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Adderall Tolerance: Causes & How To Prevent It

Nearly all individuals taking Adderall can attest to the fact that its psychostimulatory effect is most potent after an initial “first-time” dosage.  Thereafter, its efficacy is generally maintained for weeks, or perhaps months after the initial dosage with favorable results.  However, eventually Adderall users may notice that its therapeutic psychostimulation seems to have dwindled and/or “worn off,” leaving them to speculate that the drug has simply stopped working.

Typically, Adderall doesn’t simply stop working overnight, it takes a period of months for users to notice a gradual decline in its efficacy.  Long-term users may report that the same 20 mg dose of Adderall is no longer providing the same degree of focus and cognitive enhancement as it was during their first few months of usage.  It doesn’t take a neuroscientist to understand that consistent long-term usage of Adderall (an amphetamine based compound with 75% dextroamphetamine and 25% levoamphetamine) is likely to induce tolerance.

It is the tolerance induction that leads most Adderall users back to their doctors to report that their starting dose is no longer working (or effective).  At this point, the doctor suggests increasing the dosage, perhaps to 40 mg – doubling the amount of psychostimulation.  The only problem with this is that eventually (in forthcoming months) the user may become tolerant to the 40 mg dose.  The cycle continues until an Adderall user is on the highest (or possibly a supratherapeutic) dose to cope with his/her tolerance to lower doses.

Eventually, tolerance will also occur on that highest dosage and the user will have hit a proverbial “brick wall” in dosage.  They cannot increase the dosage anymore because risk of adverse effects (e.g. heart abnormalities) is too substantial.  However, decreasing the dosage may result in significant brain fog as characterized by dopamine dysfunction and receptor depletion.  Perhaps some users would benefit from being cognizant of major pharmacological underpinnings associated with Adderall tolerance, as well as hypothetical mitigation strategies.

What is Adderall tolerance?

Adderall tolerance is defined as a reduction in neurophysiologic response associated with repeated administration of Adderall.  As a result, the user must increase the Adderall concentration (dosage) to attain the desired and/or therapeutic effect.  In nearly all cases, Adderall tolerance is considered reversible, but the duration it takes to reverse is contingent upon the same factors that induce Adderall tolerance.

Factors that influence Adderall tolerance onset

Should you become tolerant to the effects of Adderall, it is necessary to analyze the factors that likely contributed to tolerance development.  It is these factors that explain why one individual may develop tolerance within 6 months of Adderall usage, yet another may take 2 years to become tolerant.  Factors that influence tolerance development include: dosage, frequency of use, time span, co-ingested agents, and individual factors.

  1. Dosage (5 mg to 40 mg)

The greater the daily dosage of Adderall that an individual administers, the quicker he/she can expect to develop tolerance. At high dosages, greater quantities of norepinephrine and dopamine are released within the brain, and endogenous production of these neurotransmitters is outpaced by depletion via the dextroamphetamine/levoamphetamine combo.  The higher the dosage of Adderall administered, the greater the the dopaminergic/noradrenergic release.

At a low dosage, concentrations of dopamine and norepinephrine are increased, but not to the same extent as a high dose.  A 5 mg dose should theoretically yield half (50%) the potency of a 10 mg dose.  Lower doses are essentially depleting or “mining” less of the endogenous dopamine/norepinephrine stores when compared to higher doses.

For this reason, users taking the minimal effective dose of Adderall for as long as possible (to manage ADHD symptoms) won’t rapidly develop tolerance to the highest daily dosages.  An individual taking high doses (e.g. 40 mg) from the start of his/her treatment should be thought to deplete dopamine and norepinephrine much quicker than someone taking just 5 mg.  Jumping to a high starting dose without tolerance will yield potent effects, and faster tolerance to all lower doses than all gradual upward titrations.

  1. Frequency of usage

The number of times that you use Adderall per day can affect how quickly you develop tolerance.  Someone that’s using Adderall “all day” is likely to be ingesting a greater overall daily dose, which was already noted to expedite tolerance development.  Someone administering a single dose of Adderall IR (instant release) will have Adderall in his/her system for a shorter duration than someone taking Adderall XR (extended release).

Adderall XR remains active for 12 hours, whereas the IR version elicits a 4 to 6 hour effect.  The time between Adderall doses is likely an important factor to consider regarding tolerance.  The less time between dosages (as a result of highly-frequent administration), the greater the extent of dopamine/norepinephrine depletion and further an individuals’ physiology shifts away from homeostasis.

If you were to take a single-dose of Adderall IR once per day, tolerance onset would be slower than if you were to take Adderall XR once per day.  This is because you are essentially giving your body 18-20 hours “drug-free” – letting your neurophysiology resume (or at least attempt to resume) homeostatic functioning without Adderall; neurotransmitters may be replenished and/or somewhat restored before your next dose.  If you were to take the XR version or multiple IR doses, your neurophysiology will only have 12 hours (significantly less time) to readjust to functioning without Adderall; resulting in faster tolerance onset.

  1. Time span (Weeks, Months, Years)

The total timespan that you’ve been taking a particular dosage of Adderall consistently, the greater your likelihood of tolerance to that dose.  Someone that’s been taking a 40 mg dose of Adderall XR daily for 20 years likely has developed greater tolerance than someone using it for 2 weeks daily.  However, total timespan may be misleading in regards to tolerance onset among those that have gone on “Adderall holidays” or used the drug on an “as needed basis.”

