[Transcript edited for clarity]

Hello, and welcome to the Carlat Psychiatry webinar, where we're going to talk about the difference between amphetamines and methylphenidate. 

Learning Objectives

After taking this webinar, clinicians should understand how amphetamine and methylphenidate differ in respect to their:

1. Risks of psychosis, mania, and substance use

2. Neurotoxic and neuroprotective properties

3. Efficacy and tolerability

4. Use across the lifespan

We're going to learn about their mechanism of action, which one's more effective, and how they differ in their tolerability levels and their psychiatric risks.

I'm Chris Aiken, Editor in Chief of The Carlat Psychiatry Report. And although I have nothing to disclose, I should let you know that I'm an adult psychiatrist. Some of what I'm going to be saying is influenced from that point of view, particularly when it comes to making the diagnosis of adult ADHD, because adult ADHD is a concept that's only been widely accepted since the late 1990s and we have a lot less research on this condition.

Diagnosis

We're often unsure of this diagnosis in adults. It's also something where the symptoms can be mimicked by other conditions we commonly treat in adults – everything from PTSD to bipolar disorder to schizophrenia can cause symptoms of ADHD. This is not just when the patient has an acute episode, like a manic episode where their mind is racing and distracted and they're hyperactive, but between the episodes of these major psychiatric illnesses, patients often have cognitive problems that can mimic ADHD. 

For a lot of reasons, the treatment of ADHD is not on as firm ground in adults as it is in children. And here are three things that I'm going to look for to make sure this is an accurate diagnosis.

1. Did the symptoms begin before age 12? 
2. Are they better explained by one of those other disorders? 
3. Do they generally have the DSM-5 criteria all met? 

And to that, I might use a structured interview like The Mini International Neuropsychiatric Interview (MINI) or the DIVA-5, which is just for ADHD and adults. They have a child version as well. It's been well validated and consists of a series of structured questions. Like the one you see here, it's around $12 at this website, https://www.divacenter.eu/DIVA.aspx, and it takes about 10 or 15 minutes to complete and practice. 

As I make that diagnosis, I'll be learning whether they have predominantly inattentive or hyperactive impulsive symptoms. So far that distinction makes no difference in which of these two stimulants they're going to do better with, or whether they'll respond to treatment at all. But it does tell us one thing – if they have primarily hyperactive and impulsive symptoms, even though those symptoms tend to decline in adulthood, if there's still some trace of them or more prominence in their childhood, I am more sure of the diagnosis because that's the kind of ADHD most of the research we have available has focused on.

The inattentive type only came into the DSM in the mid-90s with DSM-IV. It's not as well established as the hyperactive type. Hyperactive symptoms are also more observable by outside observers so we’re more certain that they exist.

Stimulants

Once you make a diagnosis of ADHD, stimulants are usually going to be the first-line treatment, unless they're contraindicated, in which case you might try a nonstimulant, but the nonstimulants generally have about half the effect size of the stimulants. 

When you come to the list of stimulants, you'll see about 30. How do you choose among them?

Well, to begin with, all of them distill down to two key ingredients. Though they may differ in their duration of action and in the mix of isomers that they put into that capsule, they all have methylphenidate or amphetamine.

Here's how they work. Amphetamine goes into the nerve terminal, causing it to release more dopamine, flooding the cytoplasm with dopamine. Methylphenidate also increases dopamine and the cytoplasm, but it does it in a more subtle, indirect way by blocking its reuptake. Bottom line, amphetamine is going to give you a bigger punch of dopamine.

Which one to choose? Most textbooks and review articles are going to tell you that they're both the same. Just choose one. I'm going to take a different approach, but let's take that and see where it goes. 

Suppose you did just give your patients six weeks of methylphenidate or six weeks of amphetamine. Let them try both and see what happens. It's actually not a bad strategy. They've tried it in children, and they find that about half of them respond equally well to either one while about half respond preferentially to one of those two stimulants. Another 16% respond to neither of them. Those are still pretty good odds at around 84% of recovery just by trying two in a row (Arnold LE, J Atten Disord 2000;3(4)200-211; Wolraich ML et al, Pediatrics 2019;144(4):e20192528).

