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Featured article Amphetamine is a featured article; it (or a previous version of it) has been identified as one of the best articles produced by the Wikipedia community. Even so, if you can update or improve it, please do so.
Main Page trophy This article appeared on Wikipedia's Main Page as Today's featured article on April 3, 2015.

Adding a table of binding affinities[edit]

As the title, I think it will enhance the readability of this article, making it even perfect. =) --It's gonna be awesome!#Talk♬ 14:37, 11 April 2017 (UTC)

I'm not sure that would actually be particularly useful because it only has 1 known high affinity receptor target in humans: TAAR1. I suppose I could add the binding data if you're really interested in that though. Seppi333 (Insert ) 02:16, 26 May 2017 (UTC)
Wouldn't monoamine transporter affinities help us determine the amount that goes into each respective type of monoaminergic neuron? (talk) 18:19, 4 September 2017 (UTC)
Sounds reasonable to me. I'll work on adding it soon. Seppi333 (Insert ) 01:19, 5 September 2017 (UTC)
PMID 11071707 - reuptake and release from cloned human monoamine transporters.
IUPHAR VMAT2 cites PMID 8643547, which includes more data than IUPHAR (covers both enantiomers and kinetics at VMAT1 and VMAT2) on this page: [1].
Need to look for other sources. Seppi333 (Insert ) 05:16, 10 September 2017 (UTC)


Dopaminergic alterations associated with stimulant abuse[edit]

  • May 2017 meta-analysis[1]


  1. ^ Ashok AH, Mizuno Y, Volkow ND, Howes OD (May 2017). "Association of Stimulant Use With Dopaminergic Alterations in Users of Cocaine, Amphetamine, or Methamphetamine: A Systematic Review and Meta-analysis". JAMA Psychiatry. 74 (5): 511–519. doi:10.1001/jamapsychiatry.2017.0135. PMID 28297025. 


Things to add when I get a chance (citations are in the collapse tab below):

Seppi333 (Insert ) 21:11, 6 December 2016 (UTC)

Pharmacodynamics diagram updates + new pharmacodynamics table

CAMKII signaling[edit]

Check for newer research involving:

  • PMID 26162812 – could participate in CAMKIIα phosphorylation[4]
    • mentioned in [3] in the section on CAMKII
  • PMID 24854234 – same as above with MDMA and SERT[5]

Seppi333 (Insert ) 02:00, 31 March 2016 (UTC) Updated 02:05, 27 April 2016 (UTC)

RhoA/ROCK signaling + DAT/EAAT3 internalization[edit]

  • Review[6] - covers effects of amph on RhoA signaling and RhoA-mediated EAAT3 internalization
  • Primary[7] - covers amph's cytosolic targets, effects of amph on RhoA signaling, ROCK activation, and ROCK-mediated DAT internalization (Note: this ref indicates that VGlut2 - the vesicular transport protein for glutamate which is located on glutamatergic synaptic vesicles - is expressed in mesolimbic TH-positive [i.e., dopamine] neurons; this implies that glutamatergic synaptic vesicles are present in mesolimbic DA neurons, which is one DA projection from midbrain nuclei [VTA+SNc] where EAAT3 is highly expressed according to PMID 25033183.)
Quote from ref[7] on VGlut2
Here we focused on the actions of AMPH on RhoA-dependent internalization of the DAT and explored how these effects on DAT trafficking might contribute to the acute behavioral response to the drug. However, recently we also demonstrated that a neuronal glutamate transporter, EAAT3, can be internalized in response to AMPH through a process that also appears to require Rho activation (17). This EAAT3 internalization in response to AMPH leads to a potentiation of glutamatergic synaptic responses in dopamine neurons and reveals a previously undescribed action of AMPH on glutamatergic signaling. A recent study has shown striking compartmentalization of glutamatergic and dopaminergic release sites within the processes of TH-positive neurons, where the two vesicular transporter types, VMAT2 and VGluT2, are segregated within distinct subcompartments (31). Intriguingly, we observe Rho activation broadly distributed within the processes of dopamine neurons. Taken together, these findings suggest a complex integration of dopaminergic and glutamatergic transmission within the mesoaccumbens pathway.
  • Primary[8] - covers amph's RhoA-mediated signaling cascade to DAT: transporter internalization via ROCKs (note to self: this ref covers PKC-mediated EAAT2 internalization; this is very likely the protein kinase that mediates TAAR1-mediated EAAT2 internalization by methamphetamine in astroglia - still have no clue why amphetamine doesn't do this)
  • Primary already cited in the article[9] - first paper to describe amphetamine-induced, RhoA-mediated internalization of EAAT3 in midbrain DA neurons

