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Paradoxical reaction

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A paradoxical reaction (or paradoxical effect) is an effect of a chemical substance, such as a medical drug, that is opposite to what would usually be expected. An example of a paradoxical reaction is pain caused by a pain relief medication.

Paradoxical reactions may be more common in people with ADHD.[1]



Amphetamines are a class of psychoactive drugs that are stimulants. Paradoxical drowsiness can sometimes occur in adults.[2] Research from the 1980s popularized the belief that ADHD stimulants such as amphetamine have a calming effect in individuals with ADHD, but opposite effects in the general population.[3] New research however disputes this claim, suggesting that ADHD stimulants have similar effects in adults with and without ADHD.[4][5]


The paradoxical effect or Eagle effect (named after Harry Eagle, who first described it) refers to an observation of an increase in survivors, seen when testing the activity of an antimicrobial agent.[6] Initially when an antibiotic agent is added to a culture media, the number of bacteria that survive drops, as one would expect. But after increasing the concentration beyond a certain point, the number of bacteria that survive, paradoxically, increases.


In a minority of cases, antidepressants can lead to violent thoughts of suicide or self-harm, as observed in some patients during and after treatment, which is in marked contrast to their intended effect.[7] A 1991 study found that children and adolescents were more sensitive to paradoxical reactions of self-harm and suicidal ideation while taking fluoxetine (commonly known as Prozac).[8] This can be regarded as a paradoxical reaction but, especially in the case of suicide, may in at least some cases be merely due to differing rates of effect with respect to different symptoms of depression: If generalized overinhibition of a patient's actions enters remission before that patient's dysphoria does and if the patient was already suicidal but too depressed to act on their inclinations, the patient may find themself in the situation of being both still dysphoric enough to want to commit suicide but newly free of endogenous barriers against doing so.[citation needed]


Chlorpromazine, an antipsychotic and antiemetic drug which is classed as a "major" tranquilizer, may cause paradoxical effects such as agitation, hallucinations, excitement, insomnia, bizarre dreams, aggravation of psychotic symptoms and toxic confusional states.[9]

These may be more common in elderly dementia patients. Apparent worsening of dementia may be due to the anticholinergic side effects of many antipsychotics.[10]


Phenobarbital can cause hyperactivity in children. This may follow after a small dose of 20 mg, on condition of no phenobarbital administered in previous days.[11] Prerequisity for this reaction is a continued sense of tension. The mechanism of action is not known, but it may be started by the anxiolytic action of the phenobarbital.

Barbiturates such as pentobarbital have been shown to cause paradoxical hyperactivity in an estimated 1% of children, who display symptoms similar to the hyperactive-impulsive subtype of attention deficit hyperactivity disorder. Intravenous caffeine administration can return these patients' behaviour to baseline levels.[12]


Benzodiazepines, a class of psychoactive drugs called the "minor" tranquilizers, have varying hypnotic, sedative, anxiolytic, anticonvulsant, and muscle relaxing properties, but they may create the exact opposite effects. Susceptible individuals may respond to benzodiazepine treatment with an increase in anxiety, aggressiveness, agitation, confusion, disinhibition, loss of impulse control, talkativeness, violent behavior, and even convulsions. Paradoxical adverse effects may even lead to criminal behavior.[13] Severe behavioral changes resulting from benzodiazepines have been reported including mania, hypomania, psychosis, anger and impulsivity.[14]

Paradoxical rage reactions due to benzodiazepines occur as a result of an altered level of consciousness, which generates automatic behaviors, anterograde amnesia and uninhibited aggression. These aggressive reactions may be caused by a disinhibiting serotonergic mechanism.[15]

Paradoxical effects of benzodiazepines appear to be dose related, that is, likelier to occur with higher doses.[16]

In a letter to the British Medical Journal, it was reported that a high proportion of parents referred for actual or threatened child abuse were taking medication at the time, often a combination of benzodiazepines and tricyclic antidepressants. Many mothers described that instead of feeling less anxious or depressed, they became more hostile and openly aggressive towards the child as well as to other family members while consuming tranquilizers. The author warned that environmental or social stresses such as difficulty coping with a crying baby combined with the effects of tranquilizers may precipitate a child abuse event.[17]

Self aggression has been reported and also demonstrated in laboratory conditions in a clinical study. Diazepam was found to increase people's willingness to harm themselves.[18]

Benzodiazepines can sometimes cause a paradoxical worsening of EEG readings in patients with seizure disorders.[19]


Caffeine is believed by many to cause paradoxical calmness or sedation in individuals with ADHD.[20] There is insufficient evidence to determine if sedation caused by caffeine is due to a true paradoxical reaction, or rather from dehydration and sleep deprivation caused by the caffeine.[21] Furthermore there are no conclusive studies showing a different effect of caffeine on individuals with ADHD compared to the general population.


