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Stimulants (MPH, AMP) for ADHD

Stimulants (MPH, AMP) for ADHD

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WARNING:
Medications for ADHD should only be prescribed after a thorough diagnosis by specialized physicians. This information is not a substitute for professional medical advice and is intended solely to support discussions with doctors and therapists.

Stimulants (psychotonics, psychoanaleptics, colloquially known as “uppers”; singular: stimulant) are psychotropic substances that have a stimulating effect by increasing, accelerating, or enhancing nervous system activity.
The opposite of these are sedatives (colloquially known as “downers”).

ADHD medications are divided into stimulants (methylphenidate, amphetamine-based medications) and non-stimulants (atomoxetine, guanfacine, and others).

A fundamental distinction must be made between stimulants used as medications and stimulants used as drugs. A rapid, high dose that largely occupies the receptors and wears off quickly (= drugs) leads to an excess of neurotransmitters and thereby triggers states of intoxication. In contrast, a slow, low-dose administration that only partially occupies the receptors (= medications) merely compensates for the neurotransmitter deficiency present in ADHD and eliminates the symptoms caused by it.

Stimulants improve cognitive abilities. In a very large-scale study involving N = 766,244 participants, a significant improvement in test scores was observed among people with ADHD who were taking stimulant medication, although their performance levels did not reach those of people without ADHD. Selective serotonin reuptake inhibitors, on the other hand, had no effect on test scores.1

Methylphenidate is one of the most important medications used to treat ADHD and is also used to treat narcolepsy and depression. Methylphenidate is a stimulant.
In Europe, methylphenidate is the first-line choice of medication for ADHD in children and the second-line choice of medication (after amphetamine-based medications) in adults. It has been known since 1944.
In the United States, 52.9% of adolescents with ADHD were initially prescribed MPH, and 39.3% were prescribed amphetamine-based medications as their first ADHD medication. Over the course of treatment, MPH was the primary medication prescribed for about 40% of patients, and AMP for 33%.2

1. Stimulants: Chemical and Neurophysiological Aspects

  • Phenethylamines
    Phenethylamine is the parent compound of all naturally and synthetically produced phenethylamines. It is the parent chemical group and is classified as a “trace amine” because it is found in the body only in small amounts. Many substances within this large group have psychotropic effects.
    • Catecholamines
      • Dopamine
      • Norepinephrine
      • Adrenaline
    • Phenylethylamines
      • Methylphenidate
    • Amphetamines
      A group of mostly synthetically produced phenethylamines that are also known as “wake-up amines” because of their stimulating effects
      • Dexamphetamine
        • The active ingredient in many ADHD amphetamine medications
      • Methamphetamine
        • was developed in the late 19th century and used as a military drug (Pervitin, available commercially in Germany until 1988; Desoxyn (U.S.))
        • commonly known in the drug scene as “meth,” “crystal,” or “crystal meth,” among other names
      • Cathinones.
        These include both natural and synthetic amphetamines, which differ only slightly in chemical structure from the main substance, amphetamine (amphetamine derivatives).
        • Bupropion

(Thanks to Nephilim)

Stimulants primarily act as dopaminergic reuptake inhibitors and, to a lesser extent, as noradrenergic reuptake inhibitors. Nicotine has an indirect stimulating effect by binding to acetylcholine receptors, which in turn indirectly triggers the release of (among other things) dopamine.3
Stimulants exert dopaminergic effects on the nucleus accumbens and improve symptoms of hyperactivity and self-initiation/reinforcement processes, while problems with response delay and working memory are mediated by noradrenergic effects of the locus coeruleus on the PFC. The effects of stimulants on attention and behavioral control are mediated by dopaminergic and noradrenergic mechanisms.4
Stimulants (e.g., nicotine, methylphenidate, amphetamines, entactogens, cocaine) enhance dopaminergic neurotransmission in the striatum by increasing dopamine release and/or inhibiting presynaptic dopamine reuptake. Opioidergic substances (e.g., alcohol, cannabis, opioids) exert an indirect dopaminergic effect via a μ-opioid receptor mechanism by activating dopaminergic neurons in the VTA and by directly targeting opioid receptors.5 These mechanisms are utilized by every healthy brain through endogenous dopamine, endogenous endorphins, and endogenous opioids. The euphoric effect results from a very rapid (phasic) increase in dopamine in the brain, which can only be caused by an increased release of dopamine from the vesicles. ADHD medications, on the other hand, act as reuptake inhibitors and, through a slow (tonic) increase, do not produce a euphoric effect but rather raise the tonic/extracellular dopamine level.