Seppi333 (Insert ) 22:02, 6 November 2016 (UTC); Updated 17:53, 14 November 2016 (UTC)

Wikitable to add when updating pharmacodynamics diagram[edit]

Will probably need to add something analogous to the following sentence in a note in order to explain how the columns in the table below are related:

  • Amphetamine interacts with a biological target, which triggers an intracellular signaling cascade that activates a protein kinase. The activated protein kinase in turn phosphorylates a transporter, which causes a change in transporter function that affects neurotransmission.
Effects of amphetamine on membrane transport proteins in dopamine neurons
Biological target
of amphetamine
protein kinase
Effect on transporter function Effect on neurotransmission Source
TAAR1 PKA DAT Transporter internalization Dopamine reuptake inhibition [10][11]
TAAR1 PKC DAT Reverse transport of dopamine
Transporter internalization
Dopamine efflux into synaptic cleft
Dopamine reuptake inhibition
Unidentified CAMKIIα DAT Reverse transport of dopamine Dopamine efflux into synaptic cleft [1][2][3]
Unidentified ROCK
[citation needed]
DAT Transporter internalization Dopamine reuptake inhibition
Unidentified ROCK†
[citation needed]
EAAT3 Transporter internalization Glutamate reuptake inhibition
Note: ROCK-mediated transporter internalization is transient due to the inactivation of RhoA, which activates ROCK, by PKA. [6][7][8]

The phosphorylation / inactivation of RhoA by PKA occurs roughly 10–15 minutes following neuronal exposure to amphetamine and more or less plateaus by 20–30 minutes post-exposure, based upon in vitro research. Seppi333 (Insert ) 17:53, 14 November 2016 (UTC)

Amphetamine-induced ERK1/2-mediated phosphorylation of DAT on the Thr53 residue, which induces DA efflux, also appears to occur;[2][3] ERK1/2 is likely activated by the PKCβ isoform of PKC.[3]

