TCPR: How do we know if a drug is potentially addictive?

Dr. Pierre: I like the updated definition of the American Society of Addiction Medicine (ASAM), which calls addiction a “chronic medical disease involving interactions among brain circuits, genetics, the environment, and an individual’s life experiences” (www.tinyurl.com/mr3kbk3a*). The ASAM acknowledges that addiction has biological, genetic, psychosocial, and even spiritual components while also characterizing addiction along five features that form an ABCDE mnemonic (www.tinyurl.com/ycxs6fp3*):

Abstain. Inability to consistently abstain from use.
Behavioral. Impairment in behavioral control.
Craving, including craving in response to cues.
Diminished recognition of problems associated with the use.
Emotional. Dysfunctional emotional responses.

TCPR: What kind of behavioral and emotional dysfunction is the ASAM referring to?

Dr. Pierre: They’re saying that addiction itself can be understood as an impairment of behavioral control as well as a dysfunctional emotional response. So behavioral disinhibition and compulsivity (like spending time trying to obtain a substance) and trouble regulating use (like drinking 20 glasses of wine instead of two) are part of that. You’ll notice that the ASAM definition does not talk about physiologic dependence. The DSM-5 moved in that direction as well, which is important when we talk about whether or not a drug is addictive. Antidepressants are associated with a withdrawal phenomenon, but that doesn’t mean they’re addictive per se.

TCPR: How is misuse different from addiction?

Dr. Pierre: We use a lot of different words to describe drug use. Some, like “addiction” and “abuse,” carry a lot of stigma. When I talk about “misuse,” I’m talking about the excessive self-administration of prescription meds, such as when people take more than prescribed, snort them, divert them for money or other services, or demonstrate malingering symptoms in order to get more.

TCPR: This definition focuses on behaviors around the drug rather than the drug itself, but the DEA takes a different approach with their schedule of drugs.

Dr. Pierre: Classification is challenging, and medications are always more complex than the schemes we come up with. With the DEA, there are also some political elements involved, so the scheduling doesn’t always make sense. A good example is cannabinoids being Schedule I. It’s increasingly clear that some cannabinoids might have legitimate medicinal applications. There is also some inconsistency between states in how the gabapentinoids like gabapentin (Neurontin) and pregabalin are scheduled.

TCPR: Why do people misuse medications?

Dr. Pierre: The reasons vary. We sometimes think simplistically about “uppers” and “downers,” but many patients are less discriminating. It’s not so much about “I want to feel this specific way” as sometimes it is “I just want to feel different than whatever my reality is.” Some drugs have rewarding properties, but others just alter reality. Ketamine, psilocybin, and the psychedelics alter reality, but they are not rewarding in the same way as other scheduled drugs.

TCPR: How do you know if a drug is rewarding?

Dr. Pierre: The concept of reward is more specific than what I am talking about with medication misuse. “Rewarding” means that the drug is reinforcing—it gives some sort of gratification that leads to repetitive and escalating use. One of the best models of reward involves stimulants. When rats are trained to self-administer cocaine, they will do so all day at the expense of food and water until they flop over and die. Opiates, benzos, and the z-hypnotics (eszopiclone, zaleplon, and zolpidem) are rewarding. It’s these rewarding drugs that cause the most problems in practice, but antidepressants, antipsychotics, and gabapentinoids can also be misused without reward or addiction.

TCPR: What are the signs in practice that a patient is misusing a medication?

Dr. Pierre: One of the biggest red flags is when a patient repeatedly says, “I lost my medication. I ran out early.” Another red flag is feigning or exaggerating symptoms to get medications or negotiate higher doses. This can be difficult to detect, especially in the age of social media where you can find TikTok videos teaching how to fake symptoms of ADHD to get stimulants. We should also be vigilant for signs and symptoms that can point to intoxication, such as slurred speech and altered consciousness.

TCPR: What about gut feelings?

Dr. Pierre: Those are important to pay attention to. It may feel like the patient sees you as just a prescriber. There is a pressure to prescribe certain medications based on claims like, “Dexedrine is the only thing that helps me.” I’d worry if somebody told me, “This pill makes me happy. Can I take it twice a day because it only makes me happy for half the day?” That’s not how our medications are supposed to work. On the other hand, you must guard against biases—racial, socioeconomic, or otherwise—that make gut feelings less reliable.

TCPR: Do outside resources help?

Dr. Pierre: Yes. I recommend checking your state’s controlled substance database, which is required to prescribe controlled substances in some states. Chart review is invaluable. Many times, I’ve done a thorough evaluation only to look at a patient’s old hospital records and find a different story. Patients often withhold information about past substance use disorders because they don’t want us to see them in a negative light. But this can lead to the wrong intervention, like when patients with psychosis don’t tell me that the symptoms occurred in the context of methamphetamine use. Input from family is also helpful. If a patient refuses to grant access to their records or allow family input, that might also be a red flag, though of course there may be legitimate reasons for privacy concerns as well.

TCPR: What do you do when you suspect misuse?

Dr. Pierre: Most of us don’t have a lot of training about what to do. We’re not in the habit of upsetting or disappointing our patients. But you have to draw a firm boundary. It’s not easy, but often it’s really about saying no. Or explaining, “I’m sorry, but I’ve decided I’m not going to prescribe this medication anymore because I’m worried that it’s causing problems related to overuse or could lead to risks like seizures or even death.” It’s important to communicate that you are acting out of compassion and concern, not to punish the patient for “breaking the rules.”

TCPR: What if the patient says, “If you gave me Klonopin, I wouldn’t want to kill myself.”

