Medications: Development of Tolerance

In rare cases, tolerance to stimulants may develop.¹
While this is rather uncommon², it is possible.³⁴
Tolerance develops more frequently at high doses⁵⁶ and, in this respect, could possibly also be a consequence of an overdose. However, there are known cases in which an overdose definitely did not occur.
A diminishing effect can also result from⁷

• Sleep problems/lack of sleep
• Diseases
• Pain
• social stress
• changing environmental factors

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

• Methylphenidate
• Amphetamine-based medications
• Atomoxetine
• α2-antagonists (guanfacine, clonidine)

Caution: Studies on the development of tolerance to MPH in rats—which examined administration at drug doses (10 mg/kg are not uncommon) or drug routes of administration (intravenous, resulting in a rapid and high rise in dopamine)⁹ —are not transferable to the effects of medication administration (oral/patch, slower and lower dopamine rise), as this defines the key difference between drugs and medications. Furthermore, particularly high doses were often administered.

People with ADHD showed a marked recurrence of hyperactivity and inattention upon discontinuing MPH after 2 years of treatment.¹⁰¹¹ However, this is not a sign of the development of tolerance, but rather the completely normal recurrence of symptoms of ADHD, which is no longer being treated.

1. Types of Tolerance Development¶

One-time dose adjustment within the first 6 months¶

During the first six months of treatment, mild tolerance may develop, requiring a 20 to 30 percent increase in the dose. ¹²

Types of tolerance development include:³

• early development of tolerance
  • rare
• gradual or “late tolerance” over the course of several years
  • slightly more common than early tolerance
• “complete tolerance” (complete loss of the drug’s efficacy)
  • very rare
• partial tolerance (partial loss of benefit)
  • more common than complete tolerance
• Tachyphylaxia
  • rapid development of tolerance to certain drugs
  • Unlike with classic tolerance, in the case of tachyphylaxia, the system is initially exhausted, and increasing the dose has no effect.¹³
  • A systematic review on tolerance and tachyphylaxis with ADHD medications identified 17 empirical studies that varied greatly in design and duration. The evidence was contradictory. Reports of symptom worsening despite regular use could neither be confirmed nor ruled out. There was only preliminary evidence of tachyphylaxis, i.e., a loss of efficacy within a single day. Before increasing the dose due to suspected tolerance, other causes should therefore be investigated, including declining adherence, changing demands, sleep deprivation, comorbidities, or a dose that was too low from the start.¹⁴

1.1. Development of Pharmacokinetic Tolerance¶

One form of pharmacokinetic tolerance development is increased synthesis of transporters that remove the substance from the site of action. Examples:¹⁵

• P-glycoprotein (permeability glycoprotein)¹⁶
  • A transporter protein in the cell membrane that removes foreign substances from brain cells
  • Member of the ABC transporter family (ATP-binding cassette transporters)
  • is expressed particularly in blood-brain barrier cells
  • affects the permeability of the blood-brain barrier for certain medications
  • facilitates the active transport of many relatively large (> 400 Da) hydrophobic drugs back into the bloodstream
  • P-glycoprotein reduces the effect of these drugs
  • P-glycoprotein is encoded by the MDR1 gene¹⁷
    • Variants of the MDR-1 gene affect the effectiveness of P-glycoprotein
    • When P-glycoprotein function or expression is reduced, the blood-brain barrier is weakened, and drugs can cross into the brain in greater quantities, which may increase their effects even though plasma levels remain unchanged.¹⁷

Learn more about how medications work at Duration of Medication Effect in ADHD.

There is a wide range of data regarding the frequency of true tolerance development. In one clinical study, 24.7% of people with ADHD developed tolerance within days to weeks; in another, 2.7% did so over a period of ten years. In a retrospective chart review of 166 people with ADHD treated with methylphenidate between 1976 and 1990, 68 (41%) were affected. Changes in receptor or transporter density are discussed as possible mechanisms. In a PET study of previously untreated adults, the availability of the dopamine transporter in the striatum increased by 24% after twelve months of MPH treatment. ³

1.2. Development of Tolerance to Amphetamine-Based Medications and MPH¶

A study measured acute tolerance to amphetamine. When the perceived effect and blood pressure are plotted against blood concentration, the curves follow a clockwise path (hysteresis). At the same blood level, the effect was weaker in the descending branch than in the ascending one. The perceived stimulating effect lasted only about eight hours, even though the concentration of amphetamine in the blood remained high. The heart rate curve followed a counterclockwise trend; the effect lagged behind the concentration, showed no tolerance, and remained elevated for up to 24 hours. (Randomized, double-blind, placebo-controlled crossover study in healthy subjects, N = 24, E 1b)¹⁸ The authors speculate that the cause is that amphetamine releases neurotransmitters from their storage sites, thereby depleting them, whereas methylphenidate only inhibits reuptake. In comparable studies, no tolerance to the perceived effects was observed with methylphenidate. The authors themselves describe this explanation as speculative. The single dose of 100 mg used exceeds the approved maximum dose of 70 mg and was chosen to simulate abuse and to achieve steady-state plasma levels below 70 mg. The drug was administered on an empty stomach. According to other studies, when taken after a meal, the time to peak concentration is prolonged by about one hour. Furthermore, no difference was found between men and women, neither in kinetics nor in effect.

