Editor’s note: We know that our reviews of the withdrawal literature are incomplete, and we urge readers to help us add to these withdrawal reviews. Please send study citations that are relevant to the withdrawal literature for stimulants to [email protected].
Much of the research on withdrawal from stimulant drugs is focused on the effects of withdrawal from recreational use or abuse of these drugs, as opposed to modeling discontinuation of these drugs following treatment for ADHD. This is true of both the animal studies and human studies. Nevertheless, this research literature provides insight into how stimulant use changes the brain; possible long-lasting behavioral effects from such brain changes, and withdrawal symptoms.
Mechanism of Action and Drug-Induced Compensatory Response
Both stimulants and non-stimulants are prescribed to treat ADHD. Stimulant medications are the most commonly prescribed, and are of two classes: amphetamines and methylphenidate. The amphetamines include mixed amphetamine salts (Adderall), dextroamphetamine (Dexedrine), and lisdexamfetamine (Vyanse). Amphetamines increase the amount of norepinephrine, serotonin, and dopamine in the brain by increasing the neuronal release of these neurotransmitters into the synaptic cleft (the tiny gap between neurons.)
The methylphenidate stimulants include Ritalin, Concerta, and Daytrana, and also dexmethylphenidate (Focalin). Methlyphenidates increase dopamine and norepinephrine activity in the brain by blocking their reuptake from the synaptic cleft. The neurotransmitters thus remain longer than normal in the synaptic cleft.
There are also two classes of non-stimulants for ADHD. Atomoxetine (Strattera) inhibits the reuptake of norepinephrine, and thus increases norepinephrine activity in the brain. The second class of non-stimulants are alpha adrenergic agents, such as guanfacine (Intuniv) and clonidine (Kapvay). Alpha adrenergic agents mimic epinephrine and norepinephrine and stimulate the same receptors as these neurotransmitters.
Given that these drugs increase dopamine and norepinephrine activity, they trigger compensatory responses in the brain that, in one way or another, alter this activity. These compensatory changes may include a change in the density of dopamine and norepinephrine receptors; a decrease in the production and release of these molecules by the presynaptic neurons; and changes in the density of transporter molecules involved in the reuptake of the neurotransmitters from the synaptic cleft.
There is an abundance of animal research on the effects of withdrawal from stimulant drugs, mainly in the form of rat studies. Many of these studies focus on the effect of medications during adolescence on later drug abuse, with contradictory findings. However, in general, the animal studies on stimulant drug withdrawal strongly suggest that the drug exposure leads to a number of both short-term and long-lasting behavioral effects and brain changes.
Models of brain changes follow withdrawal from ADHD medications
- Barr JL, Renner KJ, Forster GL. Withdrawal from chronic amphetamine produces persistent anxiety-like behavior but temporally-limited reductions in monoamines and neurogenesis in the adult rat dentate gyrus. Neuropharmacology. 2010;59(6):395-405. PubMed Link
In this study, researchers exposed adult male rats to amphetamine for two weeks and monitored them for four weeks of withdrawal. Results showed that rats had increased anxiety behaviors during withdrawal. The rats’ corticosterone levels were unchanged. Their norepinephrine and serotonin levels in the dentate gyrus of the brain were reduced immediately following treatment, showing evidence of reduced neurogenesis, or new neuron growth, but the levels did not remain low by the end of the study.
2) Sadasivan S, Pond BB, Pani AK, Qu C, Jiao Y, Smeyne RJ. Methylphenidate exposure induces dopamine neuron loss and activation of microglia in the basal ganglia of mice. PLoS One. 2012;7(3):e33693. PubMed Link
Researchers administered methylphenidate at two doses to rats for 90 days during the developmental period that matches adolescence and young adulthood in humans, and studied the effects on the brain seven days after withdrawal. Researchers found increased levels of dopamine in the striatum for the lower dose, but not higher dose, of methylphenidate. The authors concluded that long-term therapeutic doses of methylphenidate can have long-term degenerating effects in the brain.
3) Somkuwar SS, Kantak KM, Dwoskin LP. Effect of methylphenidate treatment during adolescence on norepinephrine transporter function in orbitofrontal cortex in a rat model of attention deficit hyperactivity disorder. Journal of Neuroscience Methods. 2015;252:55-63. PubMed Link
Researchers orally exposed rats to methylphenidate from early to late adolescence and then discontinued the drug. Researchers found that during treatment, rats exposed to methylphenidate had lower than normal rates of norepinephrine reuptake. and considered this a normalization of the norepinephrine transporter through treatment. Three to five weeks after discontinuation, norepinephrine transporter function remained at this lower rate which the researchers concluded as persisting treatment effects even after drug discontinuation.
Impacts of ADHD medication treatment and withdrawal on later drug use
4) Brandon CL, Marinelli M, Baker LK, White FJ. Enhanced reactivity and vulnerability to cocaine following methylphenidate treatment in adolescent rats. Neuropsychopharmacology. 2001;25(5):651-61. PubMed Link
Researchers exposed rats to methylphenidate during adolescence, withdrew the drug, and then studied rats’ behavior toward cocaine as adults. Findings showed that rats exposed to low doses, but not moderate doses, of methylphenidate engaged in more cocaine self-administration. Researchers concluded that early exposure to low doses of methylphenidate may increase susceptibility to low doses of cocaine, and consequently increase risk of cocaine use as adults.
