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Finding "undocumented" compounds

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Hi, I'm not sure if this is the right place to ask this.

I've seen a lot of pharmacology navboxes (such as muscarinic receptor modulators, for an example), lots of them contain a lot of drugs that are not really known (a lot of them are redlinks), which is what I mean by "undocumented compounds"

I was just curious if anyone knew how to find names of these compounds (like specific keywords in a search engine)

Because so far I've been creating a lot of articles that were redlinks on the navboxes, but I'd love to add new compounds to said templates.

So if anyone knew how to find lists (or something similar) with names of investigational drugs (names like "ADX-71441") that would be really great Themonkey942 (talk) 22:29, 7 September 2024 (UTC)[reply]

Importance ratings need review

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An editor first labeled Legality of cannabis as top-importance for this group, and after I removed the rating, has changed it to high-importance. Please decide for yourselves how you'd like to have it assessed.

I've seen a couple of editors "upgrade" their favorite subjects, perhaps in the mistaken belief that this will result in more editors working on the articles. I specifically suggest taking a look at what's in Category:Top-importance pharmacology articles and Category:High-importance pharmacology articles in particular, to see whether any spammers have been at work. WhatamIdoing (talk) 04:41, 26 September 2024 (UTC)[reply]

Dose and dosage

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Is there a good, well-sourced page that describes the technical difference between dose and dosage? WhatamIdoing (talk) 17:52, 30 September 2024 (UTC)[reply]