Section reflist
  1. ^ a b Steinkellner T, Mus L, Eisenrauch B, Constantinescu A, Leo D, Konrad L, Rickhag M, Sørensen G, Efimova EV, Kong E, Willeit M, Sotnikova TD, Kudlacek O, Gether U, Freissmuth M, Pollak DD, Gainetdinov RR, Sitte HH (October 2014). "In vivo amphetamine action is contingent on αCaMKII". Neuropsychopharmacology. 39 (11): 2681–2693. doi:10.1038/npp.2014.124. PMC 4207348Freely accessible. PMID 24871545. Our findings demonstrate that amphetamine requires the presence of αCaMKII to elicit a full-fledged effect on DAT in vivo: αCaMKII does not only support acute amphetamine-induced dopamine efflux but is also important in shaping the chronic response to amphetamine. 
  2. ^ a b c d Wang Q, Bubula N, Brown J, Wang Y, Kondev V, Vezina P (May 2016). "PKC phosphorylates residues in the N-terminal of the DA transporter to regulate amphetamine-induced DA efflux". Neurosci. Lett. 622: 78–82. doi:10.1016/j.neulet.2016.04.051. PMID 27113203. The DA transporter (DAT), a phosphoprotein, controls extracellular dopamine (DA) levels in the central nervous system through transport or reverse transport (efflux). Multiple lines of evidence support the claim that PKC significantly contributes to amphetamine-induced DA efflux. Other signaling pathways, involving CaMKII and ERK, have also been shown to regulate DAT mediated efflux. ... The results of in vitro experiments using a recombinant N-terminal peptide of DAT [11,17] indicate that PKC phosphorylates the S4, S7, and S13 residues, that the S7 and S13 residues are also phosphorylated by PKA and CaMKII respectively, and that the T53 residue is phosphorylated by ERK1/2 (Fig. 1). ... Together, these findings suggest that PKC is not the only protein kinase that regulates amphetamine-induced DA efflux and, importantly, that it may function in concert with others at multiple residues in the N-terminal of the DAT to fully regulate its function. Indeed, DA efflux is regulated by several kinases in addition to PKC, including CaMKII and ERK1/2 [5,6], and all are capable of regulating the DAT by phosphorylating residues in its N-terminal [11–15,17] ... As some but not all findings indicate that CaMKII contributes to acute amphetamine-induced DA efflux and behaviors [12-14; cf,20], it remains possible that the inhibitory effect of the DAT-S13A mutant on DA efflux observed in the present study might in part reflect an action of CaMKII ... In addition, in the present experiments, S/T-A mutation of the non-PKC residue S12 and the ERK1/2 residue T53 were each found to reduce amphetamine-induced DA efflux by approximately 25% as well. ... Indeed, the lack of inhibition of amphetamine-induced DA efflux observed in the present study with the DAT-S7A mutant may reflect the integration at S7 of antagonistic signaling by PKC and PKA pathways as this residue is phosphorylated by both kinases [17]. 
  3. ^ a b c d e Bermingham DP, Blakely RD (October 2016). "Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters". Pharmacol. Rev. 68 (4): 888–953. doi:10.1124/pr.115.012260. PMID 27591044. The Amara laboratory recently provided evidence that AMPH triggered DAT endocytosis is clathrin-independent and requires the small GTPase Rho (Wheeler et al., 2015), which mediates another dynamin-dependent mode of endocytosis (Croise et al., 2014). These lines of evidence are consistent with a PKC-independent mode of DAT internalization by AMPH. ... Recent work from the Amara laboratory has implicated PKA signaling in the regulation of Rho-mediated DAT internalization, specifically in response to AMPH treatment (Wheeler et al., 2015). ...
    Whereas little support for CaMKII regulation of DA uptake exists, substantial evidence supports a role for the kinase in DAT-dependent DA efflux triggered by AMPH or DAT mutations. ... Importantly, AMPH treatment of DAT transfected cells produced a rise in intracellular Ca2+ that could be blocked by thapsigargin or cocaine, supporting a model whereby AMPH is first transported into cells where it can then produce release of endoplasmic reticulum Ca2+ stores. Subsequently, AMPH was shown to activate CaMKII in DAT transfected cells (Wei et al., 2007). ... As noted above, an important role for CaMKII activity in AMPH-evoked DA efflux has been defined through the use of organic and peptide CaMKII inhibitors, intracellular kinase perfusion and the use of CaMKII KO/knock-in mouse models. The question naturally arises as to whether this contribution arises from direct, CaMKII-mediated DAT phosphorylation. ... At present, information is lacking as to the site(s) that support CaMKII phosphorylation of DAT in vivo ... The current model for how CaMKII participates in AMPH-triggered DA efflux involves binding of the kinase to the transporter C terminus followed by phosphorylation of one or more Ser residues in the transporter N terminus. This phosphorylation is then thought to facilitate conformational changes that place the transporter in a “DA efflux-willing” conformation. ...
    Thus, Kantor et al. (2004) described enhancement of DA efflux by PC-12 cells that was dependent on external Ca2+ and is blocked by the voltage-gated Ca2+ channel (VGCC) inhibitors v-conotoxin and nifedipine. The reader will recall that evidence suggests that DAT-mediated DA efflux after AMPH treatment relies more on intracellular Ca2+ stores than extracellular Ca2+, ... Interestingly, AMPH also elicited a greater increase in Ca2+ elevations after repeated treatment, suggesting possible changes in expression/activity of Ca2+ channels as well. The actions of AMPH to elevate Ca2+ levels were blocked by desipramine, suggesting that AMPH-induced depolarization may be responsible for Ca2+ channel activation. Consistent with this idea, Cameron et al. (2015) recently reported an ability of AMPH to activate VGCCs via transporter-mediated depolarization. ...