5) Andersen SL, Arvanitogiannis A, Pliakas AM, LeBlanc C, Carlezon WA. Altered responsiveness to cocaine in rats exposed to methylphenidate during development. Nature Neuroscience. 2002;5(1):13-4. PubMed Link
Researchers exposed pre-adolescent rats to methylphenidate and then withdrew the drug in order to study its effects on the rats’ responsiveness to cocaine in adulthood. They found that the rats were less responsive to cocaine’s rewarding effects and concluded that pre-adolescent exposure to methylphenidate may cause lasting changes to dopaminergic function. The researchers also studied rats exposed to methylphenidate in adulthood and concluded that neurobiological effects differ depending on the developmental stage when rats are exposed to the medication.
6) Carlezon WA, Mague SD, Andersen SL. Enduring behavioral effects of early exposure to methylphenidate in rats. Biological Psychiatry. 2003;54(12):1330-7. PubMed Link
In this study, researchers examined how exposure to methylphenidate or cocaine in preadolescence affected behaviors in adult rats. Researchers found that exposure to methylphenidate in preadolescence can cause behavioral changes in adulthood including finding cocaine less rewarding and demonstrating depressive-like symptoms.
7) Mague SD, Andersen SL, Carlezon WA. Early developmental exposure to methylphenidate reduces cocaine-induced potentiation of brain stimulation reward in rats. Biological Psychiatry. 2005;57(2):120-5. PubMed Link
Researchers exposed rats to methylphenidate during pre-adolescence, withdrew the drug, and then studied the impacts on cocaine’s ability to simulate the reward system in the brain. The authors found that early exposure to methylphenidate resulted in a decreased effect of cocaine on the reward system, suggesting that the dopamine system functioned in an abnormal manner.
8) Augustyniak PN, Kourrich S, Rezazadeh SM, Stewart J, Arvanitogiannis A. Differential behavioral and neurochemical effects of cocaine after early exposure to methylphenidate in an animal model of attention deficit hyperactivity disorder. Behavioural Brain Research. 2006;167(2):379-82. PubMed Link
Researchers exposed pubertal rats to methylphenidate and then withdrew the drug to examine its effects on cocaine use and dopamine levels in adulthood. The researchers found that the exposure reduced the rats’ sensitivity to cocaine in adulthood, but did not alter the dopamine system in the mesolimbic brain pathway.
9) Gill KE, Pierre PJ, Daunais J, Bennett AJ, Martelle S, Gage HD, Swanson JM, Nader MA, Porrino LJ. Chronic treatment with extended release methylphenidate does not alter dopamine systems or increase vulnerability for cocaine self-administration: a study in nonhuman primates. Neuropsychopharmacology. 2012;37(12):2555-65. PubMed Link
In this rhesus monkey model for ADHD treatment, monkeys were given methylphenidate for a year and studied 3-5 months after discontinuation of treatment. Findings showed that methylphenidate-treated monkeys had unchanged levels of specific dopamine receptor, D2/D3, while controls had a decreasing number of receptors (a decrease of receptors in this context is seen as a developmental process of synaptic pruning). The authors found no evidence that methylphenidate increases vulnerability to cocaine later in life.
10) Somkuwar SS, Jordan CJ, Kantak KM, Dwoskin LP. Adolescent atomoxetine treatment in a rodent model of ADHD: effects on cocaine self-administration and dopamine transporters in frontostriatal regions. Neuropsychopharmacology. 2013;38(13):2588-97. PubMed Link
Researchers exposed rats to atomoxetine during adolescence, withdrew the drug, and then studied the impacts on cocaine self-administration and on dopamine and norepinephrine transporters. Findings showed that atomoxetine did not increase vulnerability to cocaine and authors concluded that atomoxetine may be a better treatment choice than methylphenidate when the prescriber is worried about drug abuse.
11) Jordan CJ, Harvey RC, Baskin BB, Dwoskin LP, Kantak KM. Cocaine-seeking behavior in a genetic model of attention-deficit/hyperactivity disorder following adolescent methylphenidate or atomoxetine treatments. Drug and Alcohol Dependence. 2014;140:25-32. PubMed Link
Researchers exposed rats to methylphenidate and atomoxetine during adolescence, withdrew the drug, and then studied rats’ cocaine-seeking behavior as adults. Results showed that adult rats previously treated with methylphenidate had increased cocaine intake, but there was no increase in cocaine intake for rats previously treated with atomoxetine. Neither drug resulted in increases in cocaine seeking in adulthood.
12) Jordan CJ, Taylor DM, Dwoskin LP, Kantak KM. Adolescent D-amphetamine treatment in a rodent model of ADHD: Pro-cognitive effects in adolescence without an impact on cocaine cue reactivity in adulthood. Behavioural Brain Research. 2016;297:165-79. PubMed Link
Researchers exposed rats to d-amphetamine during adolescence, withdrew the drug, and then studied rats’ cocaine-seeking behavior as adults. The findings showed that d-amphetamine exposure during adolescence did not change self-administration of cocaine and decreased cocaine-seeking behavior in adulthood. The authors concluded that treatment with d-amphetamine may result in lower risk of future cocaine use than methylphenidate treatment.