Apparently we did not have such an article, but I created dosage (pharmacology) which hopefully is a start. Boghog (talk) 18:58, 30 September 2024 (UTC)[reply]
Thanks for creating that. WhatamIdoing (talk) 19:41, 30 September 2024 (UTC)[reply]
Perhaps dosage (pharmacology) should be merged into Medical prescription. Thoughts? Boghog (talk) 19:48, 30 September 2024 (UTC)[reply]
I'm inclined not to make a hasty decision (either way). Part of this is because I generally prefer merging, but other people tell me that a short, focused article is better for mobile users (which is most of our page views).
I did some copyediting on Dose (biochemistry). WhatamIdoing (talk) 20:27, 30 September 2024 (UTC)[reply]
In my opinion, a dosage and a prescription are two different (albeit related, of course) things. I'd be inclined not to merge, for that reason. --Tryptofish (talk) 20:44, 30 September 2024 (UTC)[reply]
My view is that they are synonyms, and, with respect ot Boghog for work done, I don't think that we need that new page. Indeed, my reading of the key source in that new article is not consistent with the definition in the lede. Rowbotham et al (2019) actually say we found dose and dosage to be used interchangeably. We recommend a distinction between these terms, with ‘dosage’ having the advantage of capturing change to amount ‘dispensed’ over time (in response to effects achieved). Dosage therefore acknowledges the inevitable dynamic and complexity of implementation. So, the current state is that they are synonyms; their recommended use is a very subtle one that doesn't reflect the lede of the current article. My own UK-centric view is that dosage is an abomination that should be eliminated wherever it rears its ugly head, and that the term dose suffices for all civilized discussion. Given that bias, I suggest merging Dosage (pharmacology) to Dose (biochemistry), describing any differences in use on that page. Klbrain (talk) 21:56, 2 October 2024 (UTC)[reply]
Dorland's (2007) gives these definitions:
dosage
the determination and regulation of the size, frequency, and number of doses.
dose
quantity to be administered at one time, such as a specified amount of medication.
The latter continues for three-quarters of a page to cover all the sub-definitions (e.g., total dose, daily dose, median effective dose...), but they don't use them as synonyms. That said, even though there is a verifiable technical distinction between the two, I think we could still merge the articles. It is not unusual for an article to have a note about the technical distinction between two words, especially when that distinction is more often ignored outside of technical documents. And to go even further than Klbrain, we might want to consider using the plain old English word amount when appropriate, for even greater clarity. WhatamIdoing (talk) 22:44, 2 October 2024 (UTC)[reply]
See also Collins: dosage and Collins: dose. My understanding of the two terms matches what has been written in the Wikipedia articles. I suggest changing "given at one time" to "given at any one time" in case anyone thinks dose only refers to a one-off consumption. And that definition seems to match what Collins says is the British English use, as far as medicine is concerned. However, the US English use (citing Websters and their own definition in two sections) suggests some ambiguity with "the amount used in a dose" and "the amount of medicine to be given". At first this seems to indicate Americans are sometimes using "dosage" where they should say "dose" but then I considered what "amount" means, and it is cumulative.
WAID mentions both "total dose" and "daily dose" which are different from an individual dose. A medicine of 100mg taken three times a day for two days has an individual dose of 100mg, daily dose of 300mg and total dose of 600mg. In each case the word dose is used, not dosage, though we might qualify use of the word that isn't referring to the individual dose if that isn't clear. Sometimes the word on its own can refer to the quantity consumed daily or in total. For example, if someone suffered ill effects from being on "too high a dose" of a medicine, this could be because they are taking it four times a day rather than two. If someone died from being given a "huge dose" of a medicine, this could be because the dose consumed over three days was ultimately fatal, whereas one individual dose might not. This all says to me that dose can be used to refer to an accumulation. The worse "dosage" couldn't be used for that at all.
So perhaps in addition to "at any one time" (the individual dose) we could say "or in total over a period" (the daily dose or total dose). The American English usages in Collins would permit that definition. Have we got a source that say so more explicitly? -- Colin°Talk 08:00, 3 October 2024 (UTC)[reply]
I see that in Dose (biochemistry)#Vaccines it says "Vaccinations are typically administered as liquids and dosed in milliliters" Clearly this isn't millilitres of vaccine. For example this Covid vaccine is a 0.3ml dose containing 30 micrograms of the vaccine. A liquid medicine such as Epilim liquid is 200mg/5ml. The dose in that case might refer to 400mg twice a day or 10ml twice a day or most precisely as 400mg as 10ml twice a day. One doesn't care about the size of a pill, though one might need to take two pills if the dose requires it.
As the lead of of Dose (biochemistry) says, it can refer to the taking of some unit of medicine without anyone giving a size in mg or ml. For example this government report says "Up to 23 August 2022, 53 million people received a first dose of COVID-19 vaccine, 50 million received a second dose and 40 million received a third or booster dose."
I wonder if the dose article could say more about how sometimes dose references the quantity of the containing liquid or pills rather than the amount of medicinal compound. "Take two paracetamol". "Draw up 0.3ml of covid vaccine from the vial". "Take 30ml of cough medicine". -- Colin°Talk 08:30, 3 October 2024 (UTC)[reply]
I think that Dose (biochemistry), though not even close to our worst articles, is sufficiently weak that any editor who's looked in a dictionary/has a basic grasp of the concept could improve it through a quick copyedit. WhatamIdoing (talk) 19:54, 3 October 2024 (UTC)[reply]
Look the drug up by full name in most wifi and ull find all that sort of info : 2600:1000:A121:5319:712C:16E4:EA57:57EE (talk) 22:27, 13 November 2024 (UTC)[reply]

Good article reassessment for Mephedrone

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Mephedrone has been nominated for a good article reassessment. If you are interested in the discussion, please participate by adding your comments to the reassessment page. If concerns are not addressed during the review period, the good article status may be removed from the article. Z1720 (talk) 16:10, 12 October 2024 (UTC)[reply]

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I noticed the new list of investigational autism and pervasive developmental disorder drugs today, which is one of many articles submitted via AfC by the prolific IP editor 76.174.0.57. The list is clearly worthwhile but I do note that it has 89 external links in its main sections and only three actual references. This seems to go against the guidance at WP:ELLIST but is common in similar lists of interest to the Pharmacology Project. Some of the external links may be totally unnecessary, since there are valid wikilinks to existing articles where reference sources can be found. In other cases, it might be better to convert the EL to cites. Is this worth discussion and agreement on a consistent approach? Mike Turnbull (talk) 14:53, 28 October 2024 (UTC)[reply]