Since the exact mechanisms of action vary by active ingredient, they are described for each specific active ingredient (methylphenidate, amphetamine, etc.).

2. Stimulants as Medications vs. Stimulants as Drugs

Amphetamines are also illegally trafficked and used as drugs (e.g., as ecstasy or crystal meth).
As with any substance, the amount and method of use determine whether it is helpful or harmful. With amphetamines, the intoxicating effect is caused by

  • A much higher dose than when used as a medication
    • Only a high dose occupies more than 50% of the dopamine receptors—enough to induce a sense of euphoria6
    • Only a high dose triggers dopamine release via the VMAT2 receptors.
      AMP drugs, which act purely as reuptake inhibitors, do not utilize this mechanism of action
  • Rapid absorption of the active ingredient (e.g., through the nose)6
    • Even a high dose, when administered slowly, does not act like a drug
  • Short duration of action (the key factor is the rapid rate at which dopamine levels rise and fall)6

Stimulants used as medications are administered in low doses, have a consistent long-term effect, and are taken orally, which results in such a slow release of the active ingredient that no intoxicating effect can occur.
When taken as prescribed by a doctor, there are no known addictive effects, which, unfortunately, cannot be said of many other prescription medications.

Immediate release MPH, when taken in succession, as well as sustained release MPH, produces multiple dopamine peaks (all of which are so low that they do not produce any drug effects). Lisdexamfetamine, on the other hand, produces only one peak and thereby results in a more consistent inhibition of dopamine (and norepinephrine) reuptake.
To achieve as steady an increase in DA and NE levels as possible with immediate release MPH, it should be administered at shorter intervals (2 to 2.5 hours) in doses lower than the actual optimal single dose. So instead of (for example) administering 7.5 mg every 3.5 hours, administering 5 mg every 2.5 hours would result in more consistent DA and NE levels and thus better symptom relief. Stahl illustrates the difference between a short-term high/rapidly declining amount of stimulant (= phasic DA) and a low, long-term, constant amount of stimulant (= tonic DA) as the decisive distinction between the effects of drugs and the therapeutic effects of medication.7

3. Misuse of Prescribed Stimulants

A meta-analysis of k = 13 studies showed that half of the studies reported a prevalence of stimulant abuse among adults of 0% (zero). In other studies, the range was from 2% to 29%. Certain characteristics increased the risk of abuse:8

  • older age
  • previous or more frequent use of ADHD medications
  • Taking short-acting medications
  • a past diagnosis of alcohol or substance abuse

In an Israeli study, 3.74% of the 598 students surveyed reported using stimulants without a prescription.9