Behavioral impacts of withdrawal
13) Herman ZS, Trzeciak H, Chruściel TL, Kmieciak-Kołada K, Drybański A, Sokoła A. The influence of prolonged amphetamine treatment and amphetamine withdrawal on brain biogenic amine content and behaviour in the rat. Psychopharmacologia. 1971;21(1):74-81. PubMed Link
Researchers exposed rats to D–L-amphetamine sulphate for 9 months and studied the behavioral effects of the drug and drug withdrawal. Authors found that, during withdrawal, rats moved around less (measured for 12 days post-withdrawal) and had lower levels of noradrenaline and serotonin in the cerebellum part of the brain (measured at 3 days post-withdrawal).
14) Leith NJ, Barrett RJ. Amphetamine and the reward system: evidence for tolerance and post-drug depression. Psychopharmacologia. 1976;46(1):19-25. PubMed Link
In this study, researchers measured the effects of withdrawal from d-amphetamine on self-electrical brain stimulation, examining effects on the reward system in the brain. One day after d-amphetamine withdrawal, rats had reduced self-stimulation, which the authors interpreted as dysregulation in the brain’s reward system and depression.
15) Schreiber H, Bell R, Conely L, Kufner M, Palet J, Wright L. Diminished reaction to a novel stimulus during amphetamine withdrawal in rats. Pharmacology Biochemistry and Behavior. 1976;5(6):687-90. PubMed Link
Researchers examined the effects of d-amphetamine withdrawal on response to a new stimulus. Rats were exposed to two doses of d-amphetamine or saline for eight days and tested one day after discontinuing the drug. Findings showed that rats exposed to more d-amphetamine had the least response to a new stimulus and rats exposed to the smaller dose of d-amphetamine had less response than control rats.
16) Simpson DM, Annau Z. Behavioral withdrawal following several psychoactive drugs. Pharmacology Biochemistry and Behavior. 1977;7(1):59-64. PubMed Link
In this rat study, researchers assessed behavioral withdrawal from four types of psychoactive drugs, including amphetamine, by measuring self-electrical stimulation of the brain. Findings showed that rats exposed to amphetamine had increased rates of self-stimulation while on the drug, but decreased their self-stimulation during withdrawal.
17) Cassens G, Actor C, Kling M, Schildkraut JJ. Amphetamine withdrawal: Effects on threshold of intracranial reinforcement. Psychopharmacology. 1981;73(4):318-22. PubMed Link
In this rat study, researchers examined the effects of withdrawal from d-amphetamine on the threshold to activate the reward system in the brain. Results showed an increased threshold, meaning rats found a stimulus less rewarding than control rats, within 24 hours of withdrawal, with the highest threshold increase around 24 to 72 hours.
18) Kokkinidis L, Zacharko RM, Anisman H. Amphetamine withdrawal: A behavioral evaluation. Life sciences. 1986;38(17):1617-23. PubMed Link
In this study, researchers exposed mice to amphetamines for 10 days and studied the behavioral effects of withdrawal 24 hours after the mice’s last exposure to amphetamine. Results showed that withdrawn mice responded less to electrical stimulation in the brain, and moved less in the forced swim test. However, withdrawn mice did not differ from controls on behaviors in the shuttle escape task or acoustic startle reflex. The authors concluded that depressive behaviors induced by amphetamine withdrawal are due more to motivation than mechanisms of motor-activity or arousal.
19) Paulson PE, Camp DM, Robinson TE. Time course of transient behavioral depression and persistent behavioral sensitization in relation to regional brain monoamine concentrations during amphetamine withdrawal in rats. Psychopharmacology. 1991;103(4):480-92. PubMed Link
In this rat study, researchers investigated the withdrawal syndrome for d-amphetamine. Researchers found that withdrawn rats showed depressive behaviors as soon as two days post-withdrawal, but the behaviors were gone by one month. Depressive behaviors were associated with short-term lower levels of norepinephrine in the hypothalamus part of the brain.
20) Schindler CW, Persico AM, Uhl GR, Goldberg SR. Behavioral assessment of high-dose amphetamine withdrawal: importance of training and testing conditions. Pharmacology Biochemistry and Behavior. 1994;49(1):41-6. PubMed Link
In this rat study, researchers investigated the effects of withdrawal from chronic (2 weeks) versus acute (one time) d-amphetamine use. Results showed that chronic rats engaged in less movement in a locomotor activity test 24-54 hours after withdrawal, and engaged in less movement during a swim test 36-72 hours after withdrawal.
21) Wise RA, Munn E. Withdrawal from chronic amphetamine elevates baseline intracranial self-stimulation thresholds. Psychopharmacology. 1995;117(2):130-6. PubMed Link
In this rat study, researchers measured self-stimulation of the lateral hypothalamus in the brain after withdrawal from amphetamine. Rats were exposed to amphetamine for six weeks and self-stimulation was measured starting at 36 hours post-withdrawal up to three weeks. Authors found that drug withdrawn rats engaged in self-stimulation less frequently and had higher thresholds, meaning they required a stronger stimulus to engage in self-stimulation. By two weeks after drug discontinuation, amphetamine exposed rats did not differ from control rats.