Fine for the links to be turned into refs. It's mostly just that it's too overwhelming to do it myself. Especially considering that the lists require regular updating, which usually entails remaking them from scratch. Ideally turning the refs into links would be automated via a batch method somehow. But I'm not aware of a tool for that. (Perhaps User:Boghog might, since I see them templating a lot of bare URLs?) I will admit that it is also significantly easier to check the status of the drugs (e.g., many at once) when the cites are formatted as external links rather than as refs though. But if Wikipedia policy dictates that they should be formatted as refs then that's how they should be. – 76.174.0.57 (talk) 21:45, 28 October 2024 (UTC)[reply]
I went ahead and converted the external links into citation tags. Although this might make them slightly harder to follow, templated citations could be useful when turning the red drug links into stubs. For anyone interested, pasting the following RegEx into the "search and replace" function of Wikipedia’s editing toolbar will convert the external links into refs containing bare URLs:

Search for: \[https(.*?)\]

Replace with: <ref>https\1</ref>

In a second step, the WP:reFill (link) tool will convert the bare URLs into {{cite web}} templates. Boghog (talk) 06:51, 29 October 2024 (UTC)[reply]
@Boghog Thanks for teaching me something new and useful! I'm going to apply that technique to the other lists I linked above. Two comments: 1) the search string needs to be \[http(.*?)\] in older articles using http rather than https and 2) you had a typo in your replace string, which should be <ref>https$1</ref> Had me fooled for a moment! Mike Turnbull (talk) 13:24, 29 October 2024 (UTC)[reply]
@Mike Turnbul I forgot about non-secure URLs. Good catch. Alternatively, the search regex could be modified to \[https?(.*?)\]. "s?" will match zero or one occurrence of "s", and hence will match both "http" and "https". The back reference designation for most regex parsers I am familiar with is "\1" which worked when I tested it. When I tried "$1", instead of inserting the captured URL, it inserted literally "$1". So I am a bit confused by your second statement. Boghog (talk) 13:59, 29 October 2024 (UTC)[reply]
@Boghog I've had little experience with regex searches but when I tried your original "\1" version this was the diff, which I reverted as it had added the "\" into the output. I then looked at the table in Regular_expression#Examples, where the second row on bracketed groups says that $1 can be used "later" to refer to the matched pattern. I then used the $ version successfully. My instinct is always to do the experiment and when something works I rarely worry about why it did! That entry in the table does say that some implementations use "\1". Mike Turnbull (talk) 14:41, 29 October 2024 (UTC)[reply]
Such a simple solution. Thanks Boghog and Mike Turnbull. Saved an otherwise huge amount of work. – 76.174.0.57 (talk) 21:08, 29 October 2024 (UTC)[reply]

Contra TAAR1 agonism as the mediator of amphetamine actions

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It is widely stated or implied across the English Wikipedia that amphetamine and related monoamine releasing agents (MRAs) induce their effects by agonism of the trace amine-associated receptor 1 (TAAR1). This notion is generally presented as fact and is stated in many relevant Wikipedia articles (e.g., amphetamine, methamphetamine, dextroamphetamine, Adderall, lisdexamfetamine, MDMA, stimulant, trace amine, TAAR1, etc.). It is even presented in figures (e.g., Template:Amphetamine pharmacodynamics).

The promotion of this theory seems to have originated with User:Seppi333, who has done a large amount of seemingly excellent work on the amphetamine and related articles. User:Seppi333 cites studies published in the 2000s by Xie and Miller and colleagues who found that monoamine transporter (MAT) reversal and monoamine efflux induced by phenethylamine and amphetamines was dependent on TAAR1 activation in-vitro.[1][2][3][4] These findings would appear to substantiate the theory.