Someone that uses Adderall daily (without missing a single day) may develop tolerance to a 40 mg dose within 6 months, whereas someone who’s been taking Adderall on an “as needed” basis may take 1 to 2 years to develop tolerance to that same dosage.  Therefore, when contemplating time span in relation to tolerance, always consider whether Adderall was used regularly or with breaks – and if it was used with breaks, the length of the “breaks” between dosages.

  1. Co-ingested agents

Many drugs and/or supplements have potential to either expedite or prolong (possibly prevent) tolerance to Adderall.  If you’re taking a drug or supplement that potentiates the effects of Adderall such as via triggering dopamine release and/or norepinephrine reuptake inhibition – it is plausible that tolerance development may be expedited.   On the other hand, if you’re taking a supplement that enhances endogenous production of dopamine/norepinephrine and/or attenuates depletion of neurotransmitters (as induced by Adderall) – tolerance onset may be prolonged (or prevented).

  1. Individual variables

It is also necessary to consider individual variables that may affect Adderall tolerance onset including: a user’s baseline neurophysiology, genetics, diet, stress, and sleep quality.  Someone with favorable neurophysiologic activity pre-Adderall, genes that rapidly restore homeostatic neurotransmission (e.g. generate lost dopamine), eating a healthy diet, with low stress, and quality sleep – is less likely to experience rapid Adderall tolerance than someone in the opposite scenario.  Individuals eating an unhealthy diet with high stress and poor sleep may use up excess dopamine stores quicker while taking Adderall – leading to quicker tolerance.

What causes Adderall tolerance?

There are likely several multifaceted mechanisms by which Adderall tolerance is induced within a user’s neurophysiology.  Repetitive (daily) ingestion of Adderall (75% dextroamphetamine, 25% levoamphetamine) triggers neurophysiologic changes within the central nervous system (CNS) – some of which are induced by the drug and others which accommodate for the drug.  Examples of some alterations that we’d expect following Adderall administration include: neurotransmission (particularly catecholamine levels), neural connectivity, regional activation, and autonomic nervous system function.

When a user initially takes their first dosage of Adderall, he/she experiences a noticeable change in neurophysiology, shifting away from homeostasis; the higher the dose, the greater the shift.  Adderall in particular alters function within the central nervous system to elicit a psychostimulatory effect.  However, over time (with repeated administration), the body learns to not only accommodate, but expect the psychostimulation from Adderall.

As a result, it adapts to regular Adderall administration at an equipotent dosage via desensitization.  The longer an individual takes Adderall at the same dosage, the more desensitized he/she will become to its effect.  As desensitization sets in, rather than responding significantly to the Adderall, a user may perceive it as having lost its initial psychostimulatory “mojo” (effect).

Perhaps an easier-to-understand example of desensitization would be that of partners in a long-term relationship.  The initial time two long-term partners meet, they were likely on their best behavior – trying to impress the other individual with optimal, attractive behavior.  After awhile though (e.g. 6 months), the two become more relaxed and comfortable around the other, engaging in behavior that they would’ve surely avoided on the first date (e.g. farting).

At this point, the initial honeymoon phase of the relationship, and the partners have become desensitized to the other; essentially “tolerant” to the presence of the other – each knows what to expect.  Though some may argue that the relationship is a poor example of desensitization, others may find it useful for this explanation.  Just know that your CNS adapts to any stimulus to which it is regularly and predictably exposed – resulting in desensitization.

Pharmacologic Mechanisms of Adderall Tolerance (Possibilities)

The exact mechanisms by which Adderall induces tolerance aren’t fully elucidated.  Tolerance to Adderall is speculated to principally involve: alterations in catecholamine transmission, particularly dopamine concentrations and receptor densities, as well as calcium ion influx at NMDA receptor sites.  That said, other aspects that may contribute to tolerance include: autonomic nervous system function, neurotoxicity, oxidative stress, and synaptic reorganization.

