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 meta-analysis of 87 randomized placebo-controlled double-blind studies found no evidence of habituation effects with prolonged use of:⁷

• 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)⁸ 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.⁹¹⁰ 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
• 2. Action strategies for developing tolerance
• 3. Pharmacokinetic tolerance development

1. Types of tolerance development¶

Types of tolerance development are:³

• early tolerance development
  • rare
• gradual or “late tolerance” over the years
  • slightly more frequent than early tolerance
• “complete tolerance” (complete loss of the 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.¹¹

2. Action strategies for developing tolerance¶

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

• Examination: Change of other medication
  • 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: Changes in stomach or urine pH value?
  • Change due to medication
  • Change due to a change in diet
• 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
• short drug vacations 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
• 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 drug class are reported by Handelman et al.³
• Combination medication
  • reduced stimulant content through combination with non-stimulants can contribute to reduced tolerance build-up
• Switch to nesting stimulants
• Question the reliability of the patient’s medication intake
• clinical reassessment
  • cave: a tolerance development is not an indication that there is no ADHD!
  • natural course of ADHD over time?
  • added / removed massive chronic stress?
  • Cessation of intensive sporting activity?
    • can cause significant improvement in ADHD symptoms
  • repeat ADHD diagnosis if necessary
  • comorbid diseases
    • joined?
    • Changes in treatment?
    • Pregnancy?

3. 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:¹²

• P-glycoprotein (permeability glycoprotein)¹³
  • 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 gene¹⁴
    • 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.¹⁴

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