While I respect and appreciate User:Seppi333 and his hard work on the amphetamine-related content on Wikipedia, I have strong reservations about the TAAR1 activation theory and the widespread promotion of this theory on Wikipedia. The reasons for this are numerous, and include the following:

  • TAAR1 is non-essential for amphetamine actions in vitro and in vivo: Amphetamines and other MRAs continue to induce monoamine efflux and other MRA-type actions like DAT internalization in vitro in human embryonic kidney 293 (HEK293) cells transfected with MATs.[5][6][7][8][9][10][11][12] This is notable as these non-neuronal cells do not express the TAAR1.[5] Likewise, amphetamines continue to increase monoamine release and produce stimulant-type behavioral effects in vivo in TAAR1 knockout mice (more on that below).[13][14][15]
  • Many MRAs do not activate TAAR1 or do so very weakly: There are many MRAs that do not activate the human TAAR1 (EC50 > 30 μM). These include methcathinone, mephedrone, flephedrone, brephedrone, ephedrine, 4-methylamphetamine, PMA, 4-MTA, MDEA, MBDB, 5-APDB, 5-MAPDB, mCPP, TFMPP, and methylhexanamine (DMAA), among others.[16][5] Hence, TAAR1 agonism again appears to be non-essential for induction of monoamine release by MRAs. In addition, many amphetamines that do act as TAAR1 agonists, including amphetamine, methamphetamine, and MDMA, only activate the human TAAR1 at micromolar concentrations that are far higher than their nanomolar potencies for inducing monoamine release in vitro, and hence may not be pharmacologically relevant in humans.[16][17] Also, in contrast to many other MRAs acting as TAAR1 agonists, MDA and MDMA are notable in actually being weak partial agonists of the human TAAR1 (Emax ≈ 11–26%). As such, they seem more likely to be antagonist-like than agonist-like at the TAAR1.[16][18]
  • TAAR1 signaling is antidopaminergic and anti-reinforcing: TAAR1 activation robustly inhibits the striatal dopaminergic and rewarding effects of amphetamines and of other reinforcing drugs like cocaine, opioids, and alcohol.[3][19][20][21][22][23][24] This has been shown with TAAR1 agonists[25][26] and with TAAR1 overexpression.[27] Moreover, TAAR1 knockout mice are supersensitive to the monoamine release and behavioral effects of stimulants and MDMA.[13][15][14][28] Accordingly, TAAR1 agonists like ulotaront do not have amphetamine-like effects in animals and show no misuse potential.[29] In addition, TAAR1 agonism produces robust aversive effects in animals.[30][31] Relatedly, it has been proposed that TAAR1 agonism by amphetamines serves to auto-inhibit and constrain their effects.[14] It has also been suggested by some researchers that lack of TAAR1 agonism with cathinones like mephedrone may enhance their reinforcing effects relative to amphetamines.[32] Due to their antidopaminergic and hence antipsychotic-like effects, TAAR1 agonists like ulotaront are being studied for treatment of schizophrenia and have reached late-stage clinical trials for this indication.[33][34] Similarly, TAAR1 agonists are being investigated for potential antagonistic therapy of psychostimulant addiction.[35][20][24]
  • Experts on MRAs do not implicate TAAR1 signaling: Major literature reviews by top experts on MRAs, such as Richard B. Rothman and David J. Heal, state that the mechanism by which amphetamines induce monoamine release is unknown or poorly understood, and do not implicate TAAR1 activation.[36][37][38][39] Rothman and his group are notable in being prominent NIDA researchers and in having developed the major in-vitro assay that is used to evaluate the releasing actions of MRAs.[40] In my experience, it has been hard to find secondary source literature in general that presents TAAR1 activation as mediating amphetamine or MRA actions. It would seem to be an obscure idea in the literature.
  • An expert critiques Wikipedia's TAAR1 MRA theory: Matthew Baggott, a major MDMA researcher, founder of Tactogen (a company developing novel MDMA-like MRAs as medicines), and collaborator with the Rothman/NIDA group, has criticized and discounted Wikipedia's TAAR1 theory of MRA action on social media.[41][18][42][17][43] He has provided various arguments against it in his posts, including several of the above points. The following quote gives an idea: "My take is that TAAR1 agonism is misunderstood, especially on Wikipedia, and it decreases the effects of stimulants. TAAR1 knockout mice have increased effects of stimulants (eg here) while mice that overexpress TAAR1 have less sensitivity (eg here). A TAAR1 agonist is potentially a novel way to decrease dopamine activity."[41]