But which one should you start with? Let's look to the expert consensus. In the child guidelines, and these are international guidelines I've pulled here, they, most of them say, just choose either one. We're not going to weigh in on which one's better. The British system, the NICE guidelines, do recommend starting with methylphenidate first and second line; they choose only one amphetamine, which is Vyvanse, which delivers dextroamphetamine in such a way that it's harder to abuse.

In the adult guidelines, we see a bigger shift away from the amphetamines where they're tending to recommend them second line. In fact, the US Psychopharmacology Algorithm Project specifically warns about abuse with amphetamines in people who have had a history of substance abuse.

This is unusual because it's actually the amphetamines that were the first ones to be FDA approved and adults starting with Adderall XR in 2004. Why would they recommend methylphenidate first-line in adults? I'll look into that more in this webinar.

The first question we might ask is which one works better? Which one has the bigger effect size? There, the answer is clear. Across several meta-analyses, amphetamine consistently has a bigger effect in ADHD, child and adult, than methylphenidate. Here's the largest and most recent of those meta-analyses (Cortese S et al, Lancet Psychiatry 2018;5(9):727-738). You’ll see that amphetamines are leading the race, both in children and adults, although, I should point out that in some of these meta-analyses, it looked like most of that benefit was due to the Vyvanse studies.

More importantly, this is not based on head-to-head research. There are very few head-to-head trials of these medicines. The ones we have are small and problematic, so these are indirect comparisons. 

Stimulant side effects

But do we pay a price for that bigger effect with amphetamines perhaps in side effects? Here are the side effects you might expect to see with stimulants, both physical side effects—like dry mouth, gastrointestinal problems, headache, and of course, higher blood pressure and pulse—and psychiatric side effects. Your patients might say that they feel like a zombie. They might have compulsivity like nail-biting or skin-picking, particularly at high dosages. They might have insomnia and in the worst cases, mania, psychosis, and substance abuse. 

Going back to that large meta-analysis, they did find that the methylphenidates were better tolerated than the amphetamines, both in children and adults. It looks like we are paying a higher price for that greater efficacy. 

Now, this meta-analysis has been talked about a lot and it's starting to shape practice, and it came to the conclusion that you should start with methylphenidate in children and start with amphetamine in adults. 

You might be wondering how did they figure that? I mean, we saw the same trend here in children, as we did with adults. Well, they looked at one more metric, which is called acceptability. Acceptability is people dropping out of the trial, stopping the med for any reason. The idea here is that if the patient is getting a lot of benefit, they might not stop it, even if they're having side effects like dry mouth. Here they found that acceptability only stood out as better than placebo for methylphenidate in children and amphetamine in adults, coming to the conclusion, then, that you should start with methylphenidate in children and start with amphetamine in adults. 

I'm going to question that metric. I don't think we should decide all of medical practice based on a single metric, although in truth, that is a pretty good one. But it's missing some details we need here, like why did they drop out of the studies? Was it because of headache or was it because of psychosis and why did they stay in this study? I mean, we know these drugs treat ADHD and when you treat ADHD in children or adults, you can really change somebody's life when you get the diagnosis, right. When you get the diagnosis wrong, trouble can happen as I'll get into. But we have to look at another factor that these drugs have rewarding qualities. And when people take, say amphetamines, they tend to feel more confident, so they might tell you that they're doing better at work when they're not; that muddies the waters when it comes to making the assessment.

I've also noticed in some of these analyses that there's a greater tendency for the drugs to stand out as effective when we look at the subjective report than when we look at what the clinicians are seeing. So there's always the possibility that they might be staying on the drug due to these other factors rather than direct treatment of ADHD.

