There are many reasons why patients misuse medications. Today, Joseph Pierre shakes us out of our 1990s understanding of addiction and explains a new trend, misuse of uncontrolled medications like Bupropion, Quetiapine and the Gabapentinoids.

Publication Date: 10/23/2023

Duration: 24 minutes, 34 seconds

Transcript: 

KELLIE NEWSOME: There are many reasons why patients misuse medications. Today, Joseph Pierre shakes us out of our 1990s understanding of addiction and explains a new trend, misuse of uncontrolled medications like Bupropion, Quetiapine and the Gabapentinoids. 

Welcome to The Carlat Psychiatry Podcast, keeping psychiatry honest since 2003.  

CHRIS AIKEN: I'm Chris Aiken, the editor-in-chief of The Carlat Psychiatry Report,  

KELLIE NEWSOME: and I'm Kelly Newsome. A psychiatric NP and a dedicated reader of every issue.  

CHRIS AIKEN: I guess it's unrealistic to think that life expectancy is gonna keep rising every year. Which it has done nearly every year since the 1950s, but that trend started to reverse in 2015, from 78.9 years. To 78.7, 78.6, and then down to 77 years during the pandemic in 2020. Now, life expectancy is down to 76 in America. Sure, COVID has accelerated this problem, but the other cause is closer to home for us workers in the field of mental health. Drug overdose deaths. It's a national crisis, and it's only getting worse. I'm not myself an addictionologist, but I believe we can no longer afford to leave this work to those of our colleagues with higher training in addictions. So today, I'm going to roll up my sleeves and get into it with Joseph Pierre. You might remember him from our July issue where he gave an interview on prescription medication misuse. How to spot red flags and what to do about them. I went into this interview with some misunderstandings, and you're going to see that here. For example, I thought the drug misuse was directly related to the rewarding qualities of the drug. But as Dr. Pierre explains, that is only part of a much more complicated behavior. 

KELLIE NEWSOME: But first, a preview of the CME quiz for this episode. 

Which medication for extrapyramidal side effects has fallen out of favor because of its potential for misuse? A. Benzatropine, B. trihexyphenidyl , C. propanolol, D. amantadine.

CHRIS AIKEN: What is the difference between medication abuse and misuse? 

JOSEPH PIERRE: You know, much like the word addiction, I think the term abuse is a, a bit of a loaded term, has a lot of stigma, associated with it. And so I often think that misuse is just as appropriate. Some people will claim that there are small differences between those two words. I tend to use them interchangeably, or really collectively, to describe the use of medications via self-administration that's recreational or otherwise inconsistent with how a drug is prescribed. Clinically, what I'm really talking about is evidence of excessive self-administration. You know, the patient's taking more than you're prescribing. Self-administration by nontraditional routes, so if we're talking about oral medications, taking them by other means, like snorting them, for example. Co-administration of the drug with other drugs of abuse. Malingering psychiatric symptoms in order to obtain those prescription medications. Diversion, which of course means using that prescription and then giving it to other people for money or for, to exchange of other services. And finally, of course, evidence of toxicity from that excessive use or from overdose.  

CHRIS AIKEN: With that definition, any drug could be misused. How do we know if a drug is addictive?  

JOSEPH PIERRE: Yeah, so as I said, addiction has kind of a history, definitely a loaded term, and certainly the term addict is something that we still hear used all the time. And so accordingly, the definition of addiction sort of depends on who you're asking and what context it's being used. I like the updated definition of the American Society of Addiction Medicine. They updated the definition in 2018. They define it as a primary chronic disease of brain reward, motivation, memory, and related circuitry. And they acknowledge that it has multiple components: biological, genetic, psychosocial, even spiritual. And they really characterize addiction along five features. The first is the inability to consistently abstain from using a medication or a drug. The second is impairment in behavioral control. The third is craving, and they specifically refer to the phenomenon of cue elicited craving, that is cravings in response to cues, visual or otherwise. The fourth feature is diminished recognition of significant problems associated with the drug or medication use and the final is a dysfunctional emotional response and if that's hard to keep track of they offer an easy ABCDE mnemonic where A stands for abstain B stands for the behavioral control impairment C stands for craving, D stands for the diminished recognition of significant problems, and finally E stands for the emotional response. 

CHRIS AIKEN: Can you further state what behavioral and emotional you're referring to there? 

JOSEPH PIERRE: Really talking about behavioral disinhibition, engaging in behaviors that you otherwise wouldn't be engaging in were you not on that substance. And even tied up in that definition is the ability to regulate how much of something we're using, right? The difference between I drink a glass of wine a day and I drink 20 glasses of you know, wine throughout the day.  

CHRIS AIKEN: So, it might include intoxicated behaviors, but maybe also behaviors like spending your whole day trying to get the drug. 