I should note that TAAR1 agonism paired with concomitant uptake by MATs (i.e., MAT substrate activity) is a key part of the TAAR1 MRA theory and might help to explain differences between non-MRA TAAR1 agonists and amphetamine-type MRAs acting as TAAR1 agonists.[4] (The TAAR1 is an intracellular receptor, and uptake by MATs would in theory result in more potent activation of TAAR1 in the subset of neurons that co-express TAAR1 and MATs.) However, this still does not seem to account for many of the other findings that contradict the theory described above.

I have had reservations and suspicions about the TAAR1 and MRAs theory here on Wikipedia for years. However, I'm not an expert in this subject area and I thought I might be missing something. As a result, I opted not to raise my concerns. In any case, coming across Matthew Baggott's critiques of the theory on social media finally changed my mind and motivated me to act.

User:Seppi333 and any others, if there is something I'm missing, I'm open to being enlightened. But, considering all of the above, I don't think I'm wrong here. It appears to me that TAAR1 agonism may modulate the effects of MRAs, and theoretically might play some role in monoamine release induction in the case of some MRAs (per those Xie/Miller et al. in-vitro studies). However, it seems that the available research is overall strongly in conflict with the idea that TAAR1 activation is responsible or essential for monoamine release induced by amphetamine or MRAs generally.

Based on the above, I propose that a major clean up of the relevant content on Wikipedia may be in order.

Also pinging User:Professional Crastination, since they have done some editing on the relevant pages as well and may have input.

Thank you. – AlyInWikiWonderland (talk, contribs) 10:45, 13 December 2024 (UTC)[reply]

Wikipedia doesn’t suggest TAAR1 is a mediator of the mode of action of MRAs, but hey if you want to dispute the fact that it’s not central to amphetamine’s pharmacology, I’ll make you and “Matthew Baggott” look like retards. Never call me out like this again. Seppi333 (Insert 2¢) 22:02, 13 December 2024 (UTC)[reply]