  • Autonomic nervous system: Psychostimulatory effects derived from Adderall promote increased activation of the sympathetic pathway within the ANS (autonomic nervous system).  As a result, the parasympathetic pathway (those that facilitate relaxation) becomes underactive and sympathetic is in overdrive.  However, with continued administration, the preliminary increases in blood pressure and sympathetic function decrease as the user becomes sensitized.  Various adaptations in the autonomic nervous system following Adderall administration likely contribute to tolerance onset.
  • Calcium ion influx (Ca2+): Many speculate that the primary cause of Adderall tolerance is related to its propensity to alter influx of calcium ions via NMDA receptors.  Specifically, regular Adderall administration triggers an excess influx of calcium ions through NMDA receptors, which in turn, alters synaptic plasticity, neural connectivity, and may even cause damage.  Over time, changes in NMDA receptor function as a result of excess calcium ions may be a prominent biomarker for tolerance onset.
  • Dopamine depletion: The amphetamine mixed salt combo constituent within Adderall functions via TAAR1 agonism and VMAT2 inhibition.  TAAR1 agonism decreases firing of dopamine receptors and increases protein kinase signaling to phosphorylate the dopamine transporter (DAT).  Upon DAT phosphorylation, the DAT is thought to cease functioning or perhaps transport dopamine to the synapse.  VMAT2 inhibition triggers a release of dopamine from presynaptic vesicles into intracellular fluid.  In any regard, endogenous dopamine stores are being utilized quicker than they can be replenished, resulting in dopamine depletion in the basal ganglia and limbic system – leading to tolerance stemming from low dopamine.
  • Gene expression: Evidence suggests that psychostimulants like Adderall facilitate phosphorylation of CREB (cAMP response element binding protein) in dopamine terminals.  Upon phosphorylation of CREB, it binds to CRE within promoter regions of various genes – inducing their transcription.  Researchers have documented that altered gene expression lingers after amphetamine discontinuation and may be yet another mechanism by which individuals become tolerant to Adderall.
  • Hormone concentrations: Adderall is understood to affect concentrations of various hormones, including corticosteroids.  It is known that the body can adjust and become tolerant to increases and/or decreases in levels of hormones resulting from administration of an exogenous substance (e.g. Adderall).  For this reason, it may be necessary to consider the fact that desensitization to hormonal changes may also contribute to tolerance onset.
  • Monoamine depletion: While Adderall primarily affects catecholamine concentrations (dopamine / norepinephrine), it also affects serotonin.  The triad of these neurotransmitters are considered classified as “monoamines.”  Since Adderall affects dopamine the most, depletion of dopamine is most likely.  However, it also utilizes extra norepinephrine and (to a lesser extent) serotonin – perhaps downregulating levels of all three monoamines over a long-term – leading to tolerance development.  Is understood that vesicular storage of dopamine is disrupted following amphetamine administration, perhaps another mechanism contributing to tolerance.
  • Neurotoxicity: While methamphetamine is understood to be neurotoxic, most research suggests that the amphetamines within Adderall are not neurotoxic, especially when ingested at medically prescribed dosages for the treatment of ADHD.  However, others believe that there’s some evidence to suggest that Adderall may induce neurotoxicity, ultimately killing brain cells.  Should certain neurons die as a result of Adderall administration, the cellular loss may result in faster tolerance to Adderall’s effects.  Neurotoxicity may stem from a loss of DA uptake sites within specific regions (e.g. striatum / accumbens) and/or glutamine stimulation.
  • Oxidative stress: Ongoing ingestion of amphetamines is associated with increases in overall oxidative stress.  Therefore, we can speculate that ongoing ingestion of Adderall (dextro/levo-amphetamines) may redistribute dopamine concentrations from vesicles into cytosol (a part of the cytoplasm), thereby losing protection of vesicles and increasing oxidative stress.  This oxidative stress may have deleterious implications, one of which could be neurotoxicity.  In any regard, the oxidative stress increase may be one small mechanism that facilitates tolerance to Adderall.
  • Receptor downregulation: Studies suggest that neuroreceptors may be subject to downregulation after long-term Adderall administration.  Downregulation may occur in specific regions of the brain and may be subject to certain receptor subtypes.  For example, some studies suggest that decreased D2 (dopamine) receptor density is exhibited in the striatum of non-human primates when administered amphetamines over a long-term.  It is logical to assume that D2-receptor density may downregulate as a result of chronic and/or long-term Adderall administration – leading to feelings of anhedonia, anxiety, and depression.
  • Synaptic reorganization: The full extent to which synapses in the brain are reorganized after Adderall (dextro/levo-amphetamine) administration is unknown.  However, it is understood that Adderall alters the influx of calcium ions at NMDA receptor sites, which in turn affects synaptic plasticity.  It should be speculated that synapses reorganize, shift significantly away from homeostasis, and ultimately contribute to Adderall tolerance.
  • Transporter decreases: Research speculates that dopamine transporters (DATs) are altered and/or depleted with repeated Adderall administration.  Some sources estimate that following chronic amphetamine administration, dopamine transporters are decreased by up to 40%.  Although a 40% depletion is unlikely among those taking medically-approved Adderall dosages, even depletion to a lesser extent may be partially responsible for tolerance onset.

Note: Many of the neurophysiologic changes as induced by Adderall, as well as neurotoxicity risks, make it among the most dangerous psychiatric drugs – especially when administered to those without ADHD and/or at high doses.

  • Source: http://www.acnp.org/g4/GN401000166/Default.htm

How to Prevent Adderall Tolerance: Hypothetical Strategies

There are a multitude of opinions floating around the internet regarding how users can prevent Adderall tolerance.  While certain supplements, medications, dosing strategies, etc. – may prolong tolerance development, they are unlikely to fully prevent it.  Tolerance from Adderall is not solely due to a single mechanism (e.g. Ca2+ influx) – if it were, it may be easier to correct.

That said, certain mechanisms appear to account for a greater percentage of tolerance induction from Adderall than others.  It is likely that excess Ca2+ influx at NMDA receptors accounts for a major percentage of tolerance induction, as well as downregulation of dopamine receptors and endogenous levels.  Oxidative stress may account for a smaller percentage of tolerance onset than Ca2+ influx and dopamine receptor downregulation, but it is still necessary to consider.

  1. NMDA Antagonists

Since excess Ca2+ influx at NMDA receptor sites is thought to account for a majority of Adderall tolerance, many believe that concomitant administration of an NMDA antagonist is a viable tolerance prevention strategy.  There are plenty of options regarding NMDA antagonists including: supplements and pharmaceuticals.  Due to the fact that pharmaceuticals are often associated with a host of adverse effects and long-term safety issues, the most practical NMDA antagonist is a magnesium supplement.