JOSEPH PIERRE: Exactly. You'll notice that nowhere in the ASAM definition does it talk about physiologic dependence. So just as in DSM, we've sort of come to a more modern definition that isn't just linked to phenomenon like dependence or withdrawal and that sort of thing. And so that's important when we talk about whether or not a drug is addictive. There may be drugs that, you know, and antidepressants is a great example. We know very well that sometimes when patients take antidepressants in the long run and abruptly stop them, they might have a discontinuation syndrome or a withdrawal syndrome. That doesn't necessarily mean that the drug is addictive. So, addiction is really defined by the other criteria that we just went through. 

CHRIS AIKEN: How do you feel about the DEA's regulations with controlled substance levels? Is that an accurate guide to how addictive these are? 

JOSEPH PIERRE: You know, I think clearly the, the DEA, there are some political elements to it, certainly based on its history. I think nowhere is there a better example than when we talk about cannabinoids. 

Still being Schedule 1, I think there's certainly a lot of people, whether it's consumers or... for want of a better word, marijuana advocates, but also researchers who really think that cannabis shouldn't be on schedule one. I think it's increasingly clear that some cannabinoids might have legitimate medicinal applications. I think at the very least, there's very good rationale to say that it should be removed from schedule one so that we can at least do research with it in a more easy way. So, I would not say that I'm a huge fan of the scheduling. One thing we'll talk about today, for example, is the presence of gabapentinoids, how those are scheduled, and there's some inconsistency there. 

CHRIS AIKEN: Well, with our medications that we commonly prescribe, which one should we be alert to regarding misuse and abuse? 

JOSEPH PIERRE: So, I mean, the discussion, of course, has to start with the ones that are really well recognized, right? The controlled substances. We know that Opiates, you know, we're not routinely prescribing those as psychiatrists, but certainly opiates. And then in terms of psychiatric drugs, we're talking about benzodiazepines to include C drugs and then stimulants. The area that I've been interested in is really about the non-controlled substances that we prescribe. And just for simplicity's sake, I would focus on three classes. The first would be antidepressants, the second would be antipsychotics, and the third would be gabapentinoids. 

CHRIS AIKEN: Can you walk us through each of those? 

JOSEPH PIERRE: Let's go, go one by one. So, if we talk about antidepressants, going back in the literature for decades, there have been a number of different specific antidepressants that have been described as potential drugs of misuse or abuse. Those include things like, somewhat surprisingly, some of the MAOIs, or some of the tricyclics. But in the modern era, what we're really mostly talking about now is bupropion. It will be true, of course, by trade name. Going back a couple decades now, we've seen increasing evidence that people use bupropion in substantial doses, you know, in the thousands of milligrams, range. They're not only taking it orally, they take it through nasal insufflation or snorting, basically. And so, for at least a decade or more now, it has sometimes even been referred to as poor man's cocaine because of the stimulating properties that one can get from excessive dosing and things like intranasal use. That was also noticed early on to be a fairly rampant phenomenon in forensic settings. So much so that a number of different forensic settings actually banned bupropion from use, from clinical use, from therapeutic use. And obviously one of the big concerns with that medication when it's misused or abused is seizures.  

CHRIS AIKEN: You might want to remind our readers if you agree that it has amphetamine like properties.  

JOSEPH PIERRE: Well, I should...I'll preface my answer by saying that I'm always a little reluctant to talk about mechanisms of action in psychiatry because there's, you know, what we learn about in terms of receptors and then, you know, how did the, how does the drug really work? Who could say, but for sure, one of the things that has been discussed about bupropion that makes it somewhat novel among the options that we have is that it does have, it seems to have some pro-dopaminergic qualities. Now, depending on what I've read, I've read sometimes that's sort of overemphasized and it's not as big as, you know, maybe sometimes we make it out to be, but nonetheless, that finding is there. And I think that's a fair way to at least conceptualize how the drug behaves differently. I think clinically when we use it, we often reach for it as an option for somebody who, for example, might have particular difficulties with anergia in the context of depression.  

CHRIS AIKEN: I'd love to know if you're aware. Any research suggesting that it acts differently at the therapeutic versus the 2000 dose?  

JOSEPH PIERRE: That's really what we're struggling against here. When we prescribe medications, we know more or less what they do therapeutically, or in terms of adverse events that conventional medicine, but there's very little research. I mean, how are you going to design a study and say, oh, let's give people 3000 milligrams of bupropion per day. So, you know, what we mostly know is about adverse effects. 

CHRIS AIKEN: Well, seizures, and are there other risks? 

JOSEPH PIERRE: Well, seizures for sure are the most concerning from a clinical standpoint on a more mundane level. You know, we, we see that in clinical practice as well, you know, just anxiety, nervousness, potentially autonomic arousal, just, you know, akathisia, those kinds of symptoms. 