References

  1. ^ Xie Z, Miller GM (July 2009). "A receptor mechanism for methamphetamine action in dopamine transporter regulation in brain". J Pharmacol Exp Ther. 330 (1): 316–25. doi:10.1124/jpet.109.153775. PMC 2700171. PMID 19364908.
  2. ^ Xie Z, Miller GM (May 2008). "Beta-phenylethylamine alters monoamine transporter function via trace amine-associated receptor 1: implication for modulatory roles of trace amines in brain". J Pharmacol Exp Ther. 325 (2): 617–28. doi:10.1124/jpet.107.134247. PMID 18182557. We confirmed that TAAR1 was activated by trace amines and demonstrated that TAAR1 activation by β-PEA significantly inhibited uptake and induced efflux of [3H]dopamine, [3H]norepinephrine, and [3H]serotonin in transfected cells. In brain synaptosomes, β-PEA significantly inhibited uptake and induced efflux of [3H]dopamine and [3H]serotonin in striatal and [3H]norepinephrine in thalamic synaptosomes of rhesus monkeys and wild-type mice, but it lacked the same effects in synaptosomes of TAAR1 knockout mice.
  3. ^ 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): 164–76. doi:10.1111/j.1471-4159.2010.07109.x. PMC 3005101. PMID 21073468.
  4. ^ a b Lewin AH, Miller GM, Gilmour B (December 2011). "Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class". Bioorganic & Medicinal Chemistry. 19 (23): 7044–7048. doi:10.1016/j.bmc.2011.10.007. PMC 3236098. PMID 22037049. While our data suggest a role for TAAR1 in eliciting amphetamine-like stimulant effects, it must be borne in mind that the observed in vivo effects are likely to result from interaction with both TAAR1 and monoamine transporters. Thus it has been shown that the selective TAAR1 agonist RO5166017 fully prevented psychostimulant-induced and persistent hyperdopaminergia-related hyperactivity in mice.42 This effect was found to be DAT-independent, since suppression of hyperactivity was observed in DAT-KO mice.42 The collected information leads us to conclude that TAAR1 is a stereoselective binding site for amphetamine and that TAAR1 activation by amphetamine and its congeners may contribute to the stimulant properties of this class of compounds. [...] it has been shown that β-PEA and methamphetamine effects in cells expressing TAAR-DAT significantly exceed those observed in cells expressing DAT only. Consistent with this conclusion is the higher potency of (S)-[amphetamine] in rat synaptosomes relative to cloned human DAT cells (EC50 60 nM vs 240 nM).
  5. ^ a b c Small C, Cheng MH, Belay SS, Bulloch SL, Zimmerman B, Sorkin A, Block ER (August 2023). "The Alkylamine Stimulant 1,3-Dimethylamylamine Exhibits Substrate-Like Regulation of Dopamine Transporter Function and Localization". J Pharmacol Exp Ther. 386 (2): 266–273. doi:10.1124/jpet.122.001573. PMC 10353075. PMID 37348963. [...] a proposed intracellular target for amphetamine is the [TAAR1], a [GPCR] that is expressed on intracellular membranes in DA neurons (Miller, 2011). Phenethylamine stimulants have been proposed to activate TAAR1, leading to increased cAMP generation and RhoA activation, with subsequent enhancement of DAT reverse transport and endocytosis (Xie and Miller, 2007, 2008, 2009; Underhill et al., 2021). Methamphetamine-induced DAT endocytosis was found to be dependent on TAAR1 expression and PKA activity as suggested by use of the kinase inhibitor H89 (Xie and Miller, 2009). However, evidence indicating that amphetamine-induced endocytosis is independent of TAAR1 includes 1) HEK-293 cells do not express TAAR1 (Reese et al., 2007; Xie and Miller, 2007) but do exhibit amphetamine-induced DAT endocytosis [present studies and (Saunders et al., 2014; Cheng et al., 2015; Wheeler et al., 2015)]; 2) cAMP and PKA activation, which are stimulated by TAAR1, antagonized amphetamine-induced DAT endocytosis in heterologous cells and DA neurons [present studies and (Wheeler et al., 2015)]; and 3) in cell lines and rodent striatal synaptosomes, PKA activation increased DAT Vmax, consistent with increased plasma membrane expression (Pristupa et al., 1998; Page et al., 2004; Batchelor and Schenk, 2018). Additionally, DMAA induced DAT endocytosis (Figs. 3 and 4) despite exhibiting no activity at human TAAR1 in receptor binding studies (Rickli et al., 2019). Therefore, although some evidence does support a role of TAAR1 in modulating amphetamine-induced DAT endocytosis, the present studies suggest that DMAA and amphetamine promote DAT endocytosis through a TAAR1-independent mechanism