Magnesium: Magnesium is an effective NMDA receptor antagonist, meaning it’ll prevent excess Ca2+ influx if administered along with Adderall.  Since Adderall’s absorption is affected by a user’s pH, and an acidic GI tract is known to decrease absorption – it may be best to supplement with magnesium glycinate or taurate (rather than citrate).  Some experts recommend taking around 200 mg three times per day.  It may take some experimentation (and blood work) to determine the optimal amount of magnesium you should take relative to your Adderall dosage to prevent tolerance.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/18557129

Zinc: Supplemental zinc is considered an effective supplement for altering NMDA receptor function via modulation of ion influx.  One study found that children taking zinc supplements (up to 30 mg per day) for 8 weeks were able to reduce their Adderall dose by around 37%.  Obviously you may want to assess blood levels of zinc prior to, and after consistent supplementation to avoid toxicity.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/21309695
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/21504727

Huperzine-A: Though most people know huperzine-A as a reversible acetylcholinesterase inhibitor, may are unaware of its effect as an NMDA receptor antagonist.  Research indicates that administration of huperzine-A may interfere with and/or protect overstimulation associated with elevated calcium levels via the NMDA receptor.  Therefore, some speculate that huperzine-A may effectively prevent the onset of Adderall tolerance.  Despite the fact that huperzine-A is considered a “nootropic” by many, users of huperzine-A should be cognizant of potential adverse effects.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/11920920

Memantine: Many believe that memantine (brand name “Namenda”) is a highly effective pharmaceutical drug to prevent Adderall tolerance.  It exerts an array of pharmacodynamic functions, but its NMDA antagonism is thought to be superior to that derived from agents such as magnesium.  Some Adderall users have managed to convince their psychiatrists/doctors that Namenda is viable concomitant agent for tolerance prevention.

Since Namenda is considered a cognitive enhancer in its own right, perhaps it is synergistic with Adderall as well for treating ADHD, allowing for dosage reductions.  Realize that tolerance may eventually develop to this agent and/or that you may experience unwanted Namenda side effects that could be tough to deal with.  That said, some individuals attribute lack of Adderall tolerance to regular memantine administration.

DXM (Dextromethorphan): Some individuals skip the aforementioned options (magnesium, zinc, huperzine-A, memantine) and start using DXM (dextromethorphan) to offset Adderall tolerance.  DXM is an antitussive (cough prevention) agent found in many over-the-counter drugs such as Mucinex, NyQuil, and Robotussin.  DXM acts as an NMDA receptor antagonist, which may reduce onset of amphetamine tolerance.

However, as a result of its other pharmacodynamic targets, DXM should be avoided among Adderall users.  It is a very “dirty drug” to take solely for the NMDA receptor antagonism.  Most individuals would be far better off pursuing a cleaner, less problematic NMDA antagonist.

  1. Dopaminergic upregulators

Many individuals attempting to halt and/or prolong Adderall tolerance forget that tolerance isn’t solely a byproduct of excess Ca2+ ion influx.  Another prominent mechanism by which Adderall tolerance is established is via dopaminergic adjustments.  Changes in endogenous levels of dopamine, receptor densities (particularly D2) and dopamine transporter (DAT) activity are associated with amphetamine tolerance.

Specifically, Adderall inhibits neurochemical processes from breaking down dopamine, which leads to abnormally high dopamine concentrations.  The high dopamine concentrations decrease the density of dopamine receptors.  As a result, you may want to administer agents that have demonstrated efficacy in upregulation of dopamine receptors (especially D2).

Inositol: There’s modest evidence suggesting that chronic inositol administration significantly increases D2 receptor density in the striatum.  There’s also evidence to suggest that inositol increases 5-HT2 receptor density (to a lesser extent).  Since the Adderall may have downregulated D2 receptors in the striatum, ongoing concomitant administration of inositol may attenuate this downregulation.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/11267629

Choline: Studies suggest that exogenous choline administration increases dopamine receptor densities in animals by up to 11% compared to animals that didn’t receive any choline.  Ensuring that you’re consuming sufficient choline may slightly mitigate some dopamine receptor downregulation associated with Adderall.  Eating plenty of eggs (particularly the yolks) is considered a viable modality of attaining choline, but supplementation is also effective.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/1839138

Sulbutiamine: Though literature is relatively sparse regarding sulbutiamine, one study noted that sulbutiamine administration increases the number of dopamine binding sites within the prefrontal cortex.  Individuals may want to increase dopamine receptor count while simultaneously increasing the number of binding sites for maximal efficacy.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/10996447
  1. Neuroprotective Agents / Antioxidants

Though calcium ion influx (Ca2+) and dopaminergic downregulation (e.g. D2 receptors) may be principally responsible for Adderall tolerance, they may not cover all pharmacologic bases.  Someone may still become tolerant even if they’re taking magnesium or memantine along with inositol and choline.  Another mechanism to consider that may induce Adderall tolerance is that of neurotoxicity and/or oxidative stress.

Due to the oxidative stress as induced by Adderall (possibly via cytosolic redistribution of dopamine stores from vesicles), it may be necessary to take additional neuroprotective agents and/or antioxidants.  Neuroprotective agents and antioxidants decrease amphetamine-induced brain damage and prevent excessive oxidative stress.  Though it cannot be proven that all of these supplements will reduce Adderall tolerance, some may prolong it.