CHRIS AIKEN: Maybe psychosis, maybe, I don't know.  

JOSEPH PIERRE: Yeah, that's a good one. That was certainly discussed, has been discussed through the years. Always a little bit of debate are, as to, you know, are you inducing mania? When you see emergent psychosis, there's always a little bit of a question when we're talking about antidepressants of, is there a true psychotic liability? Are we flipping people into mania? Nonetheless, very clearly, there have been case reports of people developing, psychosis in the context of bupropion. 

CHRIS AIKEN: Yeah, I don't have much experience with this, but I'll share with you. You know how hard it is to cure dysthymia. So, I cured my dysthymic patient, totally cured, and he came in, he was like...Oh, I've accidentally been taking 600 of bupropion a day. That was the cure. So, I had to be like, sorry, you can't do that.  

JOSEPH. PIERRE: Yeah, perfect case example for today's discussion. So technically that, that would constitute misuse. 

CHRIS AIKEN: Yes, so you don't know why they take more bupropion. It's a wild guess that it might be amphetamine like effects, but we really don't know. 

JOSEPH PIERRE: Well, you know, when we start talking about misuse and abuse, it's often the mantra is just more is, you know, better, in terms of the effect that I'm trying to achieve. So, you know, most people, if they're taking a hundred milligram tablet of bupropion, they're not necessarily going to feel that there's not going to be a buzzy quality. No one calls, 300 milligrams would be appropriate as poor man's cocaine. But at those higher levels, there's just more of a stimulating effect. So in that sense, you could say it's cocaine like or amphetamine like. 

CHRIS AIKEN: Tell me about antipsychotics.  

JOSEPH PIERRE: Yeah, so similar to antidepressants, that story actually goes back some decades. So that in a sort of minority of patients who were treated with antipsychotics back in the 1970s. There were occasionally people who would, misuse or abuse the low potency D2 antagonist like chlorpromazine. 

Likewise, something I wasn't planning on talking about during this hour, but in a related fashion, there was a, a sort of well observed pattern where some patients were abusing anticholinergic medications, the ones that we typically prescribed in conjunction with first generation antipsychotics. And by far the worst offender was trihexyphenidyl, where there were patients who were, you know, asking for more trihexyphenidyl, taking it predominantly orally. And just developing, for want of a better word, a kind of buzz from that medication. And so, we know that the anticholinergic properties of antipsychotics have historically been sought after as potential drugs of misuse or abuse. That said, in the modern era, or in the second-generation antipsychotic era, We're really now talking about quetiapine. I mean, I've never heard a patient ask for, you know, twice the dose of Haldol. You know, ooh, I really liked the way Haldol makes you feel. But one of the nice things about the second-generation agents is you increasingly have people who don't have the same kind of toxicity, the extrapyramidal side effects, the dysphoria, really just, they like the way the second-generations make them feel. And with quetiapine, certainly and fairly early on, we saw some evidence that people really liked how it made them feel, to the point that-and this actually happened with lanzapine as well, to a lesser extent- there was a said to be a street value for quetiapine. Now, back in, I think it was 2004, my colleagues and I were actually the very first folks to report the phenomenon of intranasal quetiapine abuse in the prison population, or in the jail population rather, in the Los Angeles County Jail. And what we were told is that patients were routinely malingering psychotic symptoms, saying they were hearing voices and such, specifically in order to get quetiapine. And we learned that they were not only, you know, ingesting it for recreational purposes, they were, the standard practice was to crush it up and snort it. So, to do intranasal administration. And since we first reported that you know, a decade and a half ago, that has become a pretty wide, widespread, well recognized phenomenon. Again, often in forensic systems, so that like bupropion, it has been banned in a number of different forensic systems. And not just intranasal use, but intravenous use, so crushing it up, dissolving it in water and injecting it. Just a little interesting side story there. So, in street parlance, it's well known that you can mix heroin and cocaine together, that's often referred to as a speedball. And someone reported some years ago that people were mixing intravenous cocaine with intravenous quetiapine, so sort of in place of the heroin. And they refer to that as a cue ball. And then also case reports of things like rectal administration of quetiapine. So, quetiapine, potential misuse and abuse, I think is a pretty widespread and well recognized phenomenon now. Certainly within the forensic system, but also quite a bit among young people. And it's cases where young people are getting it from their friends, or, you know, perhaps, like, stealing it from their parents medicine cabinet kind of thing surreptitiously. So quite a bit of quetiapine misuse and abuse among adolescents. 

CHRIS AIKEN: Any idea what these various populations are getting out of it? 