22) Barr AM, Phillips AG. Withdrawal following repeated exposure to d-amphetamine decreases responding for a sucrose solution as measured by a progressive ratio schedule of reinforcement. Psychopharmacology. 1999;141(1):99-106. PubMed Link
In this rat study, researchers investigated whether withdrawal from d-amphetamine after four days of exposure reduced rats’ effort for a natural reward of sugar water. Results showed that rats withdrawing from the drug were less motivated to obtain a natural reward.
23) Barr AM, Fiorino DF, Phillips AG. Effects of withdrawal from an escalating dose schedule of d-amphetamine on sexual behavior in the male rat. Pharmacology Biochemistry and Behavior. 1999;64(3):597-604. PubMed Link
In this rat study, researchers investigated the impact of withdrawal from d-amphetamine on sexual behavior in male rats. Rats were exposed to d-amphetamine for four days and tested 12 hours after final dose. The results showed decreased motivation in preparatory sexual behaviors, but no change in consummatory behaviors.
24) Barr AM, Phillips AG. Increased successive negative contrast in rats withdrawn from an escalating-dose schedule of D-amphetamine. Pharmacology Biochemistry and Behavior. 2002;71(1):293-9. PubMed Link
In this rat study, researchers examined the effects of withdrawal from d-amphetamine on behavior by measuring their consumption of sugar water compared to rats not exposed to the drug. Findings showed rats withdrawn from d-amphetamine that were previously given 34% sugar water and then given 4% sugar water consumed much less than controls for up to 60 hours. The authors understood this behavior to be connected to higher emotionality during withdrawal.
25) Russig H, Durrer A, Yee BK, Murphy CA, Feldon J. The acquisition, retention and reversal of spatial learning in the Morris water maze task following withdrawal from an escalating dosage schedule of amphetamine in Wistar rats. Neuroscience. 2003;119(1):167-79. PubMed Link
In this rat study, researchers examined the effects of d-amphetamine withdrawal on spatial learning using the Morris water maze task. Researchers found that rats withdrawing from amphetamine had enhanced reversal learning (learning to locate a new place in the water maze) than control rats.
26) Cryan JF, Hoyer D, Markou A. Withdrawal from chronic amphetamine induces depressive-like behavioral effects in rodents. Biological Psychiatry. 2003;54(1):49-58. PubMed Link
In this rat study, researchers investigated behavioral effects of amphetamine withdrawal. Findings showed a number of changes in behavior that reflect depressive symptoms including higher thresholds to activate reward system, less swimming and climbing behaviors in a forced swim test, and less movement in a mouse tail suspension test, lasting for the 72 hours of observation.
27) Peterson JD, Wolf ME, White FJ. Impaired DRL 30 performance during amphetamine withdrawal. Behavioural Brain Research. 2003;143(1):101-8. PubMed Link
In this rat study, researchers measured impulsivity during amphetamine withdrawal by measuring rats’ ability to wait at least 30 seconds to poke a hole with their nose in order to receive food. Rats were exposed to amphetamine for five days and then withdrawn from amphetamine for three days before testing began. Researchers found amphetamine withdrawn rats had more nose pokes than controls, demonstrating higher rates of impulsivity, for up to two weeks after withdrawal.
28) Che Y, Cui YH, Tan H, Andreazza AC, Young LT, Wang JF. Abstinence from repeated amphetamine treatment induces depressive-like behaviors and oxidative damage in rat brain. Psychopharmacology. 2013;227(4):605-14. PubMed Link
In this rat study, researchers explored causes of depressive symptoms in amphetamine withdrawal. Results showed that rats demonstrated depressive symptoms during withdrawal and that withdrawal caused oxidative damage in the brain.
Physiological Impacts of Withdrawal
29) Lynch MA, Leonard BE. Changes in brain γ-aminobutyric acid concentrations following acute and chronic amphetamine administration and during post amphetamine depression. Biochemical pharmacology. 1978;27(14):1853-5. PubMed Link
In this rat study, researchers investigated changes of GABA, an inhibitory neurotransmitter, in different parts of the brain from d-amphetamine exposure and withdrawal. After an increase in GABA during administration of the drug, researchers found that GABA levels decreased to normal levels compared to the control group within 7 days of withdrawal in the striatum and brain stem. They also found that GABA levels in the amygdala increased during withdrawal. The authors described the rats as behaviorally depressed during withdrawal.
30) Cassens G, Kuruc A, Orsulak PJ, Schildkraut JJ. Amphetamine withdrawal: effects on brain levels of MHPG-SO4 in the rat. Communications in psychopharmacology. 1979;3(4):217. PubMed Link
In this rat study, researchers measured brain levels of a metabolite of norepinephrine, MHPG-SO4, after withdrawal from d-amphetamine. The authors found that up to 48 hours after withdrawal, rats had decreased MHPG-SO4 levels.
31) Koike Y, Togashi H, Shimamura K, Yomaida I, Saito H. Effects of abrupt cessation of treatment with clonidine and guanfacine on blood pressure and heart rate in spontaneously hypertensive rats. Clinical and experimental hypertension. 1981;3(1):103-20. PubMed Link
In this rat study, authors researched the impact of guanfacine withdrawal on blood pressure. Rats had low blood pressure while exposed to 5 weeks of guanfacine, and abrupt discontinuation of the medication did not result in a fast rise in blood pressure.