  • Acetyl-L-Carnitine: A mitochondrial enhancer known as “acetyl-l-carnitine” is a known neuroprotective agent.  Some research shows that concomitant administration of Acetyl-L-Carnitine with amphetamine can prevent neurotoxicity.  It may also bolster cognitive performance as a standalone treatment, serving as a viable adjunct to Adderall.
  • Alpha-Lipoic Acid (ALA): A highly effective agent to mitigate oxidative stress within the brain is alpha-lipoic acid.  Alpha lipoic acid is a potent antioxidant that has demonstrated neuroprotective effects.  If Adderall significantly increases oxidative stress, the increase in oxidative stress may cause damage or dysfunction – leading to tolerance.  To prevent oxidative stress (potentially a mechanism contributing to tolerance), supplementation with ALA may be helpful.
  • CoQ10: Many individuals supplement with CoQ10 or Ubiquinol to optimize overall health and improve neurophysiologic functions.  Deficiencies of CoQ10 have been associated with increases in oxidative stress.  Supplementation with CoQ10 may not only improve cognitive function, but may attenuate certain aspects of Adderall tolerance.
  • Curcumin: There are a host of benefits associated with curcuminoids within turmeric, particularly curcumin.  Although its bioavailability is low, administration of a supplement that’s properly formatted (e.g. with bioperine or BCM-95) may decrease oxidative stress and neuroinflammatory markers.  Furthermore, curcumin is thought to act as a neuroprotective agent that is capable of modulating: dopamine receptors, CREB, and gene expression.  Though not well-researched in regards to concomitant administration with Adderall, some speculate that it may decrease tolerance.
  • Creatine: Supplementation with creatine monohydrate elicits synergistic effects with CoQ10 in regards to neuroprotection.  Creatine monohydrate supplementation may reduce oxidative stress and protect the brain from Adderall-induced dysfunction, some of which may lead to tolerance.  In addition to creatine’s efficacy as a mitochondrial enhancer, (which could bolster cognitive function), creatine could aid in Adderall tolerance prevention.
  • Glutathione: Among the most potent of all antioxidants to consider taking with Adderall (especially if you’re an adult) is glutathione.  Glutathione may prevent Adderall-induced oxidative stress and mitigate neurotoxic effects.  Other therapeutic health implications may be associated with regular glutathione administration among adults.
  • Melatonin: Administration of exogenous melatonin has potential to drastically alter your circadian rhythm, which could be deleterious.  However, if administered at a proper time (e.g. 3 hours before bed) at an acceptable dose, melatonin may mitigate oxidative damage associated with Adderall.  It may also prevent circadian rhythm disruption and exhibit neuroprotective effects against neurotoxicity – all of which may influence tolerance.

Note: Contraindications and safety of the aforementioned agents necessitate evaluation with a medical professional prior to usage.  Don’t simply take everything listed here hoping to offset Adderall tolerance – you may alter your neurophysiology to such an extent that your cognitive function is impaired.

  1. Lifestyle interventions

In addition to the drugs and supplements that may offset Adderall tolerance, you could also consider lifestyle interventions.  Most people want to take the “quick and easy” route for tolerance prevention.  Popping another pill to offset tolerance may create more problems than a user initially suspects.

Using any strategy to mitigate Adderall tolerance should be accompanied with strategic lifestyle interventions.  Examples of such lifestyle interventions include: proper hydration, eating a nutrient-dense diet, getting plenty of quality sleep, reducing stress, and modest exercise.  Failure to implement these lifestyle interventions while taking Adderall may expedite tolerance onset, and possibly aging.

Dietary intake & Hydration: It is extremely necessary that any Adderall user ensures optimal dietary intake of nutrient-dense foods.  Failure to consume adequate food is a problem, but a greater problem is a lack of nutrients within one’s diet.  Eating a bag of chips with a soda simply because “you can” while taking Adderall may contribute to disastrous neurological effects (associated with malnutrition) – and faster tolerance onset.

Consume a spectrum of colorful vegetables, protein (foods that increase dopamine), healthy fats, and select whole grains.  Healthy fats may be especially important for offsetting Adderall’s dopaminergic downregulation as they can increase D2 receptors.  In addition to diet, consider that inadequate hydration detrimentally affects brain function – so stay hydrated.

Sleep: Many Adderall users take the drug to compensate for a poor night’s sleep.  Not only will this exacerbate dopamine dysfunction, but it may lead to faster Adderall tolerance.  Getting at least 8 hours of quality (deep) sleep may be necessary after Adderall to help your brain and body recover from excess stimulation.

A reason many people experience “Adderall crashes” after their final dose of the day is because they simply need more time to recover from the excess energy expenditure from the drug.  Don’t skimp on the sleep just because Adderall gives you a psychostimulatory boost.  Sleep deprivation is associated with a host of toxic long-term neurological effects.

Stress reduction: A great way to burn yourself out, induce neurotoxicity, and expedite brain aging is to maintain high stress.  If you’re feeling stressed, your sympathetic nervous system will kick into overdrive, accentuating the effects of Adderall.  Stress takes a toll on your neurotransmission and may deplete catecholamine levels (e.g. dopamine) quicker than necessary.  Consider meditation, deep breathing, or biofeedback (such as with the emWave2) while taking Adderall.