    Based on work from Chen et al. (2013) that showed that PKCβ appears to function upstream of ERK1/2, which are strong candidates for targeting Thr53 (Gorentla et al., 2009), it is possible that PKCβ may act through ERK1/2 to increase Thr53 phosphorylation and therefore positively regulate DAT, whereas other PKC isoforms act to downregulate DAT activity, potentially through direct phosphorylation of the transporter or other interacting proteins. ... As an equivalent loss of AMPH evoked efflux capacity was observed for both Ala and Asp substitutions, the precise role of phosphorylation at Thr53 in AMPH-induced DA efflux remains to be established.
  4. ^ Cameron KN, Solis E, Ruchala I, De Felice LJ, Eltit JM (2015). "Amphetamine activates calcium channels through dopamine transporter-mediated depolarization". Cell Calcium. 58 (5): 457–66. doi:10.1016/j.ceca.2015.06.013. PMID 26162812. One example of interest is CaMKII, which has been well characterized as an effector of Ca2+ currents downstream of L-type Ca2+ channels [21,22]. Interestingly, DAT is a CaMKII substrate and phosphorylated DAT favors the reverse transport of dopamine [48,49], constituting a possible mechanism by which electrical activity and L-type Ca2+ channels may modulate DAT states and dopamine release. ... In summary, our results suggest that pharmacologically, S(+)AMPH is more potent than DA at activating hDAT-mediated depolarizing currents, leading to L-type Ca2+ channel activation, and the S(+)AMPH-induced current is more tightly coupled than DA to open L-type Ca2+ channels. 
  5. ^ Ruchala I, Cabra V, Solis E, Glennon RA, De Felice LJ, Eltit JM (2014). "Electrical coupling between the human serotonin transporter and voltage-gated Ca(2+) channels". Cell Calcium. 56 (1): 25–33. doi:10.1016/j.ceca.2014.04.003. PMC 4052380Freely accessible. PMID 24854234. S(+)MDMA (ecstasy) and 5HT (serotonin) induce Ca2+ mobilization in cultured muscle cells expressing hSERT. ...
    The electrical coupling between hSERT and CaV1.3 takes place at physiological concentrations of 5HT.
    hSERT-mediated depolarization activates voltage-gated calcium channels.
  6. ^ a b Bjørn-Yoshimoto WE, Underhill SM (September 2016). "The importance of the excitatory amino acid transporter 3 (EAAT3)". Neurochem. Int. 98: 4–18. doi:10.1016/j.neuint.2016.05.007. PMID 27233497. Recently, it was reported that amphetamine decreases the surface expression of EAAT3 (Underhill et al., 2014). This was dependent on a C-terminal sequence, VNGGF, which has previously been identified as important in targeting the transporter to dendrites in hippocampal neurons (Cheng et al., 2002). This also overlaps with motifs important for internalization (YVNGGF) via interaction with the AP2 complex (D’ Amico et al., 2010) and PDGF-stimulated increased surface expression (YVN) (Sheldon et al., 2006). The amphetamine-induced decrease in surface EAAT3 was mediated by RhoA (see figure 3). Amphetamine also increased both AMPAR and NMDAR-mediated evoked excitatory post-synaptic currents in substantia nigra pars compacta slices when stimulating glutamatergic inputs, and this was blocked by a VNGGF peptide in the recording pipette. These observations are consistent with the effects being mediated by increased local Glu concentrations due to decreased post-synaptic EAAT3, suggesting that EAAT3 regulation could be a mechanism involved in the learning and memory aspect of amphetamine addiction (Tzschentke and Schmidt, 2003). Interestingly, it was recently reported that the dopamine transporter follows the same RhoA dependent mechanism of amphetamine-induced endocytosis (Wheeler et al., 2015). This effect is time-dependent due to increased cAMP inactivating RhoA, which could suggest a similar regulation for EAAT3 trafficking. ...
    RhoA is a downstream target of intracellular amphetamine. Both mechanisms of RhoA activation lead to a rapid decrease the surface expression of EAAT3.
  7. ^ a b c Wheeler DS, Underhill SM, Stolz DB, Murdoch GH, Thiels E, Romero G, Amara SG (December 2015). "Amphetamine activates Rho GTPase signaling to mediate dopamine transporter internalization and acute behavioral effects of amphetamine". Proc. Natl. Acad. Sci. U.S.A. 112 (51): E7138–E7147. doi:10.1073/pnas.1511670112. PMC 4697400Freely accessible. PMID 26553986. These observations support the existence of an unanticipated intracellular target that mediates the effects of AMPH on RhoA and cAMP signaling and suggest new pathways to target to disrupt AMPH action. ... To further confirm the role of Rho activation on AMPH-mediated DAT internalization in primary neurons, we investigated a potential downstream effector of Rho activation. The Rho-associated coiled-coil containing kinase (ROCK) is activated by Rho GTPases and plays a critical role in actin cytoskeletal rearrangements. Coapplication of the ROCK inhibitor, Y27632, blocked the effects of AMPH pretreatment on dopamine uptake in primary midbrain cultures (Fig. 2F). These data further support a role for Rho activation in the mechanism of action of AMPH. ... Our data using a ROCK inhibitor to block the effects of AMPH pretreatment on dopamine uptake link ROCK activation to DAT internalization, complementing previous studies that suggest a role for ROCK in some aspects of AMPH’s behavioral effects (29). ...
    The activation of intracellular signaling pathways by AMPH and the Rho-mediated internalization of DAT are also observed in nonneural cell lines transfected with DAT, which demonstrates that these effects do not require synaptic vesicles or endogenous dopamine. We also found that the presence of AMPH within the cytosol, and not the binding and transport through DAT, was essential for stimulating these signaling cascades ...