Here are the particular side effects then that I worry about as an adult psychiatrist. All of them are rare, and most of the data I'm going to present here is based on uncontrolled trials. This isn't gold standard randomized-controlled evidence, but these are rare side effects, so they're also less likely to show up in a randomized-controlled trial. Instead, I'll be presenting data from huge analyses of data sets of people who took the medications often looking at what happened to them before they took them and after they took them.

• Psychosis

In psychosis, we know that both stimulants can cause psychosis in this analysis, giving a single stimulant to a patient with schizophrenia (Moran LV et al, J Psychiatr Res 2015;71:41-47). About half of them got more psychotic. In another analysis, looking at children who had ADHD treated with stimulants versus not stimulant treatment, seemed to hasten the onset of psychosis and those who went on to develop psychotic illnesses (Curran C, Br J Psychiatry 2004;185:196-204).

But does that differ from methylphenidate and amphetamine? For years, we really had no idea. It's only recently in this 2018 article in The New England Journal of Medicine -- that I think we should all be aware of because it's very large and it looks at people with ADHD in their teens and early adulthood who prescribed stimulants, comparing the two drugs (Moran LV et al, N Engl J Med 2019;380(12):1128-1138.2019) -- they did find a low rate of psychosis, 1 in 660. Importantly, that rate was double for amphetamine versus methylphenidate.

And in some ways, it could have predicted that, because think back to that mechanism of action. Flooding the nerve terminal with dopamine by causing more release is closer to what we see in the biology of schizophrenia. In schizophrenia we don't see blockade of the reuptake as we do with methylphenidate.

• Mania

Comparing the two is going to be difficult because amphetamines have long been used as an animal model of mania. And when something is used as an animal model of mania, treatment studies with that compound are going to be very sparse. We do have a few people in bipolar and ADHD, some in bipolar depression, but they're very small studies and they don't give us enough data to compare methylphenidate amphetamine. But for me, knowing that it's an animal model in mania is going to give me pause for using amphetamines in a bipolar. 

What about methylphenidate though? Well, we did get some confirmatory data that methylphenidate causes mania in this large study, which found a seven-fold increase in mania. When patients took methylphenidate without a mood stabilizer -- that's patients with bipolar disorder. When they did use a mood stabilizer, it didn't seem to increase the risk though (Viktorin A et al, Am J Psychiatry 2017;174(4):341-348). For that one, I'll give it thumbs down for methylphenidate and bipolar. 

But then we have this. Remember that study where it looked like stimulant use was hastening the onset of psychosis in children? (Wang LJ et al, J Psychiatr Res 2016;72:6-14). Here, we find the opposite using the same kind of analysis that methylphenidate reduced the risk of converting from ADHD to bipolar by 30% while out of atomoxetine (Straterra), which has an antidepressant structure, didn't change those odds. Thumbs up from methylphenidate in the bipolar category. 

And then we have this most unusual study, a randomized controlled trial testing whether methylphenidate treats mania (Hegerl U et al, Eur Neuropsychopharmacol 2018;28(1):185-194). Why would they do this? Well, they had used it open label in the 1980s and a group of researchers developed this idea that mania was due to fragmented attention in the brain and that methylphenidate could cohere that attention and treat the mania. In this short study, two and a half days, methylphenidate did not treat mania any better than placebo. But important for what we're looking at here, it did not make the mania worse and that's a randomized controlled trial, so I'll give it thumbs up for methylphenidate and I'll keep the scorecard running as we go. The data -- not at all definitive -- but I'm seeing a tendency for a higher risk of psychosis and mania with amphetamine than with methylphenidate.

Complex comorbidities

These are often the type I see in adult practice, and here let's look back on history. Let's remember that both of these stimulants were originally described as antidepressants and marketed that way. Amphetamine came out as Benzedrine in 1935. 

