Stimulants (MPH, AMP) for ADHD

Stimulants (psychotonics, psychoanaleptics, stimulants, colloquially: upper; singular: Stimulants) are psychotropic substances that have a stimulating effect by increasing, accelerating or improving nerve activity.
The opposite are tranquilizers (sedatives, colloquially: downers).

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

• 1. Stimulants from a chemical perspective
• 2. Stimulants as medication versus stimulants as a drug
• 3. Abuse of prescribed stimulants
• 4. Stimulants as ADHD medication reduce the risk of addiction
  • 4.1. ADHD medication reduces the risk of developing addiction
  • 4.2. ADHD medications reduce addictive behavior with existing addiction
• 5. Long-term effects of stimulants
• 6. Side effects of stimulants
  • 6.1. Blood pressure, pulse
  • 6.2. Cardiovascular problems
  • 6.3. Bone problems

1. Stimulants from a chemical perspective¶

• Phenethylamines
  Phenethylamine is the chemical parent substance of all naturally and artificially produced phenethylamines. It is the parent chemical group and is a so-called trace amine, as it is only found in small quantities in the body. Many substances within this large group have a psychotropic effect.
  • Catecholamines
    • Dopamine
    • Noradrenaline
    • Adrenalin
  • Phenylethylamine
    • Methylphenidate
  • Amphetamines
    A group of mostly artificially produced phenethylamines, which are also known as wake-up amines due to their stimulating effect
    • Dexamphetamine
      • Active ingredient in many ADHD amphetamine medications
    • Methamphetamine
      • was developed at the end of the 19th century and used as a war drug (Pervitin, on the market in Germany until 1988; Desoxyn (USA))
      • common in the drug scene as “meth”, “crystal” or “crystal meth”, among others
    • Cathinone.
      These are both natural and artificial amphetamines, which differ only slightly chemically from the main substance amphetamine (amphetamine derivatives).
      • Bupropion

(Thanks to Nephilim)

2. Stimulants as medication versus stimulants as a drug¶

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

• Massively higher dosage than as a drug
  • Only a high dosage occupies more than 50 % of the dopamine receptors and thus enough to cause a perception of intoxication¹
  • Only the high dosage leads to the release of dopamine via the VMAT2 receptors.
    AMP drugs, which have a purely reuptake-inhibiting effect, do not use this route of action
• Rapid absorption of active ingredients (e.g. through the nose)¹
  • Even a high dosage, which is taken slowly, does not act like a drug
• Short duration of action (a high speed of change in the dopamine level upwards and downwards is crucial)¹

Stimulants are low doses of medication, have a long-term, consistent effect and are also administered orally, which means that the active ingredients are distributed so slowly 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 medically prescribed drugs.

Immediate release MPH, taken in succession, like sustained release MPH, sets several dopamine maxima (all of which are so low that they do not develop drug effects). Lisdexamfetamine, on the other hand, sets only one maximum and thus causes a more even inhibition of dopamine (and noradrenaline) reuptake.
In order to increase DA and NE levels as evenly as possible with immediate release MPH, it should be administered at shorter intervals (2 to 2.5 hours) than the optimal single dose. So instead of administering 7.5 mg every 3.5 hours (for example), an administration of 5 mg every 2.5 hours would result in a more even DA and NE level and thus better symptom reduction. Stahl illustrates the difference between short-term high/rapidly decreasing stimulant levels (= phasic DA) and low long-term constant stimulant levels (= tonic DA) as the decisive difference between drug effect and curative drug effect.²

3. Abuse of prescribed stimulants¶

A meta-analysis of k = 13 studies showed that half of the studies had a reported prevalence of stimulant abuse in adults of 0%. In other studies, the range was from 2% to 29%. Certain characteristics increased the risk of abuse:³

• older age
• earlier or more frequent use of ADHD medication
• Taking short-acting medication
• a diagnosis of alcohol/substance abuse in the past