    The precise nature and the pharmacological properties of the cytoplasmic target(s) of AMPH remain to be established, but a trace amine-associated receptor, TAAR1, that is expressed in dopamine neurons and has a predominantly intracellular distribution is a potential candidate. As a Gs-coupled GPCR that responds to a variety of endogenous and exogenous amines and neurotransmitter metabolites, TAAR1 has been shown to be activated by AMPH and a variety of AMPH-like compounds and is likely responsible for the increases in cAMP generally observed following the application of AMPH to cells (32, 33). Whether TAAR1 also mediates the activation of the small GTPases, RhoA, and Rac1 remains to be established.
    Together, the studies reported here indicate that the effects of AMPH not only depend on the drug’s well-established actions on uptake and efflux through the DAT, but also require the activation of multiple signaling pathways by acting on additional target(s) within the cell. Cytoplasmic cAMP appears to integrate both intracellular signals through GTPase activation and extracellular signals from GPCR-coupled pathways to shape response of a dopamine neuron to AMPH. Thus, modulation of the Rho activation/inactivation sequence provides a mechanism by which drugs and endogenous neurotransmitters can influence the response of dopamine neurons to AMPH.
  8. ^ a b Saunders C, Galli A (December 2015). "Insights in how amphetamine ROCKs (Rho-associated containing kinase) membrane protein trafficking". Proc. Natl. Acad. Sci. U.S.A. 112 (51): 15538–15539. doi:10.1073/pnas.1520960112. PMC 4697384Freely accessible. PMID 26607447. In this elegant and thorough study (7), Amara and her collaborators identify multiple novel targets for intracellular AMPH. They demonstrate that cytoplasmic AMPH stimulates a secondary pathway of cAMP production, which leads to Rho inactivation by PKA-dependent phosphorylation. ... Furthermore, the authors involve the Rho-associated coiled-coil containing kinase (ROCK) in the AMPH actions, because ROCK inhibition blocks the effects of AMPH pretreatment on DA uptake. These data support previous studies, suggesting a role for ROCK in AMPH’s behavioral effects. ... In this elegant and thorough study (7), Amara and her collaborators identify multiple novel targets for intracellular AMPH. They demonstrate that cytoplasmic AMPH stimulates a secondary pathway of cAMP production, which leads to Rho inactivation by PKA-dependent phosphorylation. The authors provide a mechanism whereby RhoA-dependent and PKA signaling interact to regulate the timing and magnitude of AMPH’s effects on DAT internalization. The pivotal role of DAT trafficking in AMPH-induced behaviors was also tested in vivo. ... These results further support the idea that the direct activation of cytoplasmic signaling cascades by AMPH might contribute to the behavioral effects of acute AMPH exposure. ... It is noteworthy to point out that in addition to its effects on Rho-mediated transporter trafficking, AMPH elevates extracellular DA through other mechanisms, such as facilitating efflux and inhibiting the DAT. 
  9. ^ Underhill SM, Wheeler DS, Li M, Watts SD, Ingram SL, Amara SG (July 2014). "Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons". Neuron. 83 (2): 404–416. doi:10.1016/j.neuron.2014.05.043. PMC 4159050Freely accessible. PMID 25033183. AMPH also increases intracellular calcium (Gnegy et al., 2004) that is associated with calmodulin/CamKII activation (Wei et al., 2007) and modulation and trafficking of the DAT (Fog et al., 2006; Sakrikar et al., 2012). ... For example, AMPH increases extracellular glutamate in various brain regions including the striatum, VTA and NAc (Del Arco et al., 1999; Kim et al., 1981; Mora and Porras, 1993; Xue et al., 1996), but it has not been established whether this change can be explained by increased synaptic release or by reduced clearance of glutamate. ... DHK-sensitive, EAAT2 uptake was not altered by AMPH (Figure 1A). The remaining glutamate transport in these midbrain cultures is likely mediated by EAAT3 and this component was significantly decreased by AMPH 
  10. ^ a b Miller GM (January 2011). "The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity". J. Neurochem. 116 (2): 164–176. doi:10.1111/j.1471-4159.2010.07109.x. PMC 3005101Freely accessible. PMID 21073468. 
  11. ^ a b Grandy DK, Miller GM, Li JX (February 2016). ""TAARgeting Addiction"-The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference". Drug Alcohol Depend. 159: 9–16. doi:10.1016/j.drugalcdep.2015.11.014. PMID 26644139. 
Tentative changes to diagram[edit]
Pharmacodynamics of amphetamine in a dopamine neuron
v · t · e
A pharmacodynamic model of amphetamine and TAAR1
via AADC
The image above contains clickable links
Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT.[1] Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2.[1][2] When amphetamine enters synaptic vesicles through VMAT2, it collapses the vesicular pH gradient, which in turn causes dopamine to be released into the cytosol (light tan-colored area) through VMAT2.[2][3] When amphetamine binds to TAAR1, it reduces the firing rate of the dopamine neuron via potassium channels and activates protein kinase A (PKA) and protein kinase C (PKC), which subsequently phosphorylate DAT.[1][4][5] PKA-phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport.[1] PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport.[1] Amphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through a CAMKIIα-dependent pathway, in turn producing dopamine efflux.[6][7]