Dr. Pierre: I would not participate in any kind of barter like that, just as I wouldn’t agree if a patient were to say, “I will take the antipsychotic if you give me Xanax with it.” We can’t allow ourselves to succumb to the pressure to prescribe something that’s not indicated or that isn’t safe.

TCPR: Do you tell them that you think they have a substance use disorder?

Dr. Pierre: That depends on the case. If a patient has a history of alcohol use disorder and now they are five years sober but are taking clonazepam and gabapentin throughout the day, then it might be useful to frame my concerns within the larger picture of addiction. But in other cases, it’s often not helpful because the word is so stigmatizing. I would rather just voice my concerns at a behavioral level—what I’m actually seeing—rather than preaching from an addiction standpoint.

TCPR: Would you end treatment when you suspect misuse?

Dr. Pierre: I might not prescribe a medication, but I wouldn’t end treatment altogether. It’s crucial to offer alternatives. I might say, “I’m sorry, I need to take you off these medications, but let’s talk about how we can address your insomnia or anxiety.” This need not be another prescription. For example, cognitive behavioral therapy is one of the most evidence-based interventions for insomnia. Psychotherapy is also effective for anxiety, and nearly every effective therapy technique involves exposure to anxiety—which is the opposite of what medications like benzodiazepines are often doing. But you have to be prepared for the refrain that “nothing else works.”

TCPR: Do you also see misuse of medications that are not scheduled by the DEA?

Dr. Pierre: Yes. There’s a literature on misuse of non-controlled substances going back to the 1970s, particularly antidepressants, antipsychotics, anticholinergics, and gabapentinoids. Misuse of such medications is often guided by the idea that “more is better.”

TCPR: How are gabapentin and pregabalin misused?

Dr. Pierre: This is a particular problem among people who have an opioid use disorder, where there’s a risk of death because both drugs suppress respiration. Gabapentinoids seem to increase the opioid high, which benzodiazepines can do as well. Gabapentin and pregabalin are used for seizures and pain, as well as off label in psychiatry for anxiety. I first encountered gabapentin misuse when I was treating benzodiazepine use disorders and trying to manage anxiety with gabapentin, but I had patients who would push me for more and more.

TCPR: Which is more dangerous: gabapentin or pregabalin?

Dr. Pierre: Pregabalin is actually Schedule V, which is the lowest abuse potential of the DEA categories. Gabapentin is only a scheduled drug in seven states (Alabama, Kentucky, Michigan, North Dakota, Tennessee, Virginia, and West Virginia). My read on this is that they are both equally problematic, but there are more data supporting a problem with pregabalin.

TCPR: How are antipsychotics misused?

Dr. Pierre: This goes back to the 1970s where there were cases of people misusing low-potency antipsychotics like chlorpromazine. In the modern era, we’re mainly talking about quetiapine, and to a lesser extent olanzapine. Some people like the way quetiapine makes them feel, and the drug even has a street value. People use it intranasally or rectally, or crush it up with water and inject it. As with bupropion, much of this misuse takes place in forensic settings, but there’s also a lot of quetiapine misuse among adolescents.

TCPR: What are they are getting out of it?

Dr. Pierre: Sedation, anxiolysis, or just a feeling of calm. People also use quetiapine to take the edge off methamphetamines or cocaine—that mixture is called a “Q ball.” Another category of drugs that is misused is the anticholinergics, such as diphenhydramine (Benadryl) and those we prescribe to treat extrapyramidal side effects, like benztropine (Cogentin) and especially trihexyphenidyl (Artane). These also have sedating effects and can make people feel drunk, spacey, or buzzed.

TCPR: How are antidepressants misused?

Dr. Pierre: The literature on this goes back a few decades and includes, somewhat surprisingly, MAOIs and tricyclics, but in the modern era, we’re mainly talking about bupropion (Wellbutrin). People sometimes take bupropion in the range of thousands of milligrams, not only orally but intranasally via snorting. For at least a decade it has been referred to as the “poor man’s cocaine.” This has been a particular problem in forensic settings, and several correctional facilities have banned bupropion as a result.

TCPR: Is this because bupropion has an amphetamine-like structure?

Dr. Pierre: That is certainly possible, but I’m reluctant to talk about mechanisms of action because so much is not understood there, even at clinical doses. Bupropion has been studied for cocaine and methamphetamine use disorders, but has not turned out to be clearly useful there (Seifried KJ et al, CNS Drugs 2020;34(4):337–365). And we have no research on what 3,000 mg of bupropion a day will do. We do know that seizures are a dose-dependent risk, and that higher doses can cause anxiety, autonomic arousal, akathisia, and possibly even mania or psychosis.

TCPR: A bupropion-dextromethorphan combination (Auvelity) just got approved for depression. Any comment?

Dr. Pierre: That’s interesting because Auvelity is not a scheduled drug, but dextromethorphan has misuse potential. I have seen cases of dextromethorphan misuse, including people who became floridly psychotic after buying it as cough syrup in bulk quantities on the internet and drinking 10–20 bottles a day. Dextromethorphan is an NMDA antagonist, so it has PCP-like or ketamine-like qualities such as dissociation. Auvelity pairs two drugs with a history of misuse—bupropion and dextromethorphan—so I can see cause for concern.

TCPR: Thank you for your time, Dr. Pierre.

*Mentioned in this article
American Society of Addiction Medicine: Definition of Addiction. September 15, 2019. https://www.asam.org/docs/default-source/quality-science/asam's-2019-definition-of-addiction-(1).pdf
American Society of Addiction Medicine: Definition of Addiction.. Public Policy Statement: Definition of Addiction. August 15, 2011. https://www.asam.org/docs/default-source/public-policy-statements/1definition_of_addiction_long_4-11.pdf.