A systematic review of k = 12 studies reports an abuse rate of 22% within the past year.10 However, this figure includes not only actual abuse (use as a drug, sale, etc.) but also any intake exceeding the prescribed dosage. While exceeding the prescribed dose without medical supervision is not to be condoned and can cause serious health problems, it is not necessarily indicative of a characteristic specific to stimulants.
Exceeding the prescribed dosage of medications is generally reported for all types of medications (14%).11 More than one-third of all diabetes patients took more medication than prescribed.12 Among patients receiving antihypertensives, lipid-lowering drugs, and oral antidiabetics, 21.9% refilled their prescriptions before the current supply had been used up, indicating overuse.13 Among pain patients experiencing severe pain, 11% took more medication than prescribed.14 Another study of pain patients reported overuse in 13.5% of patients.15
For opioids, 10.5% of patients were reported to have received prescriptions that exceeded the maximum dose specified in the guidelines. The proportion of patients whose prescriptions exceeded the recommended dose was not reported, but is likely to be significantly higher.16
This is by no means intended to justify overuse by patients. However, we believe it is appropriate, in studies on the misuse of ADHD medications, to distinguish between misuse as a drug or commodity and an increase in dosage beyond the prescribed amount, but still within the scope of medical use. Even though the latter is not to be condoned, it should not be lumped together with the former if the goal is to initiate a serious discussion about the genuine risks associated with a class of medications.

Studies show that ADHD medications can only slightly improve cognitive performance—such as attention—in people without ADHD. No improvement in academic performance was observed in people without ADHD.17
In South Africa, methylphenidate sales peak during exam months compared to other months.1819 The fact that this applies particularly to immediate release MPH could also be due to the abnormal price differences (in 2022, immediate release MPH cost about eight times as much as non-immediate release MPH in South Africa).

Due to the inverted-U profile of dopamine’s effects, an increase in dopamine levels in non-affected individuals (starting from an optimal average level) is generally detrimental. At most, in the event of severe chronic stress that lowers dopamine levels, a dopamine deficiency may develop in non-affected individuals, in which case ADHD medications can also help them. We consider it possible that this could be the case during exam periods. Indeed, there is ample evidence of stimulant abuse by students without ADHD during exam periods. However, there are no reports of voluntary, long-term use by people without ADHD after exams have ended. Otherwise, the decline in use following the exam period in South Africa would be inexplicable.
In fact, students who misuse stimulants during exam periods exhibit an above-average number of ADHD symptoms.20

In a study of N = 224,469 American college students aged 18 to 25, 2.4% reported misusing stimulants in the past 3 months. Among people with ADHD who were not taking ADHD medication, this rate was 40% higher.21

There can be various reasons for taking medication without a prescription:22
. Improving academic performance

  • Self-medication when ADHD is suspected
    • ADHD does indeed occur more frequently among stimulant abusers than among non-abusers
  • Weight loss
  • Boosts energy, helps you stay awake

4. Stimulants Used to Treat ADHD Reduce the Risk of Addiction

4.1. ADHD Medications Reduce the Risk of Developing an Addiction

For a comprehensive discussion of this topic, see Substance Abuse / Addiction Comorbid with ADHD in the article “ ” (Choosing Medication for ADHD or ADHD with Comorbidities) In the section “ ” (Choosing Medication for ADHD) in the chapter “ ” (Treatment: Medications for ADHD)

4.2. ADHD medications reduce addictive behavior in people with existing addictions

For a comprehensive discussion of this topic, see Substance Abuse / Addiction Comorbid with ADHD in the article “ ” (Choosing Medication for ADHD or ADHD with Comorbidities) In the section “ ” (Choosing Medication for ADHD) in the chapter “ ” (Treatment: Medications for ADHD)

5. Long-Term Effects of Stimulants

A study found that taking stimulants (MPH, lisdexamfetamine) for at least 24 months had a long-term effect on:23

  • spatial memory
  • Pattern separation
  • Object recognition.

These improvements did not occur immediately after taking the stimulant, but only became significant after 24 months.
The study found no adverse effects on spatial navigation, object recognition memory, or pattern discrimination.

6. Side Effects of Stimulants

A meta-analysis of long-term stimulant use found an increased incidence of mild side effects compared to placebo, none of which were clinically significant. (Meta-analysis, k = 93, N = 16,282)24
In these studies, 86 of the 93 (92.4%) used fixed doses rather than doses adjusted for individual response and tolerability, as is typical in clinical practice.