  6. ^ Simmler LD, Buser TA, Donzelli M, Schramm Y, Dieu LH, Huwyler J, Chaboz S, Hoener MC, Liechti ME (January 2013). "Pharmacological characterization of designer cathinones in vitro". Br J Pharmacol. 168 (2): 458–70. doi:10.1111/j.1476-5381.2012.02145.x. PMC 3572571. PMID 22897747.
  7. ^ Wilhelm CJ, Johnson RA, Eshleman AJ, Janowsky A (February 2006). "Hydrogen ion concentration differentiates effects of methamphetamine and dopamine on transporter-mediated efflux". J Neurochem. 96 (4): 1149–59. doi:10.1111/j.1471-4159.2005.03611.x. PMID 16417578.
  8. ^ Hasenhuetl PS, Bhat S, Mayer FP, Sitte HH, Freissmuth M, Sandtner W (March 2018). "A kinetic account for amphetamine-induced monoamine release". J Gen Physiol. 150 (3): 431–451. doi:10.1085/jgp.201711915. PMC 5839721. PMID 29439119.
  9. ^ Simmler LD, Rickli A, Schramm Y, Hoener MC, Liechti ME (March 2014). "Pharmacological profiles of aminoindanes, piperazines, and pipradrol derivatives". Biochem Pharmacol. 88 (2): 237–44. doi:10.1016/j.bcp.2014.01.024. PMID 24486525.
  10. ^ Rickli A, Kopf S, Hoener MC, Liechti ME (July 2015). "Pharmacological profile of novel psychoactive benzofurans". Br J Pharmacol. 172 (13): 3412–25. doi:10.1111/bph.13128. PMC 4500375. PMID 25765500.
  11. ^ Dunlap LE, Andrews AM, Olson DE (October 2018). "Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine". ACS Chem Neurosci. 9 (10): 2408–2427. doi:10.1021/acschemneuro.8b00155. PMC 6197894. PMID 30001118.
  12. ^ Jîtcă G, Ősz BE, Tero-Vescan A, Vari CE (March 2021). "Psychoactive Drugs-From Chemical Structure to Oxidative Stress Related to Dopaminergic Neurotransmission. A Review". Antioxidants (Basel). 10 (3): 381. doi:10.3390/antiox10030381. PMC 8000782. PMID 33806320.
  13. ^ a b Lindemann L, Meyer CA, Jeanneau K, Bradaia A, Ozmen L, Bluethmann H, Bettler B, Wettstein JG, Borroni E, Moreau JL, Hoener MC (March 2008). "Trace amine-associated receptor 1 modulates dopaminergic activity". J Pharmacol Exp Ther. 324 (3): 948–56. doi:10.1124/jpet.107.132647. PMID 18083911.
  14. ^ a b c Espinoza, Stefano; Gainetdinov, Raul R. (2014). "Neuronal Functions and Emerging Pharmacology of TAAR1". Taste and Smell. Vol. 23. Cham: Springer International Publishing. p. 175–194. doi:10.1007/7355_2014_78. ISBN 978-3-319-48925-4.
  15. ^ a b Achat-Mendes C, Lynch LJ, Sullivan KA, Vallender EJ, Miller GM (April 2012). "Augmentation of methamphetamine-induced behaviors in transgenic mice lacking the trace amine-associated receptor 1". Pharmacol Biochem Behav. 101 (2): 201–7. doi:10.1016/j.pbb.2011.10.025. PMC 3288391. PMID 22079347.
  16. ^ a b c Simmler LD, Buchy D, Chaboz S, Hoener MC, Liechti ME (April 2016). "In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1". J Pharmacol Exp Ther. 357 (1): 134–44. doi:10.1124/jpet.115.229765. PMID 26791601.
  17. ^ a b u/MBaggott (13 December 2024). "[Comment(s)]". Reddit. Retrieved 13 December 2024. I think TAAR1 simulation reduces the effects of stimulants and may not be important for many drugs in humans since potency at human TAAR1 is often much lower than at rodent TAAR1. Whatever the actual mechanism, you can model amphetamine induced release pretty well while ignoring changes in Na and Ca ions, as in work by Hasenhuetl and colleagues.
  18. ^ a b u/MBaggott (13 December 2024). "[Comment(s)]". Reddit. Retrieved 13 December 2024. "TAAR1 agonism is in fact the target through which they release these monoamines" [...] Coming at this as someone who mostly studies MDMA-like drugs, I don't think this can be completely correct, assuming we count MDMA as an amphetamine. First, MDMA is essentially inactive at hTAAR1 but releases and inhibits uptake of DA, 5-HT, and NE. Second, you see reuptake inhibition in DAT expressed in HEK or CHO and it seems unlikely to me that TAAR is as expressed in these cells as in neurons, although maybe. [...] I don't dispute that amphetamines are releasers and substrates for these monoamine transporters and that once inside the cell many of them interact with VMAT (though maybe cathinones are an exception) and TAAR (though MDMA seems to interact with rat TAAR1 but not human TAAR1). I do think there is compelling evidence that VMAT and TAAR1 interactions are not universal and are inconsistent among amphetamines.