Here's how it was first advertised for depression. Twenty years later, the advertisements hadn't changed when methylphenidate came out as Ritalin -- again for depression, apathy, fatigue, moodiness. Well for about 40 years, that was the primary use of stimulants. It wasn't until the 1970s that the FDA cracked down on all this kind of marketing and declared that there was no evidence that these help depression -- you're not allowed to market them that way. Use in adults plummeted after that. 

Let's look at the research. Maybe our forebears had a point, I mean, 40 years of using these in mood disorders, can we really conclude they were totally missing out?

Here are the studies in complex comorbidities (Lavretsky H et al, Am J Psychiatry 2015;172(6):561-569; Richards C et al, J Psychopharmacol 2017;31(9):1190-1203; Richards C et al, J Affect Disord 2016;206:151-160; Gvirts HZ et al, Int Clin Psychopharmacol 2018;33(4):233-237; Schulz SC et al, Psychiatry Res 1985;15(2):97-108; Zheng H et al, Eur Neuropsychopharmacol 2019;29(3):397-404; Shakeri J et al, Drug Alcohol Depend 2016;160:157-162; Pederson L et al, J Pain Symptom Manage 2020;60(5):992-1002).

You might hear that older adults with apathy and fatigue do better with stimulants. True. There are controlled trials looking that way. Nearly all of them involve methylphenidate though, not amphetamine, which was removed from the use in depression in the 1970s. But around 2015, the company that makes Vyvanse took another swing at that and tried to get it approved for antidepressant augmentation. They did two large controlled trials and both of them failed. When large industry sponsored trials fail to show a difference, I tend to think the drug doesn't work. Thumbs down for amphetamine in depression.

What about the risk of suicide with these drugs? Does it go up or down? With methylphenidate, it looks like it goes down, so it has a positive effect; and amphetamine, no difference, or we just don't. 

What about borderline personality disorder? There, we have a controlled trial where methylphenidate improved outcomes. Now that was in borderline with ADHD. But the amphetamines we simply don't know. And the reason is important. In the 1980s, they ran a trial of amphetamines in borderline personality, but 50% of the patients got worse, either more psychotic, more aggressive, so they’re not going to be studied it again, and they're not likely to in that population. I would stay away from it. 

In OCD, both stimulants can cause compulsive behavior, sometimes overt OCD, but interestingly methylphenidate has a controlled trial where it augmented SSRIs successfully in OCD, where amphetamine, we just don’t know.

Finally, you might hear that stimulants are useful in people with fatigue due to medical illnesses like cancer. That's true. Most of those controlled trials were done though with methylphenidate; with amphetamine, we can't be so sure.

I'm going to give you some more details on that suicide data as it recently came out and it surprised me; I didn't expect to see this kind of result. They looked at people who took methylphenidate and sometimes amphetamine before and after regarding their suicide risk in a very large sample. Methylphenidate lowered the risk of suicide attempts and self-harm by about 50% in people with ADHD. Amphetamine did not in people with depression, with personality disorders, and possibly those with bipolar and ADHD. Although there, there weren't many patients to draw a good conclusion. On the other hand, people with schizophrenia tended to get worse in this direction -- not surprising. We didn't see this benefit with amphetamine (Rohde C et al, C, Aust N Z J Psychiatry 2020;54(8):808-817; Rohde C et al, Aust N Z J Psychiatry 2021;55(4):422-424).

One thing that's interesting about the stimulants is they can do a lot of things psychiatrically, as I've already alluded to. They can cause a lot of good and a lot of harm, and what they do might change over time. And it might change at low doses versus high doses. So let's look at what happens with high doses. Unfortunately, in my practice, I often see people come in for their first visit on high doses of stimulants – we’re talking around 120 mg/day. 

I found this study; look at what happens when you go that high. The patients I see don't look so good at that dose. They often have cognitive problems at that point that seemed to go beyond anything ADHD would cause. High doses of stimulant cause a 12-fold increase in psychosis, higher rates of psychiatric hospitalization and substance abuse, and possibly higher rates of suicide. That one was not statistically significant, but suicide is fortunately so rare that often the results are not statistically significant. Now you might be thinking that it could just be that these patients are more psychiatrically ill and so they need higher doses and that's why they have worse outcomes, but this study was done in narcolepsy. So that's less likely to be the explanation (Auger RR et al, Sleep 2005;28(6):667-672).