Naltrexone blocks the opioid receptors, acting opposite to most opioid pain medications.[22] It can be used to negate the effects of opioid painkillers. At doses around one-tenth of the typical dose, naltrexone has been used for pain relief. Low-dose naltrexone is believed to have an anti-inflammatory effect. This is an off label use and not widely accepted by the medical and scientific community.[23]


Diphenhydramine (often referred to by the trade name Benadryl) is an anticholinergic antihistamine medicine commonly used to treat allergic reactions and symptoms of a common cold, such as coughing. Its central antihistaminergic properties also cause it to act as a sedative, and for this reason it is also used to treat insomnia.[24] Diphenhydramine is also used off-label for its sedative properties, particularly by parents seeking to make their children sedated or sleep during long-haul flights. This use of diphenhydramine has been criticised for a number of reasons, ranging from ethical to safety concerns,[25] but also due to the risk of diphenhydramine’s paradoxical reaction, which induces hyperactivity and irritability.[26] This phenomenon can also be observed in adults who use the medication as a sleep aid. The prevalence of this paradoxical reaction is unknown, but research into the phenomenon suggests that it may be as a result of the medicine’s interactions with the CYP2D6 enzyme, and that a metabolite of diphenhydramine may be to blame.[27]


GABAA receptor with its five subunits and where various ligands bind.

The mechanism of a paradoxical reaction has as yet (2019) not been fully clarified, in no small part due to the fact that signal transfer of single neurons in subcortical areas of the human brain is usually not accessible.

There are, however, multiple indications that paradoxical reactions upon – for example – benzodiazepines, barbiturates, inhalational anesthetics, propofol, neurosteroids, and alcohol are associated with structural deviations of GABAA receptors. The combination of the five subunits of the receptor (see image) can be altered in such a way that for example the receptor's response to GABA remains unchanged but the response to one of the named substances is dramatically different from the normal one.

See also[edit]


