Tolerance and dependence

Sources for this model

• Juliano LM, Griffiths RR. A critical review of caffeine withdrawal

  Psychopharmacology 2004. Regular caffeine upregulates adenosine receptors; withdrawal headache and fatigue typically 12–24 h after last dose and last 2–9 days. Recovery half-life in this app (~60 h) is that reverse, not CYP1A2 induction. (2004)

• Fredholm BB et al. Actions of caffeine in the brain

  Pharmacol Rev 1999. A1/A2A antagonism is the relevant CNS mechanism at dietary doses. (1999)

• Benowitz NL. Nicotine addiction

  N Engl J Med 2010 / Nicotine Chem 2008. Rapid nAChR desensitization plus slower upregulation of high-affinity receptors. The curve here is the slow pool (days–weeks). (2010)

• Hirvonen J et al. Reversible and regionally selective downregulation of CB1

  Mol Psychiatry 2012. Daily cannabis users: cortical CB1 PET signal recovers over ~2–4 weeks of abstinence. Recovery t½ in the model is 240 h. (2012)

• Nichols DE. Psychedelics

  Pharmacol Rev 2016. 5-HT2A internalization produces rapid, near-complete tachyphylaxis and LSD/psilocybin cross-tolerance, reversing over several days. (2016)

• McCann UD et al. SERT PET after MDMA

  Positron studies show reduced SERT binding after heavy MDMA use with recovery over weeks to months. One-session 5-HT depletion is the fast arm. (2008)

• Bateson AN. Basic pharmacologic mechanisms of benzodiazepine tolerance

  Sleep Med Rev / GABA-A uncoupling and subunit changes with repeated BZ occupancy. Reverse is slower than onset. (2002)

• Koob GF, Le Moal M. Drug addiction, dysregulation of reward, allostasis

  GABA-A hyposensitivity and NMDA upregulation with repeated ethanol. This app models the multi-day pool, not kindling. (2001)

• Calipari ES, Ferris MJ / Nestler EJ. Dopaminergic neuroadaptations

  Repeated amphetamine-class exposure changes DAT and receptor sensitivity. Reverse over days–weeks of abstinence. (2013)

• Williams JT, Christie MJ, Manzoni O. Cellular and synaptic adaptations to opioid

  MOR phosphorylation, internalization, and cAMP superactivation. Days–weeks to unwind. (2001)

• NMDA antagonist tolerance (limited human PD)

  Ketamine shows some functional tolerance with frequent use; evidence is thinner than for 5-HT2A or CB1. Intermittent spacing is empirical.

• H1 inverse-agonist tolerance

  Nightly diphenhydramine sedation fades (H1 down-regulation / behavioral insomnia). Days-scale reverse.

• Exogenous melatonin receptor adaptation

  MT1/MT2 down-regulation with nightly use is modest in the human literature. Treated as a small, fast pool.

• SSRI/NDRI autoreceptor desensitization

  Therapeutic adaptation over weeks, not recreational tachyphylaxis. The curve is shallow on purpose.

• Negligible PD tolerance class

  Supplements, OTC analgesics, CBD, bromantane genomic action: no well-supported rapid CNS tolerance curve at typical doses. Gain is set near zero so the graph does not invent one.