  • Dry mouth: 3.34 times
  • decreased appetite: 3.24 times
  • Insomnia: 2.1 times
  • Nausea; 2.01-fold
  • Headaches: 1.23 times
  • Anxiety: 1.23 times
  • Irritability: 1.15 times

6.1. Blood pressure, pulse

A meta-analysis involving N = 2,665 adults with ADHD identified the following side effects of stimulants:25

  • an increase in resting heart rate of 5.7 beats per minute on average
  • an average increase in systolic blood pressure of 2 mm Hg
  • a low rate of clinically significant cardiovascular events (including high blood pressure or tachycardia)

Cardiovascular parameters (diastolic blood pressure and pulse, but not systolic blood pressure) were elevated by stimulants, though not to a medically significant degree. (Meta-analysis, k = 93, N = 16,282)24

6.2. Cardiovascular Risks

A meta-analysis reports:26

  • 1 out of 7 studies involving children found an increased risk of cardiovascular problems
  • Two out of three studies in adults found an increased risk of cardiovascular problems

An analysis of N = 131,255.418 reports from the WHO’s international pharmacovigilance database spanning 1967 to 2023 revealed that, among the 146,489 reports on ADHD medications, 13,344 reports concerned cardiovascular side effects. Overall, ADHD medications were associated with a 60% increased risk of cardiovascular side effects (ROR 1.60). Women had a higher risk than men. The following occurred:27

  • Torsade de pointes/QT prolongation
  • Cardiomyopathy
  • Myocardial infarction

Only amphetamines were linked to

  • Heart failure
  • Stroke
  • Cardiac arrest/shock

Of all ADHD medications, methylphenidate showed the lowest overall association with cardiovascular side effects.
Lisdexamfetamine was associated with fewer cardiovascular side effects than other amphetamine medications
Atomoxetine showed the second-highest association with torsade de pointes/QT prolongation.

A Danish cohort study of N = 8,300 children with ADHD born between 1990 and 1999 found a 2.2-fold increased risk of cardiovascular problems associated with stimulants (n = 111 cases):28

  • Hypertension and arrhythmias were the most common among them.
  • MPH increased the risk in a dose-dependent manner. At doses above 30 mg of MPH per day, the risk was 2.2 times higher than at lower doses.

A Swedish case-control registry study of N = 62,060 individuals aged 6 to 64 with ADHD found that long-term (up to 14 years) use of ADHD medications, compared to non-use, reduced the risk of cardiovascular problems (high blood pressure and arterial diseases, but not arrhythmias, heart failure, ischemic heart disease, thromboembolic diseases, or cerebrovascular diseases):29

  • increased by 8% over the first 3 years
  • increased by 4% for each additional year

Doses of more than 45 mg of MPH or LDX, more than 22.5 mg of amphetamine, or more than 120 mg of atomoxetine per day were associated with a higher cardiovascular risk.29

Heart Rate in Children and Adolescents with ADHD:

  • Oros-MPH did not increase the heart rate any more than the placebo3031
  • The non-stimulant atomoxetine increased the heart rate more than the placebo30
  • The increase under the influence of amphetamine or atomoxetine is statistically significant but small on average (≤ 10 beats per minute)31
  • Guanfacine (1–3 mg/day) caused a decrease in heart rate, which returned to normal within one year of taking the medication32

Rise in blood pressure:

  • Statistically significant with amphetamine or atomoxetine, but small on average (≤ 5 mm Hg) (meta-analysis; k = 18, N = 5,837)31
  • Methylphenidate may cause a slight increase in blood pressure (meta-analysis; k = 18, N = 5,837)31
  • MPH in adolescents with ADHD who had been taking the medication for at least two years resulted in high blood pressure in 12.2% of them, compared with 9.6% of those who were not taking the medication33
  • Dexmethylphenidate (5–20 mg/day) caused a slight increase in systolic blood pressure, which returned to normal within one year of treatment32
  • Guanfacine (1–3 mg/day) caused a drop in blood pressure, which returned to normal within one year of taking the medication32