Things to add to or change in the {{Amphetamine pharmacodynamics}} diagram:

  • add some sort of geometric figure w/ "Unidentified intracellular target(s)" written in the center as text
  • add glutamatergic synaptic vesicles w/ VGlut2
  • add some glutamate molecules to the figure
  • add EAAT3 on the plasma membrane
  • draw pathway from amphetamine through "Unidentified intracellular target(s)", through RhoA, then through ROCK, then to both DAT and EAAT3 - indicate transporter internalization occurs†
  • draw pathway from amphetamine through "Unidentified intracellular target(s)", through CAMKIIα, then to DAT, indicate DA efflux occurs‡
  • change "DAT internalization" to "PKA- or ROCK-mediated DAT internalization"
  • change "Dopamine release" to "PKC- or CAMKIIα- mediated dopamine efflux"
  • consider removing phenethylamine + trace amine signaling from the figure if it becomes too complicated as a result of these changes

† need to wait for a ref to be published which explicitly states that DAT and EAAT3 are phosphorylated by a ROCK or a different RhoA-activated protein kinase
need to find a ref to verify that CAMKII signaling is triggered by amphetamine interacting with an intracellular target before doing this - stated in this review: "Importantly, AMPH treatment of DAT transfected cells produced a rise in intracellular Ca2+ that could be blocked by thapsigargin or cocaine, supporting a model whereby AMPH is first transported into cells where it can then produce release of endoplasmic reticulum Ca2+ stores. Subsequently, AMPH was shown to activate CaMKII in DAT transfected cells (Wei et al., 2007)."
Seppi333 (Insert ) 17:53, 14 November 2016 (UTC)

Diagram reflist
  1. ^ a b c d e Cite error: The named reference Miller was invoked but never defined (see the help page).
  2. ^ a b Cite error: The named reference E Weihe was invoked but never defined (see the help page).
  3. ^ Cite error: The named reference Amphetamine VMAT2 pH gradient was invoked but never defined (see the help page).
  4. ^ Cite error: The named reference GIRK was invoked but never defined (see the help page).
  5. ^ Cite error: The named reference Genatlas TAAR1 was invoked but never defined (see the help page).
  6. ^ Cite error: The named reference EAAT3 was invoked but never defined (see the help page).
  7. ^ Cite error: The named reference DAT regulation review was invoked but never defined (see the help page).

Menstrual cycle[edit]


  1. ^ Van Voorhees EE, Mitchell JT, McClernon FJ, Beckham JC, Kollins SH (May 2012). "Sex, ADHD symptoms, and smoking outcomes: an integrative model". Med. Hypotheses. 78 (5): 585–593. doi:10.1016/j.mehy.2012.01.034. PMC 3321070Freely accessible. PMID 22341778. research with cocaine and amphetamine in humans has found that the women report greater positive subjective effects of both substances during the follicular than the luteal phase of the menstrual cycle [129]. Moreover, men report greater positive subjective effects of stimulants compared to women who are in the luteal phase, though these gender differences disappear during the follicular phase [104, 130, 131]. Some [130, 131] but not all [132] research has found plasma or salivary estrogen levels to be associated positively with subjective response to amphetamine, and one study found that exogenously administered estrogen enhanced the discriminative stimulus effects of low doses of amphetamine [106]. 