A systematic review of tolerance and tachyphylaxis to ADHD medications found preliminary evidence of tachyphylaxis to the affective and behavioral effects of stimulants, as well as tolerance to the subjective effects of D-amphetamine (such as substance craving and arousal) in neurotypical participants over a short time period. The included studies were highly heterogeneous in terms of design and duration (Systematic Review, k = 17, E 2b)¹⁹

2. Strategies for Fostering Tolerance¶

REVIEW of Treatment Options for Treatment-Resistant ADHD: Cortese et al.¹

2.1. Review of Changed Circumstances¶

• Test: Is the person with ADHD becoming accustomed to the medication’s effects?
  • During the first few days of treatment, patients sometimes experience a mild “high” (the “honeymoon” phase). This may result from the surprise of seeing ADHD symptoms disappear, but it can also be a reaction of the nervous system to dopamine levels that are no longer suppressed. This feeling is not the goal of medication. Appropriate medication results in the person with ADHD requiring less effort to complete their tasks, but it does not result in a noticeable positive feeling. Anyone who has gone through life carrying an unconscious 15-kilo backpack will naturally feel “lighter” in the first few days after setting it down. However, the goal of medication is not to preserve the positively perceived feeling of relief experienced during those first few days, but simply to eliminate the burden. In this context, the expectations of people with ADHD may need to be reevaluated.
• Check: Have there been any changes to other medications?
  • especially in cases of first-time and sudden development of tolerance
  • Adding medications that promote the breakdown enzyme?
  • Elimination of drugs that are metabolized by the same enzyme or that inhibit it?
• Test: Were there any changes in the pH level of the stomach or urine?
  • Changes caused by medications
  • Change due to a change in diet
• Assessment: Patient adherence to medication
• Examination: comorbid conditions
  • joined?
  • Changes in treatment?
  • Pregnant?
• Assessment: Should I stop participating in intense sports activities?
  • may lead to a reversal of significant improvement in ADHD symptoms
• Assessment: Has significant chronic stress developed or subsided?
• Study: The Natural Course of ADHD Over Time?
  • ADHD symptoms may become more severe over the course of a person’s life.

2.2. Options for Action¶

2.2.1. Increasing the dose of stimulants¶

• At most, a short-term stopgap solution
• This does not refer to the usual dose adjustment required once or twice during the first year of treatment, but rather to a gradual loss of efficacy
• Higher doses increase the risk of tolerance⁵⁶ and, as such, may be a consequence of an overdose
• When taken orally or as a patch, stimulants can always be discontinued without any problems
• Continuously increasing the dose of stimulants at short intervals is not a solution
  • to be distinguished from adjusting the dose once or twice during the first year

2.2.2. Medication Break¶

A short break from medication can help people with ADHD reduce the development of tolerance.

• Take a lower dose on weekends
• Skip weekends
• A break lasting several weeks can restore long-term effects afterward

2.2.3. Change in the 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 quite a few cases, the tolerance had disappeared after a month.⁶
  • Handelman et al. report on 3 interesting individual cases characterized by a treatment pattern of “regularly alternating drug classes.”³
• Switching to non-stimulant medications

2.2.4. Combination medication¶

Reducing the proportion of stimulants by combining them with non-stimulants can help prevent the development of tolerance.

2.2.5. Buspirone in Cases of MPH Tolerance Development¶

Methylphenidate caused the following effects in rats

• reduced 5-HT-1A-R expression²⁰
• Buspirone (a partial 5-HT1A agonist and D2R antagonist) prevented downregulation and thereby prevented the development of tolerance with regard to cognitive performance²¹²² Buspirone may potentially help limit habituation effects associated with long-term methylphenidate use.²³²⁴
• It remains to be seen whether this is also the case in humans and at doses that are safe for humans
• Buspirone also has its own beneficial effects on ADHD. For more information, see Buspirone for ADHD.

2.2.5. Clinical Reevaluation¶

The development of tolerance does not indicate that ADHD is not present. On the contrary: the medication’s initial effectiveness is an indication of ADHD.
If necessary, have the ADHD diagnosis reviewed.³