32) Ricaurte G, Seiden LS, Schuster C. Further evidence that amphetamines produce long-lasting dopamine neurochemical deficits by destroying dopamine nerve fibers. Brain Research. 1984;303(2):359-64. PubMed Link
In this rat study, researchers administered either methamphetamine or amphetamine to rats for three days and then studied the effects on the brain two weeks after withdrawal. The authors found decreased levels of dopamine and evidence of nerve fiber degeneration in the striatum.
33) Swerdlow NR, Hauger R, Irwin M, Koob GF, Britton KT, Pulvirenti L. Endocrine, immune, and neurochemical changes in rats during withdrawal from chronic amphetamine intoxication. Neuropsychopharmacology. 1991;5(1):23-31. PubMed Link
In this rat study, researchers examined the impacts of withdrawal from 10-day amphetamine exposure. The researchers found that adrenocorticotropic hormone and corticosterone levels, which are normally correlated, uncoupled by the fifth day of withdrawal, with the effect persisting for the 10 days of observation. They also found decreased levels of dopamine and its metabolite, DOPAC, in certain brain regions. The researchers concluded this represented dysregulation in the hypothalamic–pituitary–adrenal axis.
34) Rossetti ZL, Hmaidan Y, Gessa GL. Marked inhibition of mesolimbic dopamine release: a common feature of ethanol, morphine, cocaine and amphetamine abstinence in rats. European Journal of Pharmacology. 1992;221(2-3):227-34. PubMed Link
In this rat study, authors investigated the effects on dopamine levels in the brain for a number of drugs that are frequently abused. The authors found that with amphetamine withdrawal, dopamine levels decreased quickly, to about 50% of control levels in the first day, and remained low for several days, and then return to levels equivalent to controls within 10 days.
35) Persico AM, Schindler CW, Brannock MT, Gonzalez AM, Surratt CK, Uhl GR. Dopaminergic gene expression during amphetamine withdrawal. Neuroreport. 1993;4(1):41-4. PubMed Link
In this rat study, researchers studied the effects of amphetamine withdrawal on gene expression that affects dopamine. The researchers did not find changes in dopaminergic gene expression, but found a slight increase in tyrosine hydroxylase gene expression and substantially decreased expression of a specific amine transporter, both of which are involved in dopamine transmission. The authors concluded that these changes in gene expression may be involved in restoring the balance of dopamine in the brain.
36) Persico AM, Schindler CW, Zaczek R, Brannock MT, Uhl GR. Brain transcription factor gene expression, neurotransmitter levels, and novelty response behaviors: alterations during rat amphetamine withdrawal and following chronic injection stress. Synapse. 1995;19(3):212-27. PubMed Link
In this rat study, researchers explored the effects of withdrawal from amphetamine on transcription factors that impact neurotransmitter gene expression in the brain. Findings showed decreased transcription factor and decreased dopamine levels in areas of the brain within 12 hours of withdrawal. The levels returned to normal, compared to control, by 54 hours.
37) Paulson PE, Robinson TE. Regional differences in the effects of amphetamine withdrawal on dopamine dynamics in the striatum: analysis of circadian patterns using automated on-line microdialysis. Neuropsychopharmacology. 1996;14(5):325. PubMed Link
In this rat study, researchers explored behavioral symptoms and their connection to dopamine concentration in different brain regions during circadian rhythms at 3, 7, and 28 days post amphetamine withdrawal. Rats displayed depressive behaviors within a week of drug discontinuation and at 3 and 7 days post-withdrawal, rats had decreases in dopamine in the dorsolateral caudate nucleus. At 28 days, rats no longer presented with depressive behaviors and dopamine levels increased in the caudate and accumbens parts of the brain.
38) Melega WP, Raleigh MJ, Stout DB, Huang SC, Phelps ME. Ethological and 6-[18F] fluoro-L-DOPA-PET profiles of long-term vulnerability to chronic amphetamine. Behavioural Brain Research. 1997;84(1):259-68. PubMed Link
In this study on vervet monkeys, researchers used PET scans to measure dopamine function in the striatum of the brain. The researchers administered amphetamine to the monkeys to increase dopamine function, and then withdrew the drug after ten days. Findings showed that monkeys slowly recovered baseline dopamine functioning after 24 months of drug discontinuation.
39) Robinson TE, Kolb B. Persistent structural modifications in nucleus accumbens and prefrontal cortex neurons produced by previous experience with amphetamine. The Journal of Neuroscience. 1997;17(21):8491-7. PubMed Link
In this rat study, researchers examined the changes in the brain caused by exposure to amphetamine for a month after discontinuing the drug. They found a number of structural changes to neurons in specific parts of the brain that affect communication between neurons and hypothesized that these changes are connected to behavioral changes seen in humans after withdrawal from amphetamine abuse.
40) Raheem KA, Ismael N, Saad A, El-Sayad S. Gluconeogenic activity in response to chronic administration of amphetamine sulphate and drug withdrawal. General Pharmacology: The Vascular System. 1997;29(4):687-90. PubMed Link
In this rat study, researchers explored the impact of chronic amphetamine use and withdrawal on serum levels. Results showed that rats that discontinued amphetamine after four weeks of use had glucose levels close to controls, and glutamate oxaloacetic transaminase (GOT) enzyme activity returned to normal, but corticosterone levels remained elevated during 30 hours of studied withdrawal. The authors conclude rats can recover from the effects of amphetamine after withdrawing from the drug.
