla Marienfeld, MD, in CATR March/April 2021).

CATR: What other psychotherapeutic modalities have good evidence?
Dr. dela Cruz: There are a few big categories in addition to motivational interviewing. The first are 12-step programs/mutual help groups; Alcoholics Anonymous and Narcotics Anonymous are examples of these. Another is relapse prevention, which is derived from cognitive behavioral therapy (https://pubs.niaaa.nih.gov/publications/arh23-2/151-160.pdf). Making a thought record is core to relapse prevention. I’ll begin with, “Tell me about the last time you used. What were the triggers?” Once we identify the events themselves, I ask, “What were you thinking? What were you feeling?” After identifying the factors leading to substance use, we brainstorm together about how to change the behaviors: “How can we approach that situation differently?” Finally, there is contingency management.

CATR: Contingency management has some of the best evidence.
Dr. dela Cruz: That’s right. Contingency management is based on operant conditioning, the idea that reinforcers increase behavior. The targeted behavior here is sobriety. Some of the first studies in this area were conducted by Kathleen Brady (Killeen TK et al, J Child Adolesc Psychiatr Nurs 2012;25(1):33–41) in adolescents. Nancy Petry is a researcher in this area who has demonstrated contingency management efficacy in patients with stimulant use disorders (Petry NM et al, Psychol Addict Behav 2017;31(8):897–906). A typical model is a fishbowl full of raffle tickets in the clinic. Half the tickets say “good job,” a third of the tickets award a small prize worth $1–5, a few are bigger prizes worth $20, and there is one ticket with a jumbo prize worth $100. Patients get to draw tickets if they have a negative urine drug screen. The first negative gets 1 draw, the next negative gets 3, and every subsequent negative test gets them escalating numbers of tickets up to a maximum point. But if they miss a visit or have a positive drug screen, it resets back to 1 draw. There are variations, but studies show that the prizes don’t have to be especially valuable to support sobriety.

CATR: This can be difficult to establish in a typical clinical setting, though.
Dr. dela Cruz: True. It could be supported by a small grant since there is evidence that it works for relatively little money. I use an app called ReSET, which is an FDA-approved therapeutic. The patient needs a prescription in order to get access. Their website is www.resetforrecovery.com, where you get all the forms to prescribe the app. It includes therapy sessions, relapse prevention modules, and a built-in contingency management piece (Editor’s note: For more on ReSET and other apps as adjuncts for substance use treatment, see CATR Nov/Dec 2020). The contingencies are small, but they can be quite powerful. It reminds me of similar contingencies in my own life. My fitness watch buzzes when I meet my step goal or calorie count for the day. It’s important to get that pat on the back; it really does change behavior.

CATR: Recently we’ve seen a proliferation of easily obtainable designer drugs with stimulant-like properties, such as bath salts. Does the use of these substances manifest differently than the stimulants we’ve already discussed?
Dr. dela Cruz: There are no high-quality data, but it seems that bath salts are less common now than they were 5 or 10 years ago. Designer drugs and hallucinogens with stimulant properties are rising among young tech-savvy people who access the dark web.

CATR: How should providers approach patients who use bath salts or these designer stimulants/hallucinogens?
Dr. dela Cruz: Ultimately, these stimulants work similarly. We don’t have evidence that these disorders should be treated differently from one another, at least pharmacologically. Behavioral interventions might differ depending on the drug, though. For example, an approach for a patient illegally purchasing methamphetamine might be to delete a drug dealer’s contact information. Substances ordered off the dark web can be trickier—we can’t tell patients not to go on the internet. But I do talk with patients about disabling portals they use to access the dark web. In addition, many of these drugs are bought using cryptocurrencies like Bitcoin, and I talk to patients about putting their Bitcoin into an electronic vault. You can get creative around placing roadblocks to drug access, even for drugs bought over the internet.

CATR: Thank you for your time, Dr. dela Cruz.