  19. ^ Liu JF, Li JX (2018). "TAAR1 in Addiction: Looking Beyond the Tip of the Iceberg". Front Pharmacol. 9: 279. doi:10.3389/fphar.2018.00279. PMC 5881156. PMID 29636691.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  20. ^ a b Wu R, Liu J, Li JX (2022). "Trace amine-associated receptor 1 and drug abuse". Adv Pharmacol. 93: 373–401. doi:10.1016/bs.apha.2021.10.005. PMC 9826737. PMID 35341572.
  21. ^ Liu J, Seaman R, Johnson B, Wu R, Vu J, Tian J, Zhang Y, Li JX (February 2021). "Activation of trace amine-associated receptor 1 selectively attenuates the reinforcing effects of morphine". Br J Pharmacol. 178 (4): 933–945. doi:10.1111/bph.15335. PMC 8758336. PMID 33247948.
  22. ^ Cotter R, Pei Y, Mus L, Harmeier A, Gainetdinov RR, Hoener MC, Canales JJ (2015). "The trace amine-associated receptor 1 modulates methamphetamine's neurochemical and behavioral effects". Front Neurosci. 9: 39. doi:10.3389/fnins.2015.00039. PMC 4327507. PMID 25762894.{{cite journal}}: CS1 maint: unflagged free DOI (link)
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  40. ^ "Monoamine releasing agent". Wikipedia. 7 April 2009. Retrieved 13 December 2024.
  41. ^ a b u/MBaggott (13 December 2024). "[Comment(s)]". Reddit. Retrieved 13 December 2024. My take is that TAAR1 agonism is misunderstood, especially on Wikipedia, and it decreases the effects of stimulants. TAAR1 knockout mice have increased effects of stimulants (eg here) while mice that overexpress TAAR1 have less sensitivity (eg here). A TAAR1 agonist is potentially a novel way to decrease dopamine activity. [...] In general, TAAR1 agonism by stimulants seems to decrease DAT functioning. This may increase extracellular DA vs a no drug control and also decrease extracellular DA vs the stimulant alone. After all, stimulant effects require DAT while normal DA release doesn't. [...] TAAR1, which is localized inside the cell, can be stimulated by amphetamines that have entered the cell, leading to increased RhoA activity inside the cell. RhoA causes internalization of DAT, which obviously decreases the effects of amphetamines. TAAR1 varies significantly between species and stimulants are often less potent at human TAAR1 than at mouse TAAR1. Some stimulants do not seem to affect human TAAR1, even at high concentrations (30uM or more).
  42. ^ u/MBaggott (13 December 2024). "[Comment(s)]". Reddit. Retrieved 13 December 2024. "All monoamine releasers will cause serotonin release. Binding to TAAR1 is how they all work." [...] Sorry but this doesn't make any sense to me (a neuroscientist running a company that develops monoamine releasers). TAAR1 may play some role, but mice that lack it still have DA and 5-HT release from releasers like MDMA and tons of amphetamine relatives don't seem to interact with TAAR1 at physiologically plausible concentrations (and there are important species differences). See eg Simmler et al.
  43. ^ u/MBaggott (13 December 2024). "[Comment(s)]". Reddit. Retrieved 13 December 2024. Yes, much of drug-related wikipedia and much of reddit falls prey to people who have pieced together specific, questionable theories. At best these are passionate amateurs; at worst these people are selling you something, usually supplements. In most cases, they're in over their heads and engaged in motivated reasoning. The truth is that it's really hard to fully understand the field if you haven't run some of these assays yourself and talked to researchers at conferences where you hear about unpublished failures-to-replicate. AlyInWikiWonderland note: This was not specifically about MRAs but about another topic, and I didn't include it here to be inflammatory. But he may also be referring to TAAR1 and MRAs per his other comments, and just wanted to highlight his general critiques about Wikipedia.
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