41) Lu W, Monteggia LM, Wolf ME. Withdrawal from repeated amphetamine administration reduces NMDAR1 expression in the rat substantia nigra, nucleus accumbens and medial prefrontal cortex. European Journal of Neuroscience. 1999;11(9):3167-77. PubMed Link
In this rat study, researchers investigated whether NMDA receptors, a neuron receptor for the neurotransmitter glutamate, were altered by amphetamine use even after withdrawal. The researchers did not find changes in a subunit of the NMDA receptor after three days of withdrawal, but found decreased expression of the subunit of the receptor 14 days after withdrawal. The authors hypothesized that this may signify reduced excitation in dopaminergic neurons.
42) Onn SP, Grace AA. Amphetamine withdrawal alters bistable states and cellular coupling in rat prefrontal cortex and nucleus accumbens neurons recorded in vivo. The Journal of Neuroscience. 2000;20(6):2332-45. PubMed Link
In this rat study, researchers explored changes in gap junction functioning, a type of communication between neurons, in the corticoaccumbens network after withdrawal from amphetamine. Researchers found changes in gap junction function 28 days after withdrawal.
43) Murphy CA, Russig H, Pezze MA, Ferger B, Feldon J. Amphetamine withdrawal modulates FosB expression in mesolimbic dopaminergic target nuclei: effects of different schedules of administration. Neuropharmacology. 2003;44(7):926-39. PubMed Link
In this rat study, researchers investigated the effects on gene expression of withdrawal from a low dose compared to a moderately high dose of amphetamine. Findings showed an increased expression of the FosB gene only in the higher dose. The authors concluded that withdrawal from a higher dose of amphetamine changes gene expression that impacts dopamine, but that does not affect monoamine levels.
44) Kolb B, Gorny G, Li Y, Samaha AN, Robinson TE. Amphetamine or cocaine limits the ability of later experience to promote structural plasticity in the neocortex and nucleus accumbens. Proceedings of the National Academy of Sciences. 2003;100(18):10523-8. PubMed Link
In this rat study, researchers examined the effects of amphetamine and cocaine use on neural plasticity, the ability for the brain to adapt, after 3.5 months of withdrawal. The authors found that rats previously exposed to amphetamine had inhibited neural plasticity when exposed to a complex environment and concluded that even after withdrawal, amphetamine use may lead to persistent behavioral and cognitive deficits.
45) Mohila CA, Onn SP. Increases in the density of parvalbumin-immunoreactive neurons in anterior cingulate cortex of amphetamine-withdrawn rats: evidence for corticotropin-releasing factor in sustained elevation. Cerebral Cortex. 2005;15(3):262-74. PubMed Link
In this rat study, researchers investigated changes to the inhibitory neurotransmitter, GABA’s, signaling in the brain during withdrawal from amphetamines. Researchers concluded that withdrawal from amphetamine alters GABA signaling.
46) McCracken CB, Patel KM, Vrana KE, Paul DL, Roberts D. Amphetamine withdrawal produces region‐specific and time‐dependent changes in connexin36 expression in rat brain. Synapse. 2005;56(1):39-44. PubMed Link
In this rat study, researchers explored changes in gap junction functioning, a type of communication between neurons, after withdrawal from extended amphetamine exposure. Findings showed that during the withdrawal period there were changes in the expression of a gap junction protein, connexin36, in brain regions considered to be involved in sensitization and addiction.
47) Russig H, Pryce CR, Feldon J. Amphetamine withdrawal leads to behavioral sensitization and reduced HPA axis response following amphetamine challenge. Brain Research. 2006;1084(1):185-95. PubMed Link
In this rat study, researchers investigated stress hormone release related to depression-like symptoms during amphetamine withdrawal. Rats were exposed to amphetamine three times a day for three days and withdrawal was studied for 30 days. Results showed no effect of withdrawal on release of adrenocorticotropic hormone or corticosterone in stressful situations.
48) Parelkar NK, Wang JQ. Upregulation of metabotropic glutamate receptor 8 mRNA expression in the rat forebrain after repeated amphetamine administration. Neuroscience Letters. 2008;433(3):250-4. PubMed Link
In this rat study, researchers measured gene expression of glutamate receptors in the forebrain in response to amphetamine exposure and withdrawal. Findings showed significant increases in glutamate receptor gene expression at both one and 21 days after withdrawal.
49) Boikess SR, O’Dell SJ, Marshall JF. A sensitizing d-amphetamine dose regimen induces long-lasting spinophilin and VGLUT1 protein upregulation in the rat diencephalon. Neuroscience Letters. 2010;469(1):49-54. PubMed Link
In this rat study, researchers investigated synaptic protein expression in the diencephalon part of the brain one month after discontinuing amphetamine. Results showed differences from controls in some, but not all areas of the diencephalon. Authors concluded that amphetamine use does alter the brain even after medication is discontinued, and changes may occur more in excitatory synapses.