  1. ^ Carroll ME, Smethells JR (February 2016). "Sex Differences in Behavioral Dyscontrol: Role in Drug Addiction and Novel Treatments". Front. Psychiatry. 6: 175. doi:10.3389/fpsyt.2015.00175. PMC 4745113Freely accessible. PMID 26903885. Environmental Enrichment ...
    In humans, non-drug rewards delivered in a contingency management (CM) format successfully reduced drug dependence [for a review see Ref. (188)]. In general, CM programs promote drug abstinence through a combination of positive reinforcement for drug-free urine samples. For instance, voucher-based reinforcement therapy in which medication compliance, therapy session attendance, and negative drug screenings reinforced with vouchers to local business (e.g., movie theater, restaurants, etc.) directly reinforces drug abstinence, provides competing reinforcers, enriches the environment, and it is a robust treatment across a broad range of abused drugs (189). ...
    Physical Exercise
    There is accelerating evidence that physical exercise is a useful treatment for preventing and reducing drug addiction [see reviews in Ref. (28, 178, 190, 191)]. In some individuals, exercise has its own rewarding effects, and a behavioral economic interaction may occur, such that physical and social rewards of exercise can substitute for the rewarding effects of drug abuse. ... The value of this form of treatment for drug addiction in laboratory animals and humans is that exercise, if it can substitute for the rewarding effects of drugs, could be self-maintained over an extended period of time. Work to date in laboratory animals [for review, see Ref. (191)] and humans [for review, see Ref. (178)] regarding exercise as a treatment for drug addiction supports this hypothesis. ... However, a RTC study was recently reported by Rawson et al. (226), whereby they used 8 weeks of exercise as a post-residential treatment for METH addiction, showed a significant reduction in use (confirmed by urine screens) in participants who had been using meth 18 days or less a month. ... Animal and human research on physical exercise as a treatment for stimulant addiction indicates that this is one of the most promising treatments on the horizon. [emphasis added]


  • [1] - may be worth covering some content from this chapter:
    1. acute effect on glucocorticoids via HPA axis  Done
    2. amphetamine increases orgasm pleasure, libido increases more in women than in men, high/supratherapeutic doses significantly promote libido Pending

Seppi333 (Insert ) 08:28, 4 December 2015 (UTC)

Updated 06:54, 9 October 2016 (UTC)


  1. ^ Gunne LM (2013). "Effects of Amphetamines in Humans". Drug Addiction II: Amphetamine, Psychotogen, and Marihuana Dependence. Berlin, Germany; Heidelberg, Germany: Springer. pp. 247–260. ISBN 9783642667091. Retrieved 4 December 2015. 

Completed updates[edit]


I haven't read through the whole prescribing information sheet for Mydaysis, but this "new" drug looks like it's a near perfect clone of Adderall XR with an almost trivial difference in pharmacomkinetics (i.e., the mean plasma concentrations of d-amphetamine over time from Mydayis relative to Adderall XR diverge slightly after 4 hours and converge at 10 hours).

Anyway, I was wondering which article others thought Mydayis should redirect to: Adderall or amphetamine? Seppi333 (Insert ) 07:00, 6 August 2017 (UTC)