  1. Adderall Potentiation

A strategy that may be feasible to implement is that of Adderall potentiation.  Potentiating the effects of Adderall via concomitant ingestion of a less potent substance may allow users to reap the same therapeutic benefits at lower-than-average dosages.  Dosage reduction of Adderall may help prolong and/or prevent tolerance onset.

  • Alkalinization: A strategy that some have suggested for potentiating the effects of Adderall is alkalinization.  Increasing alkalinity is considered effective in maximizing absorption of Adderall due to the fact that acidity decreases absorption.  Some believe that administering half of a teaspoon of baking soda in water (prior to taking Adderall) could be helpful.  You’ll want to confirm the safety and credibility of this with your doctor though prior to implementing.
  • Caffeine: Intake of caffeine is reported to increase dopamine concentrations as well as upregulate D2 and D3 receptors in various regions of the brain.  It is possible that caffeine may help offset some receptor depletion associated with Adderall, while simultaneously potentiating its therapeutic efficacy.  Therefore, some may find that concomitant coffee consumption may result in a reduced need for high-dose Adderall. (Source: http://www.ncbi.nlm.nih.gov/pubmed/25871974)
  • L-Tyrosine: Many find that L-Tyrosine supplement (an amino acid precursor) is an effective Adderall alternative.  Tyrosine is a building block for the neurotransmitter dopamine – without adequate dietary intake of tyrosine, an individual will likely be low in dopamine.  Administration of L-Tyrosine along with Adderall is likely to potentiate its stimulatory effect, meaning you may not need as large of an Adderall dose. (Read: “L-Tyrosine benefits” for more information).
  • Nicotine: There are many benefits of nicotine, one of which is enhanced cognitive function.  Many nicotine users find that they’re able to reduce their Adderall dosage with concomitant nicotine administration.  Administration of nicotine is thought to increase concentrations of D2 receptors in certain parts of the brain, potentially helping to offset D2 receptor downregulation from Adderall.  That said, nicotine is among the most addictive drugs and receptor upregulation is not sustained after discontinuation.
  1. Adderall dosing strategies

To prevent tolerance on Adderall, an individual may want to take it as infrequently as possible.  In other words, rather than using Adderall on a daily basis, an individual may want to use Adderall once weekly and/or solely in times when ADHD is severe.  By using Adderall with lengthy breaks of interdose sobriety, a user may prolong tolerance development – especially when augmented with several aforestated strategies.

  • “As-Needed”: Some users have resorted to taking Adderall on an “as needed” basis.  Rather than taking Adderall daily, users only take the drug when absolutely necessary.  For example, unless one needs maximal cognitive resources for occupational and/or scholarly pursuits – Adderall simply isn’t taken.  And when cognitively demanding tasks necessitate completion, the Adderall is strategically administered only for the exact duration necessary to complete the task.
  • Adderall vacations: Another strategy that can be used with the “as needed” dosing is that of an Adderall vacation.  Just like people take vacations to reduce stress and take a break from work, individuals may want to take an extended break from Adderall.  Some users may simply stop taking Adderall for 6 months to overcome the tolerance that they had developed.
  • Minimal effective dose: When starting Adderall, it may be wise to only use the minimal effective dose necessary for symptom management.  If a minimal dose is taken on an “as-needed” basis, and lengthy Adderall vacations are taken, one may avoid tolerance altogether – especially when adding NMDA antagonists, dopaminergic upregulators, neuroprotective agents, antioxidants, and lifestyle interventions.  Work with your doctor to come up with a dose that isn’t higher than necessary and consider using Adderall IR as opposed to XR (to avoid extended periods under its influence).

Can everyone prevent Adderall tolerance?

It is farfetched to assume that everyone taking Adderall is capable of mitigating tolerance onset with a simplistic regimen of NMDA receptor antagonists, dopaminergic upregulators, neuroprotectives, and antioxidants.  Even if an individual took the right stack of drugs, supplements, and was leading an optimal lifestyle – does not mean Adderall tolerance can always be avoided.

Some individuals will become tolerant to the effects of Adderall no matter what strategies they implement.  However, using logical strategies as outlined above theoretically could go a long way in prevention and/or prolongation of tolerance development as compared to simply doing nothing.  Since Adderall’s mechanism of action is complex, it is likely impossible to cover all pharmacological bases with tolerance prevention strategies.

There may be some lesser-known mechanism by which Adderall could be inducing tolerance (other than Ca2+ and dopaminergic transmission), making it difficult to prevent.  That said, many anecdotal reports have documented substantial tolerance reduction with adjuvant administration of NMDA antagonists.  Despite these reports, it may be necessary to consider that one could eventually become tolerant to the agents that are working to prevent tolerance.

Furthermore, some of these agents may be intolerable for Adderall users, pose serious pharmacokinetic and/or pharmacodynamic interactions, and/or deleterious long-term implications.  For example, taking an agent such as memantine may offset Adderall tolerance temporarily, but a user may eventually become habituated to the effects of memantine and exhibit major alterations in neurochemical processes without it.  Long-term effects may also be considered detrimental to the neurophysiologic health of the user.

Have you developed Adderall tolerance?