50) Murray RC, Hebbard JC, Logan AS, Vanchipurakel GA, Gilbert YE, Horner KA. Stress and withdrawal from d-amphetamine alter 5-HT2A receptor mRNA expression in the prefrontal cortex. Neuroscience Letters. 2014;559:44-9. PubMed Link
In this rat study, researchers measured the effects of both withdrawal from amphetamine and stress, induced by a forced swim test, on serotonin receptor gene expression at 24 hours and four days post withdrawal. Findings showed that 24 hours after withdrawal, rats had decreased expression of the serotonin receptor gene than controls, with no impact based on the forced swim test. But, at 4 days, withdrawn rats showed higher levels of expression than controls, and levels were lowered by the forced swim test. The authors concluded that stress can prolong decreased serotonin functioning caused by withdrawal.
51) Renard GM, Sotomayor‐Zarate R, Blanco EH, Gysling K. Withdrawal from chronic amphetamine reduces dopamine transmission in the rat lateral septum. Journal of Neuroscience Research. 2014;92(7):937-43. PubMed Link
In this rat study, researchers investigated the impact of amphetamine withdrawal on dopamine transmission in the lateral septum, a part of the brain thought to be involved in addiction. The researchers found decreased release of dopamine in the lateral septum, but not decreased levels of dopamine in the tissue for the 14 day duration of the observation period. The authors hypothesized that the decrease in dopamine release is caused by decreased dopamine reuptake during withdrawal.
Using Rat Model for Schizophrenia
52) Murphy CA, Fend M, Russig H, Feldon J. Latent inhibition, but not prepulse inhibition, is reduced during withdrawal from an escalating dosage schedule of amphetamine. Behavioral neuroscience. 2001;115(6):1247. PubMed Link
In this rat model for schizophrenia, researchers investigated amphetamine withdrawal symptoms. Rats were exposed to amphetamine for 6 days and tested up to four weeks after withdrawal. Results showed that expression of latent inhibition was eliminated during the withdrawal period, which they interpreted as potential evidence of a depressive state caused by withdrawal.
53) Russig H, Murphy CA, Feldon J. Prepulse inhibition during withdrawal from an escalating dosage schedule of amphetamine. Psychopharmacology. 2003;169(3-4):340-53. PubMed Link
In this rat model for schizophrenia, researchers studied effects of amphetamine withdrawal on prepulse inhibition, where exposure to a previous moderate-intensity stimulus decreases responsiveness to a later, higher-intensity stimulus. Researchers observed rats for up to 60 days post-withdrawal and did not find a difference in their prepulse inhibition compared to control rats. They did find a short-term decreased acoustic startle response and disruptions in latent inhibition.
54) Peleg-Raibstein D, Sydekum E, Feldon J. Differential effects on prepulse inhibition of withdrawal from two different repeated administration schedules of amphetamine. International Journal of Neuropsychopharmacology. 2006;9(6):737-49. PubMed Link
In this rat model for schizophrenia, researchers investigated the effects of withdrawal from amphetamine at two different dosing schedules on behavior and brain monoamine levels. The researchers found that the rats that were given higher doses of amphetamine had reduced dopamine levels in the caudate putamen part of the brain 55 days after withdrawal.
55) Selemon LD, Begović A, Goldman-Rakic PS, Castner SA. Amphetamine sensitization alters dendritic morphology in prefrontal cortical pyramidal neurons in the non-human primate. Neuropsychopharmacology. 2007;32(4):919-31. PubMed Link
In this model of schizophrenia using rhesus monkeys, researchers exposed young adult monkeys to amphetamine for 6 or 12 weeks and studied changes in their brains 3 to 3.5 years after discontinuing amphetamine. Their findings suggested long-lasting degeneration of pyramidal dendrites in the prefrontal cortex.
Studies have been conducted to learn about the effects of withdrawal from stimulant drugs when being used recreationally or abused. Although these studies can provide information on potential withdrawal symptoms when discontinuing ADHD medication, it is important to note that stimulants used recreationally are often at higher doses and frequencies, as well as via different routes (such as injected, snorted, or smoked versus swallowing pills). Therefore, withdrawal effects from recreational use or abuse may be stronger than from prescription use. The most common withdrawal symptoms found in these studies were fatigue, altered sleep patterns, and depression.
56) Monroe RR, Drell HJ. Oral use of stimulants obtained from inhalers. Journal of the American Medical Association. 1947;135(14):909-15. PubMed Link
Authors studied inhaler misuse of amphetamines. Survey results from 264 inmates indicated the most common withdrawal effects were feeling tired, sleeping, shaking hands, and feeling sick to one’s stomach.
57) Oswald I, Thacore VR. Ampehtamine and phenmetrazine addiction: Physiological abnormalities in the abstinence syndrome. Br Med J, 1963;2(5354):427-31. PubMed Link
Authors studied six individuals with amphetamine addictions to assess the effect of withdrawal on sleep patterns. Withdrawal from the drug resulted in a large increase in REM sleep. Return to normal sleep patterns took up to eight weeks. Subjects also reported listlessness, depression, and sleepiness.
58) Watson R, Hartmann E, Schildkraut JJ. Amphetamine withdrawal: Affective state, sleep patterns, and MHPG excretion. American Journal of Psychiatry. 1972;129(3):263-9. PubMed Link
Authors studied four subjects who had been using moderately high doses of amphetamines for at least five months and wanted to discontinue their use. Results showed that subjects became depressed during drug withdrawal, most severely in the first few days, but persisting up to several months. Depression was positively related to increased REM sleep and decreased urine excretion of MHPG, a metabolite of norepinephrine, suggesting decreased levels of norepinephrine in the brain.