I'm going to conclude in favor of methylphenidate for patients with complex comorbidities. It seems to have some chance that might make them better, while amphetamine seems to do nothing or possibly make them worse. 

Addiction

What about addiction? First let's look at national trends. It's important to understand that amphetamine is a uniquely American prescription. While other countries use it (although it's banned in some countries completely like in Korea and in Japan), in most countries though, methylphenidate is the most commonly prescribed stimulant by far. And there's very little amphetamine use. In fact, that's why I had some trouble gathering all this data because a lot of this is international research and they only looked at methylphenidate, not amphetamines.

Amphetamine use. Those are the rates, and you see, it only stands out for amphetamine use -- this is prescribed and abuse in Australia and America. 

Amphetamine dependence. Likewise, when you look just at amphetamine dependence, the rates stand out the most in Australia and America (Farrell M et al, Lancet 2019;394(10209):1652-1667).

Is it rewarding? So how do we know if a drug is abusable many ways we can look at population data, we can look at animal data, or we can take people with a history of substance abuse and just ask them, “Do you like the drug? Are you willing to take it again? Would you pay money for it? 

There are about half a dozen studies that have looked at that. Some of them find that methylphenidate and amphetamine are similar on those questions. And a few of them find that amphetamine is more rewarding. The odds are slightly in favor of methylphenidate on that one (Stoops WW et al, J Psychopharmacol 2004;18(4):534-43; Rush CR et al, J Clin Psychopharmacol 2001;21(3):273-86).

But what about looking at diversion? A common problem. One in three college students, or I should say up to one in three, are using a stimulant without a prescription. And here are the best data we have though shows no statistical difference. The thick black line is amphetamines. It is a little higher, but it's not statistically different in rates of diversion today (Sembower MA et al, J Addict Dis 2013; 32(1):26–38).

If we look back in history, though, the rates of abuse were much more serious with amphetamine. With all of that prescribing to adults, people started to misuse the medication among the beatnik poets and other artists and jazz musicians, amphetamine abuse was very common. You might remember Alan Ginsburg sang, “I saw the best minds of my generation destroyed by madness,” and he went on to describe his friends who had become psychotic and underwent psychiatric hospitalizations after using amphetamine. Here he is though in 1965, turning against that epidemic saying that it makes people “antisocial, paranoid making, it's a drag” for the body and the mind.

Next comes Richard Nixon a few years later, whose reschedules both methylphenidate and amphetamine as Schedule-II control, although most of that abuse was with the amphetamines. I don't know if that's due to the properties of the drug or to the way they were marketed and used; we can't say for sure, but that did create a stigma around amphetamines that took a long time to overcome. 

Here's what stigma looks like in the medical profession, high rates of amphetamine prescription in 1969. Let's look at what happens after that law goes into effect in the early 70s; the dark line is going to be methylphenidate. Nearly all the stimulant prescriptions shift to methylphenidate for two decades, and all of it shifts away from adults where it was used for obesity and mood problems toward children for ADHD.

We don't see a rise in amphetamine again, until the late 90s after Adderall was released, Adderall was simply a drug that was used for obesity called Obetrol, but they rebranded it in ‘96 as Adderall, which literally means “ADD for all.” And they literally meant it because in 2004, Adderall became the first FDA-approved stimulant for adult ADHD.

But despite these historical trends for now, at least I can say that the diversion rates are pretty similar between the two drugs. 

Neuroprotection

Finally, I'm going to look at neurotoxicity. This is important to me because when I give a medication, I want to know that it's not just making people feel better, but that it's also doing some good for their brain and hopefully no harm.