If you’ve developed Adderall tolerance, it is necessary to realize that there’s no biological free lunch – the cognitive enhancement and focus you’re reaping today isn’t being magically generated from thin air.  The Adderall is essentially mining your dopamine and altering Ca2+ ionic influx, leading to future tolerance development.  With repeated administration, regardless of whether you haven’t yet become tolerant to Adderall – the dosage will lose its preliminary efficacy, leading you back to your doctor for an increase.

Increasing the dosage may seem like a logical strategy to cope with Adderall tolerance, but what happens when you reach the highest legally prescribed therapeutic dose?  Assuming you’ve reached the highest possible dosage, not only will the side effects be tougher to cope with, but you’re depleting dopamine stores at an even quicker rate than you were at lower dosages.  Eventually you will become tolerant to even the highest dosage – leading you to a dead end.

Thereafter, you may try related psychostimulants medications only to find that they don’t work and/or you may attempt to discontinue treatment only to experience horrific Adderall withdrawal symptoms (most of which are associated with low dopamine).  For this reason, if you’re going to use Adderall, it is wise to consider and discuss tolerance prevention strategies with a medical professional prior to your first dosage.  If you’ve developed Adderall tolerance and/or have a strategy to prevent it, feel free to share a comment below.

For those that have developed tolerance to Adderall, share some specifics such as: how long it took to develop, the dosage you were taking, and how frequently/regularly you administered Adderall.  No user should be considered immune to Adderall tolerance – it is likely to occur in all regular daily users; even if it may take longer to develop in some compared to others.  Although the efficacy of tolerance mitigation agents remains unclear, it is likely that they provide some degree of benefit.

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{ 9 comments… add one }
  • Myssi March 27, 2016, 3:50 pm

    I had a doctor that was helping me, but the clinic closed down due to funding. All the doctors in our area are afraid to prescribe a controlled substance. But my condition is chronic fatigue syndrome with extreme sleepiness, therefor there is no other possibility other than a controlled substance that has been effective. Is there anyone out there that knows a doctor that is not afraid to prescribe that.

    Due to the expense of what my insurance will cover on the prescription it was cheaper to use adderall than nuvigil or provigil. It seemed to help. I have no problem doing pill counts, urine screens, whatever makes them more comfortable. I just need to find one that will help me with this condition because it is impossible to have a normal life when you are continuously sleeping roughly 20 hours a day.

  • Allie1121 May 31, 2016, 3:07 am

    This website has been very helpful. Several things I knew or sort of knew already, but there was some new information and explanations. Like the other commenter Myssi I feel like I have chronic fatigue syndrome, but it could be 20 other things. All I can say is that the constant fatigue, brain fog, lack of motivation, jitteriness, etc. is ruining my life (career, income, possibility of having kids, regular adult responsibility stuff).

    I sleep so much I don’t want to sleep anymore, but I can’t seem to get up and do ANYTHING, even anything fun. I hate the feeling of when standing, I so badly just need to lie down. Even sitting up is very uncomfortable. The ONLY thing that has helped is Adderall. I’ve been taking Adderall for about 2.25 years now.

    20 ER AM / 10 ER as needed worked great for the first year alone, up until I student taught, in which my dosage increased to 30 ER AM about halfway through the 15 weeks. I think that burned me out. There should have been a much better way to preparing me for the internship etc, but that is beside the point. At some point last fall (2015) (A rough year overall with one thing on top of another happening) it was increased to 50 daily (40 morning/10 as needed later) and I was doing okay with that but after 2 months when asked if it worked any better than the 40 (30/10).

    I said not sure there’s a huge diff, so we went back down. However, I somehow lost half a months worth in January, only to find them like 2 months later, but by then I had gone 2 1/2 weeks without. Then was put on 20mg ER daily which did nothing. Then tried 1 month of Metadate 20 SR which made me feel even MORE tired, if it’s possible, and then back to 20, then 30, now 40.

    Even 40 doesn’t really work. I would love to take something else, or how about nothing at all, but I seriously cannot function and can’t find a Doctor who will really help me figure this out. Family and friends don’t truly understand what I feel like. It is so UNCOMFORTABLE to be in my body. I hate that I can’t communicate effectively enough with anyone what it’s like, as they just can’t identify.

    They tell me all these things, like “just power through it,” “suck it up,” “go exercise,” “go get a good night’s sleep and have a nice breakfast in the morning and you’ll feel better,” “it’s all in your head,” and so on… I feel like such a loser, but I can’t get past it. At night, I’ll feel better in general, and feel like I can accomplish anything in the morning. I’ll get a little hyped up. In the morning, I feel like complete crap.

    The mental difference itself is mindboggling. Anyway, I just thought I’d share.

    • Jennifer August 26, 2016, 4:15 pm

      I completely understand… I’ve struggled with extreme fatigue some I was about 8 years old, so 30 years. Diagnosed with hashimotos thyroiditis at 31 made sense but absolutely nothing helped the fatigue. Until adderall. The past year & a half I’ve lived the closest to normal than I have in over a decade, but I’ve had to increase dosage steadily over that time. Now I take 20 IR twice a day but the fatigue is setting in again & I don’t want to increase, I don’t want to damage my brain even more! But I need a nap after two hours of activity. I’m very frustrated.

  • Rob June 2, 2016, 10:51 pm

    You sound like me Allie, I could really relate, I’m on low dose Adderall right now, but am building a tolerance for it. What you may want to try is Abilify, it has really changed my life because I was so depressed, depression can cause our symptoms of feeling run down and ambition-less all the time, but not too much! 2mg a day fixed me right up.