  1. ^ Langguth B, Bär R, Wodarz N, Wittmann M, Laufkötter R (August 2011). "Paradoxical reaction in ADHD". Deutsches Ärzteblatt International. 108 (31–32): 541, author reply 541–2. doi:10.3238/arztebl.2011.0541a. PMC 3163785. PMID 21886668.
  2. ^ Tecce JJ, Cole JO (August 1974). "Amphetamine effects in man: paradoxical drowsiness and lowered electrical brain acitivity (CNV)". Science. 185 (4149): 451–3. Bibcode:1974Sci...185..451T. doi:10.1126/science.185.4149.451. PMID 4841149. S2CID 26068007.
  3. ^ Segal, D. S.; Kuczenski, R. (1987-09-01). "Individual differences in responsiveness to single and repeated amphetamine administration: behavioral characteristics and neurochemical correlates". Journal of Pharmacology and Experimental Therapeutics. 242 (3): 917–926. ISSN 0022-3565. PMID 3656119.
  4. ^ Arnsten, Amy F. T. (November 2006). "Stimulants: Therapeutic Actions in ADHD". Neuropsychopharmacology. 31 (11): 2376–2383. doi:10.1038/sj.npp.1301164. ISSN 1740-634X. PMID 16855530. S2CID 36283770.
  5. ^ Rapoport, J. L.; Inoff-Germain, G. (April 2002). "Responses to methylphenidate in Attention-Deficit/Hyperactivity Disorder and normal children: Update 2002". Journal of Attention Disorders. 6 (1_suppl): 57–60. doi:10.1177/070674370200601S07. ISSN 1087-0547. PMID 12685519. S2CID 24320882.
  6. ^ Eagle H, Musselman AD (July 1948). "The rate of bactericidal action of penicillin in vitro as a function of its concentration, and its paradoxically reduced activity at high concentrations against certain organisms". The Journal of Experimental Medicine. 88 (1): 99–131. doi:10.1084/jem.88.1.99. PMC 2135799. PMID 18871882.
  7. ^ Teicher MH, Glod C, Cole JO (February 1990). "Emergence of intense suicidal preoccupation during fluoxetine treatment". The American Journal of Psychiatry. 147 (2): 207–10. doi:10.1176/ajp.147.2.207. PMID 2301661.
  8. ^ King RA, Riddle MA, Chappell PB, Hardin MT, Anderson GM, Lombroso P, Scahill L (March 1991). "Emergence of self-destructive phenomena in children and adolescents during fluoxetine treatment". Journal of the American Academy of Child and Adolescent Psychiatry. 30 (2): 179–86. doi:10.1097/00004583-199103000-00003. PMID 2016219.
  9. ^ Chlorpromazine - Adverse Effects- Behavioral Reactions[permanent dead link]
  10. ^ Singh, R.R.; Nayak, R. (June 2012). "PMH76 Impact of Fda Black Box Warning on the Prescribing of Atypical Antipsychotics in Non-Institutionalized Dementia Patients". Value in Health. 15 (4): A95. doi:10.1016/j.jval.2012.03.521. ISSN 1098-3015.
  11. ^ "Professional Health Care Providers". Epilepsy Foundation.
  12. ^ Rubin, Joan T; Towbin, Richard B; Bartko, MaryBeth; Baskin, Kevin M; Cahill, Anne Marie; Kaye, Robin D (2004). "Oral and intravenous caffeine for treatment of children with post-sedation paradoxical hyperactivity". Pediatric Radiology. 34 (12): 980–984. doi:10.1007/s00247-004-1303-8. ISSN 1432-1998. PMID 15365651. S2CID 19473461.
  13. ^ Bramness JG, Skurtveit S, Mørland J (June 2006). "Flunitrazepam: psychomotor impairment, agitation and paradoxical reactions". Forensic Science International. 159 (2–3): 83–91. doi:10.1016/j.forsciint.2005.06.009. PMID 16087304.
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  15. ^ Senninger JL, Laxenaire M (April 1995). "[Violent paradoxal reactions secondary to the use of benzodiazepines]" [Violent paradoxical reactions secondary to the use of benzodiazepines]. Annales médico-psychologiques (in French). 153 (4): 278–81, discussion 281–2. PMID 7618826.
  16. ^ Mancuso CE, Tanzi MG, Gabay M (September 2004). "Paradoxical reactions to benzodiazepines: literature review and treatment options". Pharmacotherapy. 24 (9): 1177–85. doi:10.1592/phco.24.13.1177.38089. PMID 15460178. S2CID 38614605. Archived from the original on 2012-12-13. Retrieved 2007-04-18.
  17. ^ "Letter: Tranquilizers causing aggression". British Medical Journal. 1 (5952): 266. February 1975. doi:10.1136/bmj.1.5952.266. PMC 1672080. PMID 234269.
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  20. ^ Rainer, Langguth, Berthold Bär, Rüdiger Wodarz, Norbert Wittmann, Markus Laufkötter. Correspondence (letter to the editor): Paradoxical Reaction in ADHD. Deutscher Arzte Verlag. OCLC 809702040.{{cite book}}: CS1 maint: multiple names: authors list (link)
  21. ^ Yan, Wudan (2021-09-07). "Why Does Coffee Sometimes Make Me Tired?". The New York Times. ISSN 0362-4331. Retrieved 2023-01-15.
  22. ^ Wright, Tricia E. (September 2020), "Pharmacotherapy for Opioid Use Disorders in Special Populations", Substance Use Disorders, Oxford University Press, pp. 185–202, doi:10.1093/med/9780190920197.003.0011, ISBN 978-0-19-092019-7, retrieved 2023-01-15
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  27. ^ de Leon, Jose; Nikoloff, D. Michele (February 2008). "Paradoxical excitation on diphenhydramine may be associated with being a CYP2D6 ultrarapid metabolizer: three case reports". CNS Spectrums. 13 (2): 133–135. doi:10.1017/s109285290001628x. ISSN 1092-8529. PMID 18227744. S2CID 10856872.