Mydayis is essentially "Adderall XXR" - bioequivalent in clinical trials to Adderall XR plus a booster dose of IR taken 8 hours later. Very similar release mechanism, just an extended/modified version of what was used in Adderall XR. Anyways, Mydayis should obviously redirect to Adderall for the time being, and Adderall should probably get a new section specifically to discuss formulation-specific differences in greater detail. I can probably write an abbreviated summary of Mydayis' development if you want me to, I've been following that for years and have a decent amount of research on it saved that I can cite. Personally I still think the Adderall article should just be renamed outright to Mixed Amphetamine Salts, even more so now that Shire has abandoned the Adderall branding for their new variant of Adderall, but I don't really expect that to end up happening, irregardless of how much sense it would make. Garzfoth (talk) 10:32, 6 August 2017 (UTC)
Feel free to add whatever you think is worth covering. I'm less opposed to the idea of renaming that article now compared to before, but there's still the issue of no official nonproprietary name (usan/inn/etc) for that formulation. Seppi333 (Insert ) 18:40, 6 August 2017 (UTC)
I made a rather lengthy and well-sourced argument for naming it "Mixed Amphetamine Salts" a few years ago (Talk:Adderall/Archive_1#Proposing_a_name_change_to_Mixed_Amphetamine_Salts). Given that Mydayis is going to be marketed starting this fall, and that the Mydayis product monograph concurs with the prior XR/IR monographs in its usage of the term "mixed amphetamine salts" (in fact it seems to use the term even more frequently than the prior monographs did), I think it's not unreasonable to re-examine that name. The existence of Adzenys and Dyanavel actually supports the usage of the term much more strongly than Mydayis alone does as both of them also use the term as or even more extensively in their monographs than Mydayis does and are compared explicitly against "mixed amphetamine salts" for establishing equivalence in order to obtain FDA approval. So clearly a mixed amphetamine salts article would have to cover Adderall IR, Adderall XR, Mydayis, Adzenys, and Dyanavel - which is not at all dissimilar to how methylphenidate covers a large variety of different formulations of methylphenidate. We would have to do a little bit of rewriting so that the article was more generic in scope, but that wouldn't require too much work, and the same basic history still applies. I think this is the most logical way to reconcile the existence of five FDA-approved-as-equivalent MAS formulations. What do you think? Garzfoth (talk) 21:52, 8 August 2017 (UTC)

@Box73: I'm curious to know what you think. Seppi333 (Insert ) 19:11, 8 August 2017 (UTC)

I slightly prefer Adderall because of its common use, the lack of simplicity with "mixed amphetamine salts" and lack of official non-propriatary name. (I don't see a significant difference between the Mydayis curve and the pure Adderall XR curve from the Adderall XR label, adjusted for dose.)
Further, should the Adderall article be focusing on -- limited by -- the (mixed) salts or should we be be covering the ~3:1 proportion of enantiomers, including Adzenys ODT-XR and Dyanavel XR?
It appears Garzfoth and I share this idea. -- βox73 (৳alk) 22:53, 8 August 2017 (UTC)

Why shouldn't it be called Dextroamphetamine/Amphetamine? That's a common generic name, and it fits both mixed salts and liquid formulations. (talk) 17:57, 4 September 2017 (UTC)

@ The name "dextroamphetamine/amphetamine" is not in common use outside of pharmacies. The name "mixed amphetamine salts" on the other hand is in very common use in the scientific literature, in the FDA's literature, in the drug labels, and in Shire literature. And of course the name "Adderall" is in very common use outside of these cases (i.e. by laymen). Garzfoth (talk) 18:34, 11 September 2017 (UTC)

New edit notice for this page[edit]

I figured I should mention here that I've just created an edit notice for this page at Template:Editnotices/Page/Amphetamine; this notice appears at the top of the page when editing this article ( There have been several instances in the past few months where an edit completely borked the 3 pages where this article is transcluded, so I've covered this in the edit notice. Since I copied the edit notice template from Template:Editnotices/Page/Parkinson's disease, I also included the part from that template about discussing significant changes to the text/images on the talk page before making them in the article.

If anyone has any suggestions for changes to the edit notice for this page, please let me know. I'm open to modifying it. Seppi333 (Insert ) 02:46, 10 December 2017 (UTC)

Just to clarify, the reason I created this notice is that the removal of the 2 curly brackets – i.e., "}}" – in this edit produced only minor formatting issues in this article (i.e., "{{#ifeq:Overdose|Overdose|" appeared at the beginning of the overdose section), but it caused the Adderall article to render/appear like this to readers of that page: pdf version of the Adderall article with transclusion errors. That edit caused the entire overdose section on this page to be transcluded along with each section-specific transclusion from this page to that one. The same occurred in the dextroamphetamine and lisdexamfetamine articles.
Those transclusion errors persisted for about 7 hours until they were fixed with this edit. I'm hoping the edit notice will prevent editors from unwittingly introducing syntax errors in the transclusion templates that create problems like this; transclusion errors like this can result from adding a new template to the article with unbalanced brackets or, like the edit here did, removing either/both of the pairs of brackets for any of the WP:Selective transclusion templates. Seppi333 (Insert ) 03:57, 10 December 2017 (UTC)