    I’m not saying I’m Adderall free yet, but I can take as needed, caffeine helps also. I hate coffee so I just do a 100mg tablet in the morning, as the article said it actually works well with Adderall. I take 20 mg XR per day, I’m going to get off the XR and just get the regular kind, like it said. The XR is in your body for 12 freakin hours! Of course I’m building up an intolerance to it at that rate, I found me a new Dr, good luck. Rob

    • Allie1121 June 12, 2016, 10:02 pm

      Hi. I was taking Abilify this year for about 4 -5 months. It was added on to 80mg Prozac. I really didn’t notice anything except maybe weight gain from Abilify. I’ve done a lot of research on ways to naturally boost energy/dopamine, etc. I go to a new PCP in a few days, so we’ll see what we can talk about.

  • Jack June 13, 2016, 2:35 am

    You may want to add atomoxetine to your list of NMDA antagonists that improve tolerance: (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874851/). Although the NMDA antagonism probably only occurs in the drug’s short “active” phase, it may represent another viable option.

    Risk of adrenergic side effects are increased too, but these may abate with time. I have been on this combination (40mg w/30mg lisdexamfetamine) for a while with no such complaints. Stahl also reports this combination as effective.

  • Jack June 13, 2016, 3:29 am

    Also, you mentioned that IR preparations have superior antitolerance effect to XR ones. Wouldn’t the slower rise to max plasma concentration of XR formulations be associated with reduced tolerance? My reasoning: a slower rise means gradual entry of drug into neuron, causing slower DA release (comparable to tonic firing).

    This “trickle” favors D2 over D1 receptor binding, and therefore Ca2+ influx is diminished via D2 receptor’s inhibition of adenyl cyclase/cAMP signaling. It seems like the IR preparation, with faster (and generally more variable) entry would favor D1 binding and provoke Ca2+ release.

  • Eric September 12, 2016, 1:40 pm

    To all of view who are searching for answers… Research Iodine Deficiency and you’ll find the answers to all of your problems. You might think you don’t have it but you definitely do. Iodine is likely the most important nutrient/ mineral that your body needs.

    I also take Adderall but the true LIFE SAVER for me has been IODINE. Again, do your research and make a plan to start taking it. Supplements work in combination with other supplements, so also keep that in mind.

    Example: Iodine must be taken with Selenium, CoFactors will greatly help also. At the beginning your body will react and start detoxing, but after a while, you’ll feel better and normalize. If you’re consistent, you WILL succeed and feel like what you’re suppose to be – The Most Advanced and Evolved Organism in Planet Earth. Best wishes!

  • John September 23, 2016, 5:51 pm

    I thank you! For this extremely interesting and helpful article! I think it’s important to note regarding tolerance, the possibilities of past tolerances that may have developed from unrelated issues. Examples would be, prescription pain medications or recreational drug use. Although Adderall shouldn’t or wouldn’t be prescribed with present or recent use of these other pharmaceuticals. Does the possibility exist of brain chemistry being sensitive to rapid tolerance build up regarding any drug. Even if tolerance from past medications happened years ago? If so, the benefits of repairing this pharmacologically are paramount.

    I have noticed the reduced benefits of this medication and have been taking it for almost a year. I am prescribed 30-40mg of Adderall IR per day. It is prescribed as off label and not for ADD/ADHD. Used for Anxiety and minor Sleep Disorder. Thus far it has helped more then anything else, with emphasis on used as prescribed. I can honestly say, I am not mentally or physically dependent. Considering I have taken long breaks and as much as 3 weeks, several times without issue. My symptoms before current treatment are Clinical Depression, Anxiety and Stress (possibly PTSD). Starting by injury and a string of negative events, some happening simultaneously.

    Some years later, I sought out Mental Health counseling on my own initiative. After seeing various Doctors in the field and prescribed many types of medications, I found none helped. Every popularly prescribed drug, resulted in negative reactions and the few that helped mentally, had minor relief, very short term (not short term use) and negative physical reactions. My current Physician is completely dedicated to my health and wellbeing. Contrary to popular belief, many Doctors are on the patients side and take the Hippocratic Oath seriously.

    I would understandably assume their negative mood, cold demeanor or rushed care at times. Result from stress, exacting decisions and hindrance of medical talent. Controlled by Health Insurance policies and limitations, that many Doctors work under. It is completely logical to assume, most patients would want to maintain the maximum beneficial effect of their medication. Which relates to any medication or supplement, especially if proven effective (non placebo). Especially considering the patient, truly feels better and can function normally.

    My question and it may be obvious, is why many of these protective supplements and nootropics aren’t widely recommended. It would be beneficial if Physicians also studied and recommended supplements. I am sure physicians would, if effective and approved. Also considering nootropics and many supplements are not FDA and medically approved, prevents this. It would be beneficial and medically reasonable for the study, approval and marketing of these possibly beneficial items.

    I know that many will protest the change into a prescription drug. Due to the massive price increase and elimination of obtaining by legal avenues to protect profits. Perhaps not researched currently, as benefits do not warrant the high cost of research. However if some found to be truly beneficial, medically proven and prescribed by physicians. This can only help more then the self medicating, self research and greater chance of harmful side effects currently happening.

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