Comorbid eating disorders (binge eating, bulimia nervosa, anorexia nervosa) with ADHD increase cardiovascular risks:34

  • People with anorexia nervosa exhibit structural and functional abnormalities that pose the greatest risk for cardiovascular complications
  • Bulimia nervosa or purging anorexia nervosa often result in electrolyte imbalances
  • Binge-Rating: Obesity is a known risk factor for cardiovascular disease here
  • 60% of adolescents and young adults with an eating disorder develop a substance use disorder at some point in their lives

Co-occurring substance abuse (nicotine, alcohol, cannabis) with ADHD increases cardiovascular risks:34

  • Cannabis may lead to a clinically significant reduction in heart rate variability.
  • Cannabis is acutely associated with tachycardia, high blood pressure, platelet activation, and endothelial dysfunction
  • Cannabis is chronically associated with cardiovascular disease, cardiomyopathy, and arrhythmias
  • Daily cannabis use is higher among cannabis users than among non-users
    • the risk of heart attacks by 25%
    • the risk of stroke by 42%

The increased risk should lead to close medical monitoring, but not to withholding medication. Given the consequences of untreated ADHD (including a life expectancy reduction of 8 to 11 years) and the proven protective effects of stimulants, failing to provide treatment would be irresponsible. It has been proven that ADHD medications increase life expectancy in people with ADHD, which shows that their overall effect is positive, even when their impact on cardiovascular risks is taken into account.
Even though high blood pressure and arrhythmias are unpleasant, they represent a far lesser impairment to quality of life compared to premature death, an anxiety disorder, or depression. In the event of severe cardiovascular symptoms, the use of stimulants—and especially non-stimulants—should be discontinued immediately, and the prescribing physician should be consulted.

The reduction in anxiety and depression alone should help counteract the increased risk of cardiovascular problems over the course of a person’s life.
Untreated ADHD is associated with a 4- to 5-fold increased risk of comorbid anxiety disorders and comorbid depression. ADHD treatment reduces the risk of an anxiety disorder by up to 85% and the risk of depression by 20% to 60%.
An anxiety disorder alone increases the risk of cardiovascular disease by 62% to 72%35; depression alone by 107% to 115%35; and a combination of anxiety disorder and depression by 186% to 189%35.
Since comorbidities associated with ADHD often do not emerge until later in life and are even less common in children, we believe that the protective effect of ADHD treatment on cardiovascular risks—resulting from reduced anxiety and depression—will also become apparent only later.

A meta-analysis of Mendelian randomization studies, which can be used to determine the direction of causality between correlated effects, showed (meta-analysis, k = 14)36

  • A genetic predisposition to ADHD increased the risk of coronary heart disease, heart failure, and various types of strokes.
  • A genetic predisposition to ASS increased the risk of atrial fibrillation and heart failure
  • Atrial fibrillation was found to have a causal link to an increased risk of ADHD
  • High blood pressure was not associated with either ADHD or ASD at the genetic level

For more information on the overall effect of stimulants on ADHD symptoms, see also the following articles:

6.3. Bone Problems

A meta-analysis of k = 44 studies reports that the use of MPH or AMP, through downstream effects on osteoblast- and osteoclast-related genes, leads to a deterioration in specific bone properties and biomechanical integrity.37

On the other hand, it is important to note that stimulants significantly reduce the risk of (accident-related) bone fractures in ADHD. More on this in the chapter Consequences of ADHD).

6.4. Upper Respiratory Tract Infections

People with ADHD who took stimulants had an 11% higher risk of upper respiratory tract infections than people with ADHD who did not take stimulants.38

6.5. Core body temperature

Methylphenidate and amphetamine-based medications raise the body’s core temperature.39
People who are sensitive or at risk should consult their doctor before taking this medication during hot weather.

In cases of passive heat stress (high ambient temperature), MPH is less effective or has no effect.40

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