4. Stimulants as ADHD medication reduce the risk of addiction¶

4.1. ADHD medication reduces the risk of developing addiction¶

Stimulants do not increase the risk of developing an addiction, neither to non-medical stimulants⁴ nor to stimulant medication. People with ADHD often enough forget to take their medication, which would not happen with addictive pressure.
On the contrary, stimulants as ADHD medications significantly and sustainably reduce the risk of addiction. A case report provides an example.⁵

One study reports that factors such as the onset and discontinuation of medication use for ADHD may influence the likelihood of addiction later in life.⁶ However, it should be noted that addiction is epidemic in the USA (one in 13 Americans has a diagnosis of addiction), which can be attributed in particular to inappropriate painkiller prescriptions (opioids), which never occurred in Europe. The extent to which the study could be transferred to conditions outside the USA and especially in Europe is unclear.

A meta-analysis of k = 6 studies with n = 1,014 subjects showed a significantly reduced risk of later addiction for participants medicated with stimulants (here: MPH).⁷ The risk of later addiction, whether to alcohol or other substances, was found to be 1.9 times lower (i.e. almost halved).⁸
This is consistent with the experiences from the ADHD forum of ADxS.org. Many more people with ADHD report that their craving for alcohol or nicotine has decreased significantly since taking stimulant medication, while reports to the contrary tend to be isolated cases.

Amphetamine drugs are now available as pro-drugs (lisdexamfetamine). This means that they are available in a form in which they are simply ineffective when abused (abusive ingestion in massive overdoses through the nose or intravenously) because they are present in an active substance compound, are only metabolized over many hours in the blood, very slowly, to the active drug substance and therefore cannot trigger a drug high, but can only bring about the healing effect of a flatly rising and falling functional dopamine level.
Daberkow et al⁹ show in this Graph under D the slow increase in dopamine (drug) at 1 mg/kg AMP and the rapid increase (drug) at 10 mg/kg AMP. The level development at 1 mg/kg AMP corresponds to the curves known from amphetamine drugs.

4.2. ADHD medications reduce addictive behavior with existing addiction¶

People with ADHD with comorbid cocaine addiction showed a significant reduction in addictive behavior when treated with stimulants, corresponding to the reduction in ADHD symptoms.¹⁰

Nevertheless, for persons with ADHD with a pre-existing acute or previous addiction (dependence) to amphetamines or cocaine, it should be taken into account that the receipt of similarly acting drugs could trigger them to try to abuse them again as a drug.
Other acute or former addictions (alcohol, THC without amphetamine addiction) should barely produce a trigger effect.
Isolated amphetamine abuse (weekend use) in the past is also unlikely to pose a risk and is more likely to be a sign of self-treatment in people with ADHD, even if repeated.
It should also be borne in mind that there are cheaper and easier to obtain substances in every disco and behind every train station that produce considerably more intoxicating effects. In our opinion, the risk of abuse of ADHD medication is rather theoretical. Considering the importance for the treatment of people with ADHD, we doubt that the restrictions make sense from a socio-political point of view.

5. Long-term effects of stimulants¶

One study found a long-term effect when taking stimulants (MPH, lisdexamfetamine) for at least 24 months:¹¹

• spatial memory
• Sample separation
• Object recognition.

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

6. Side effects of stimulants¶

6.1. Blood pressure, pulse¶

A meta-analysis with n = 2,665 adults with ADHD found the side effects of stimulants to be:¹²

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

6.2. Cardiovascular problems¶

Another meta-analysis reports:¹³

• 6 out of 7 studies in children found no increased risk of cardiovascular problems
• 2 out of 3 studies on adults found evidence of increased risks of cardiovascular problems

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

• Protective effect of ADHD treatment In the article Consequences of ADHD
• MPH Part 2: Dosage, side effects, contraindications
• Side effects of amphetamine medication

6.3. Bone problems¶

A meta-analysis of k = 44 studies reported that the use of MPH or AMP leads to a deterioration of specific bone properties and biomechanical integrity via downstream effects on osteoblasts and osteoclast-related genes.¹⁴

In contrast, it should be borne in mind that stimulants in ADHD massively reduce the risk of (accidental) bone fractures. *More on this in the chapter Consequences of ADHD). *