59) Gossop MR, Bradley BP, Brewis RK. Aphetamine withdrawal and sleep disturbance. Drug and Alcohol Dependence, 1982;10(2):177-83. PubMed Link
Authors studied sleep patterns in 20 amphetamine dependent individuals during drug withdrawal in a hospital setting for 20 days. Results showed an initial period of over-sleeping followed by a longer period of under-sleeping. Amphetamine users also had more variability in their sleep patterns than the control group.
60) Tuma TA. Depressive stupor following amphetamine withdrawal. British Journal of Hospital Medicine. 1993;49(5):361-3. PubMed Link
Author provided case studies of three men in Saudi Arabia who presented at a hospital after discontinuing recreational use of amphetamine. The author described depressive symptoms that all three men experienced and concluded that amphetamine withdrawal can cause a depressive stupor when the drug was taken for long periods.
61)Thompson P, Gillin J, Golshan S, Irwin M. Polygraphic sleep measures differentiate alcoholics and stimulant abusers during short-term abstinence. Biological Psychiatry. 1995;38(12):831-836. PubMed Link
Authors compared sleep patterns of individuals withdrawing from stimulants (amphetamines or cocaine) and alcohol. Results showed that individuals who abuse stimulants slept more and had more REM sleep during the first 10 days of withdrawal than days 11-14. Compared to controls, stimulant users had similar amounts of sleep during the first 10 days, but below normal amounts of sleep during days 11-14.
62) Cantwell B, McBride AJ. Self detoxication by amphetamine dependent patients: A pilot study. Drug and Alcohol Dependence. 1998;49(2):157-63. PubMed Link
Authors interviewed fifty current or past amphetamine dependent clients about previous attempts to stop using amphetamines. All but two subjects injected amphetamines intravenously. Eighty six percent of subjects reported symptoms of withdrawal with the most common symptoms being irritability, aches and pains, feeling depressed, and impaired social functioning. Subjects reported that the symptoms lasted up to three weeks.
63) Schuckit MA, Daeppen JB, Danko GP, Tripp ML, Smith TL, Li TK, Hesselbrock VM, Bucholz KK. Clinical implications for four drugs of the DSM-IV distinction between substance dependence with and without a physiological component. American Journal of Psychiatry. 1999;156(1):41-9. PubMed Link
Authors interviewed individuals diagnosed with substance dependence. Results showed that 87% of subjects identified as amphetamine-dependent experienced withdrawal effects.
Discontinuation Success Rates
Very few studies have explicitly explored how to come off of ADHD medications and withdrawal side effects in humans. The studies that have been done do not suggest there is a strong difference between tapering or abruptly discontinuing ADHD medications.
64) Wernicke JF, Adler L, Spencer T, West SA, Allen AJ, Heiligenstein J, Milton D, Ruff D, Brown WJ, Kelsey D, Michelson D. Changes in symptoms and adverse events after discontinuation of atomoxetine in children and adults with attention deficit/hyperactivity disorder: A prospective, placebo-controlled assessment. J Clin Psychopharmacol. 2004;24(1):30-35. doi: 10.1097/01.jcp.0000104907.75206.c2. PubMed Link
Researchers investigated the potential for discontinuation syndrome of atomoxetine in children and adults diagnosed with ADHD, who had been taking the medication for 9-10 weeks and then discontinued the medication all at once. Results showed that subjects had worsening of ADHD symptoms, but not to pretreatment levels. Researchers did not find evidence of a discontinuation syndrome and determined atomoxetine can be safely discontinued, and tapering is not necessary.
65) Kisicki JC, Fiske K, Lyne A. Phase I, Double-blind, randomized, placebo-controlled, dose-escalation study of the effects on blood pressure of abrupt cessation versus taper down of guanfacine extended-release tablets in adults aged 19 to 24 years. Clinical Therapeutics. 2007;29(9):1967-1979. doi: l0.1016/j.clinthera.2007.09.020. PubMed Link
Researchers investigated the effects of abrupt cessation versus taper-down of guanfacine ER on blood pressure. Researchers did not find significant differences in blood pressure for abrupt cessation compared to taper-down. Both treatment groups had a significantly greater decrease in systolic blood pressure than the placebo group by the first day that medication was reduced/withdrawn, but it was no longer significant at the end of the trial. The most common side effects were headache, dry mouth, and fatigue in the abrupt cessation group and dry mouth in the taper-down group.
In sum, the animal research suggests that there are a number of withdrawal effects when discontinuing from stimulant drugs. However, this evidence is limited as results from animal studies are difficult to translate into effects for humans and most of the animal research is mimicking abusive levels of stimulant drugs rather than prescribed doses that are common when treating ADHD. Human studies on withdrawing from stimulants for recreational use have similar findings as animal studies and outline a number of withdrawal effects, primarily fatigue, altered sleep patterns, and depression. Because individuals who abuse stimulants are often taking higher, more frequent doses of the drug, their withdrawal symptoms are most likely more severe than individuals withdrawing from prescription doses. There is very limited research in humans on the effects of coming off ADHD prescription medication, or studies that could provide information on how to come off the medication. However, compared to other psychiatric medications, ADHD medications appear easier to discontinue with less severe withdrawal effects.