JOSEPH PIERRE: Well, it's interesting because, again, when we use medications like quetiapine clinically and especially off label, I think we all recognize that it has some real value in terms of sedation, anxiolysis, just a feeling of calm. It's sort of the opposite of the bupropion, right? The bupropion is used for its stimulating properties. Quitipine is often used for its sedative and calming properties, either by itself or in its own right. Or when we're talking about things like cue balls, we're talking about sometimes using it specifically to take the edge off of stimulants that are being abused. So ,cocaine, methamphetamines, that sort of thing. We know that people who have stimulant use disorders often come to positions when they are tweaking or they want to be slowed down, they can't go to sleep, and that's when they'll ask for things like benzodiazepines or quetiapine especially. 

CHRIS AIKEN: Back to the anticholinergics, is that also in the sedative calming realm? 

JOSEPH PIERRE: You know, back when we talked about not easily putting these drugs in categories, I feel like anticholinergic just deserves its own category. I mean, that's probably the thing we have the most experience with personally, right? We've all taken, you know, diphenhydramine, Benadryl. I don't know, for me, it certainly makes me feel sedated, you know, if I've taken it, for example, for allergies, or, oh my gosh, I'm blanking on the name, but the one you take for motion sickness, you know, so they can be sedating, they can help as anti-emetics, but man, when I take them, I just feel like spaced out and, you know, a little drunk and, you know, goofy.  

CHRIS AIKEN: That makes sence, I mean Vistaril is FDA approved for anxiety, right? And is that similar?  

JOSEPH PIERRE: Well, Vistaril, hydroxyzine really is not as anti-cholinergic as, certainly not as much as Benadryl. So, I think you get certainly the anxiolytic and the sedative part of that, but I think a little less of the spaciness, and going back to what we said about Anticholinergics, that was something specific with trihexyphenidyl, where you got a little bit more of that kind of buzzy, spacey feeling, and that's why people tended to ask for that and not anticholinergics like Benztropine, for example.  

CHRIS AIKEN: And trihexyphenidyl is used to treat Parkinsonian symptoms. 

JOSEPH PIERRE: Right, exactly! 

CHRIS AIKEN: Do people use that much anymore, or has it been replaced?  

JOSEPH PIERRE: Well, Benztropine is the one that's, you know, Cogentin, a trade name, and that's why. Because of the recognized abuse potential, people really, clinicians really went away from using Trihexyphenidyl. 

CHRIS AIKEN: Yeah, maybe this is on the spectrum with the way that anticholinergics can cause delirium, this kind of altered mental state. 

JOSEPH PIERRE: When I talk to residents and medical students, I often talk about how my first job out of residency was really working in an addiction medicine setting. And, you know, this would have been late 90s, early 2000s. I didn't have a whole lot of addiction training at that point coming out of residency. It wasn't as in vogue as it is now. And frankly, we just didn't know as much about addiction, I think, as we do now. You know, working in that setting, I think I went into it kind of naively thinking, oh, well, people must use... You know, specific drugs of abuse for specific reasons, like you're a upper kind of person, right? You like stimulants in the same way that we like coffee or, you know, that kind of thing. Or maybe you're a downer kind of person and you like sedatives and you want to be calm and mellow. And I think very quickly what I saw in my patient population is that while that might be true in the moment, often 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, for whatever reason. So, you know, I was at Home Depot the other day trying to buy some spray paint and I had a heck of a time getting it because it was all locked behind a, you know, padlocked cabinet. And that's of course because people do things like they huff and they take spray paint. And inhale the aerosol and it, so that to me is such a great example of, it's not necessarily like, I want to feel this specific way, it's just, I want to be dissociated, I want to be out of it. So, there's just so many different, different kind of altered states of consciousness that, that are, are sometimes indiscriminately sought by people who have substance use disorders. 

KELLIE NEWSOME: Joseph Pierre, MD, is a professor of psychiatry at the University of California, San Francisco. He has authored over a hundred papers and chapters on substance use disorders and psychosis, and his latest work focuses on the fine line between conspiracy theories and illusions. Read his full interview on medication misuse in our July 2023 issue and check out his piece, Are Auditory Hallucinations Ever Normal from our July 2019 issue.  

Every single day, Dr. Akin posts a practice changing research study on social media. Follow on Facebook, Twitter, LinkedIn, or threads to search for Chris Akin, MD. The Carlat Report is one of the few publications that relies completely on subscribers.

__________

The Carlat CME Institute is accredited by the ACCME to provide continuing medical education for physicians. Carlat CME Institute maintains responsibility for this program and its content. Carlat CME Institute designates this enduring material educational activity for a maximum of one quarter (.25) AMA PRA Category 1 Credits^TM. Physicians or psychologists should claim credit commensurate only with the extent of their participation in the activity.