Medication: development of tolerance

In a few cases, tolerance to stimulants may develop.¹
Although this is rather unusual², it is possible.³⁴
Tolerance development occurs more frequently at high doses⁵⁶ and could therefore possibly also be a consequence of an overdose. However, there are known cases in which there was certainly no overdose.
A diminishing effect can also result from⁷

• Sleep problems/lack of sleep
• Diseases
• Pain
• social stress
• changed environmental influences

A meta-analysis of 87 randomized, placebo-controlled, double-blind studies found no evidence of habituation effects with prolonged use of:⁸

• Methylphenidate
• Amphetamine drugs
• Atomoxetine
• α2 antagonists (guanfacine, clonidine)

Caution: Studies on the development of tolerance to MPH in rats that investigated administration in drug doses (10 mg/kg are not uncommon) or drug administration forms (intravenous, rapid and high dopamine increase)⁹ are not transferable to the effect of drug administration (oral/patch, slow and low dopamine increase), as this defines the central difference between drugs and medication. In addition, particularly high doses were often given.

After 2 years of taking MPH, people with ADHD showed a clear recurrence of hyperactivity and inattention when they stopped taking MPH.¹⁰¹¹ However, this is not a sign of tolerance development, but the normal recurrence of symptoms of ADHD that is no longer being treated.

• 1. Types of tolerance development
  • 1.1. Pharmacokinetic tolerance development
• 2. Action strategies for developing tolerance
  • 2.1. Examination of changed circumstances
  • 2.2. Options for action
    • 2.2.1. Increasing the dose of stimulants
    • 2.2.2. Medication break
    • 2.2.3. Change of active ingredient
    • 2.2.4. Combination medication
    • 2.2.5. Buspirone for MPH tolerance development
    • 2.2.5. Clinical reassessment

1. Types of tolerance development¶

Types of tolerance development are:³

• early development of tolerance
  • rare
• gradual or “late tolerance” over the years
  • slightly more frequent than early tolerance
• “complete tolerance” (complete loss of benefit of the drug)
  • very rare
• partial tolerance (partial loss of benefit)
  • more often than complete tolerance
• Tachyphylaxis
  • rapid development of tolerance to certain drugs
  • In contrast to classical tolerance, the system is initially exhausted in the case of tachyphylaxis and an increase in dose is unsuccessful.¹²

1.1. Pharmacokinetic tolerance development¶

A variant of pharmacokinetic tolerance development is an increased synthesis of transporters that remove the substance from the site of action. Examples:¹³

• P-glycoprotein (permeability glycoprotein)¹⁴
  • Transporter protein in the cell membrane that transports exogenous substances out of the brain cells
  • Member of the ABC transporter family (ATP-binding cassette transporter)
  • is particularly expressed in blood-brain barrier cells
  • affects the permeability of the blood-brain barrier for some drugs
  • causes active re-transport of many relatively large (>400 Da) hydrophobic drugs into the blood
  • P-glycoprotein reduces the effect of these drugs
  • P-glycoprotein is encoded by the MDR1 gene¹⁵
    • Gene variants of the MDR-1 gene influence the efficacy of P-glycoprotein
    • If the function or expression of P-glycoprotein is reduced, the blood-brain barrier is weakened and drugs can increasingly enter the brain, which can increase their effect even though the blood plasma level is unchanged.¹⁵

More on the effects of medication at Duration of effect of medication for ADHD.

2. Action strategies for developing tolerance¶

REVIEW on treatment options for treatment-resistant ADHD: Cortese et al.¹

2.1. Examination of changed circumstances¶

• Test: Do people with ADHD become accustomed to the effects of the medication?
  • During the first few days of the medication’s effect, a slight high is sometimes noticed (honeymoon). This can result from the surprise at the cessation of ADHD symptoms, but can also be a reaction of the nervous system to the now no longer reduced dopamine levels. This feeling is not the goal of medication. Appropriate medication leads to the person with ADHD needing less effort to complete their tasks, but not to a perceptible positive feeling. Anyone who has gone through life with an unconscious 15-kilo rucksack will naturally feel “lighter” in the first few days after putting it down. However, the aim of medication is not to preserve the positively perceived feeling of relief of these first few days, but only to eliminate the difficulty. The expectations of the person with ADHD may need to be questioned here.
• Examination: Has there been a change in other medications?
  • especially in the case of initial and sudden tolerance development
  • Addition of drugs that promote the degradation enzyme?
  • Elimination of drugs that are broken down or inhibited by the same degradation enzyme?
• Test: Have there been any changes in the stomach or urine pH value?
  • Change due to medication
  • Change due to a change in diet
• Test: Reliability of medication intake by the patient
• Examination: comorbid diseases
  • joined?
  • Changes in treatment?
  • Pregnancy?
• Examination: Termination of intensive sporting activity?
  • can cause significant improvement in ADHD symptoms
• Examination: added / removed massive chronic stress?
• Exam: natural course of ADHD over time?
  • ADHD symptoms can become more severe over the course of a lifetime.

2.2. Options for action¶

2.2.1. Increasing the dose of stimulants¶

• short-term interim solution at best
• what is meant here is not the usual dose adjustment required once or twice within the first year of treatment, but an ongoing loss of efficacy
• higher dosage increases the risk of habituation⁵⁶ and therefore possibly the result of an overdose
• stimulants can always be discontinued without any problems when taken orally / patches are used
• constantly increasing the dose of stimulants at short intervals is not a solution
  • to be distinguished from one or two dose adjustments in the first year

2.2.2. Medication break¶

A short drug vacation can help sensitive people with ADHD to reduce the development of tolerance.

• Lower dosage at weekends
• Skip weekends
• a break of several weeks can then restore the long-term effect

2.2.3. Change of active ingredient¶

• from MPH to AMP
• from AMP to MPH
• If the substitute is less effective, it may help to switch back after about a month. It has been reported that in a number of cases the tolerance disappeared after one month.⁶
  • 3 interesting individual cases with a treatment pattern of regular changes of the drug class are reported by Handelman et al.³
• Switch to non-stimulants

2.2.4. Combination medication¶

A reduced stimulant content in combination with non-stimulants can contribute to reduced tolerance development.

2.2.5. Buspirone for MPH tolerance development¶

Methylphenidate had the following effects in rats

• reduced 5-HT-1A-R expression¹⁶
• Buspirone (a partial 5-HT1A agonist and D2R antagonist) prevented downregulation, thereby avoiding tolerance development in cognitive performance¹⁷¹⁸ Buspirone could potentially help limit habituation effects of long-term methylphenidate use ^{19 20}
• Whether this is also the case in humans and at doses that are acceptable for them remains to be seen
• Buspirone also has its own beneficial effect on ADHD. More on this at Buspirone for ADHD.

2.2.5. Clinical reassessment¶

The development of tolerance is not an indication that ADHD does not exist. On the contrary: the effectiveness of the medication at the beginning is an indication of ADHD.
Repeat ADHD diagnosis if necessary.