I give this drawing out to patients often when I prescribed them, antidepressants like lithium and Depakote, things that have neuroprotective properties. This drawing the dendrites increasing in connections, the brain cells strengthening as opposed to shrinking back like they do under stress.

I don't give this handout with stimulants because it's simply not true. Here's what we know. Most of these studies were done with amphetamine at high doses. High doses of amphetamine flood the cytoplasm with dopamine; that dopamine causes oxidative stress and inflammation, which damages dopamine nerve terminals, particularly in the hippocampus and cerebral cortex where memory and higher cognitive functioning take place (Berman SM et al, Mol Psychiatry 2009;14(2):123-42).

So it could be that if a patient comes in, and perhaps they don't really have ADHD, but look like they do or report the symptoms, we give them a stimulant. They will likely feel better, more confident, more pep, more energy, but that's going to fade off over time. They'll get some tolerance to that, and they're going to want a higher and higher dose.

It could be that in some cases we end up causing the very problem we were trying to treat by going too high in the dose. 

But does this happen in regular doses? There I could only find two studies that show that it does. It's concerning, but not at all definitive. One was done in rats. And one closer to our species was done in primates (Ricaurte GA et al, J Pharmacol Exp Ther 2005;315(1):91-98; Melega WP, Brain Res 1997;766(1-2):113-120). And here you see on the right, dopamine depletion at doses equivalent to 40-60 mg a day of Adderall after only four weeks in. 

Another thing that concerns me is the use of these medications in older adults. And I'm not just concerned about blood pressure and heart attacks here, although that is a real concern. But in these studies, on animals, in older animals, it looks like that toxicity is even greater. The brains of older adults might be more vulnerable (Berman SM et al, Mol Psychiatry 2009;14(2):123-42).

Now we didn't really start using a lot of stimulants for adult ADHD until about 20 years ago. So a lot of those patients are now entering their geriatric years. And while I'm concerned about neurotoxicity, I'm also concerned about the dose because in the animal studies, older patients seem to get twice as much amphetamine in the brain at the same dose. We see the same thing with lithium. That's why you usually need a lower lithium level after age 65. The blood-brain barrier breaks down a bit with age so that patients get higher levels into their brain with the same serum level. 

There's only about two or three studies of stimulants in older adults with ADHD that I could find, and they don't tell us much because they're open label. But they do tell us this: the doses they used tended to be about half what we usually use in children and adults.

Turning now to methylphenidate -- so far, I've picked on amphetamine with neurotoxicity – with methylphenidate, we do see some evidence of neurotoxicity at high doses. On the other hand, we see something that I don't see with amphetamine, which is some evidence of neuroprotection. Some drugs can perhaps be both neurotoxic and neuroprotective. Certainly, we see that with antipsychotics, which have a few neuroprotective effects, but on the other hand can cause tardive dyskinesia, a neurotoxic effect.

Some methylphenidate is particularly neuroprotective in animal models of stroke, Parkinson's disease, and importantly, in methamphetamine use disorder. Methamphetamine is simply a more potent and more neurotoxic and addictive form of amphetamine (Li P et al, Hum Exp Toxicol 2021;40(9):1422-1433; Volz TJ, Curr Neuropharmacology 2008;6(4):379-385).

Summing it up. Here's our scorecard, and here's the bottom line: methylphenidate appears safer, particularly in patients with complex comorbidities and it's better tolerated. It might be less effective, but let's remember that some patients are going to respond better to one and some to the other, so there will always be patients who respond better to methylphenidate and amphetamine, even though to its credit, amphetamine is the one with the bigger effect size overall. 

For my practice, methylphenidate is going to be first choice in adults and amphetamine, second line. However, if I was treating people where I was confident that they only had ADHD, that it was causing significant distress for their lives, they didn't have other comorbidities, those odds might shift the other way. I'll let you decide – but when you must go to make that decision, you're faced again with 30 formulations. Which one do you choose? We'll get to that in a future webinar. Thank you for joining me today. And I hope you stop next time for a talk on how to select a stimulant formulation.

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