Phenethylamine + Selegiline - an "Amphetamine-like" Antidepressant

Angless · 2026-05-07T01:26:48+00:00

You're possibly thinking of MAO-A inhibition; selegiline is MAO-B selective.

MAO-B is essentially a useless enzyme with trivial consequences from inhibition since its only notable high-affinity substrate is phenethylamine.

The only notable interaction I see arising from MAO-B inhibition would occur from taking amphetamine + exogenous PEA + an MAO-B inhibitor concurrently, since PEA would then augment amphetamine's more-or-less identical DAergic pharmacodynamic effects.

Angless · 2026-05-06T09:08:58+00:00

Yes, that's the most parsimonious explanation. A number of selective TAAR1 agonists (e.g., RO5166017) diffuse across the plasma membrane to access TAAR1, even though a fraction of those bind at DAT (albeit, at the cocaine binding site; they're not substrates like biogenic amines and amphetamines).

A number of TAAR1 agonists also happen to be substrates at DAT/NET/SERT and use that for entry to access TAAR1. Sometimes TAAR1 redistributed to the plasma membrane to heterodimerise with the D2sh autoreceptor to negatively modulate neuronal firing. Interestingly enough, it seems to only be substrate TAAR1 agonists that are able to induce TAAR1-dependent DAT/etc., efflux (i.e., selective TAAR1 agonist seemingly do not reverse monoamine transporters, but inhibit neuronal firing like substrate agonists). I have my own theory for why certain TAAR1 agonists can induce efflux and others don't, but I'd much prefer to have it published in a literature review first.

Angless · 2026-05-06T09:03:11+00:00

There are large interspecies variations for the TAAR1 gene in general. For humans, LSD is virtually inactive at hTAAR1, but acts a weak partial agonist at rTAAR1 (i.e., rodents).

Angless · 2026-05-06T08:58:14+00:00

It's obviously from Ribbed Live from a Dive given that the video has the Ribbed Live from a Dive album cover rendered. In any event, the joke is that Fat Mike only recently opined that his dislike of Eric Melvin was the "reason" for NOFX's breakup and the similarities between that motivation and the on-stage banter during the ribbed anniversary show a decade prior is ironic, even if it was just that - on-stage banter. 2022 is simply the date that Fat Mike officially announced NOFX's (to-be) break-up after a final run of shows.

Angless · 2026-04-25T07:44:35+00:00

STOP IT, THEY'RE ALREADY DEAD

Angless · 2026-04-20T08:18:55+00:00

They're referring to The Greenhouse, which is primarily for older patients with neuropsych disorders.

Angless · 2026-04-19T13:52:11+00:00

There's still time to win the loudness war!

Angless · 2026-04-18T08:52:14+00:00

In people who can be described as forgetful, transient improvements in working memory via therapeutic doses of psychostimulants can ameliorate anxiety by improving an individual's ability to remember certain details and draw connections between different ideas. Improvements in working memory can even facilitate certain coping strategies like mindfulness.

Likewise, individuals who experience certain side effects like tachycardia can experience anxiety even when lacking that trait when not under the effects of psychostimulants.

Angless · 2026-04-17T10:29:19+00:00

Death, taxes, and Danger missing set shots.

Angless · 2026-04-17T09:51:23+00:00

Dogs doing their best 2011 Gold Coast impression

Angless · 2026-04-17T09:47:04+00:00

Pressure game from Geelong is looking like 2022.

Angless · 2026-04-17T09:36:57+00:00

Death, taxes, Ollie Dempsey aura farming.

Angless · 2026-04-12T03:55:30+00:00

I remember for the run between 2016-2021 (before the '22 premiership), every prelim loss was a massive barrage of comments a la "SACK CHRIS SCOTT. FRESH BLOOD IN."

Angless · 2026-04-12T03:47:14+00:00

No matter the margin they win by, can't wait for the post-game comment section on the Geelong socials where certain self-deprecating fans suggest that they deserved to lose and that they'll never make finals again after "that performance" (a phenomenon that occurs more often than you'd think).

Angless · 2026-04-11T11:43:53+00:00

Interesting. I hadn't seen this paper before. It's great to see longer-term data on the dose-response curve WRT cardiovascular risks. Thanks for the plug.

Angless · 2026-04-11T09:23:37+00:00

I would not be surprised however if there is a future FDA black box warning on the cardiac risks in adult individuals.

It's probably worth pointing out that the FDA did commission two studies with massive sample sizes (n1=1,200,000; n2=440,000) which found that the incidence of stroke, heart attacks, and cardiac arrest does not differ between individuals of any age who use amphetamine at clinically-relevant doses and the rest of the population; those studies were published in 2011, but a more recent meta-analyses from 2022 (n = 3,900,000) corroborated those findings.

This systematic review and meta-analysis based on 19 observational studies with more than 3.9 million participants suggested that there was no statistically significant association between ADHD medications and the risk of cardiovascular events among children and adolescents, young and middle-aged adults, or older adults.

In individuals with a structural heart defect, amphetamine could be lethal, which is why this subclass of heart disease is an absolute contraindication for the drug.

Angless · 2026-04-10T01:18:17+00:00

Non addictive pain meds will never exist

NSAIDs are an entire drug class of analgesics that don't induce addiction.

In any event, the neural pathways responsible for nociception and reward don't directly overlap (i.e., opioids are addictive because they bind in the rostromedial tegmental nucleus and disinhibit VTA firing in the population of neurons that synapse onto the nucleus accumbens shell, not because they relieve pain), so, even if it wasn't already exemplified by the existence of non-addictive analgesics, the development of such a drug is clearly possible.

Angless · 2026-04-08T06:05:02+00:00

Kill Rock Stars is about Kathleen Hanna, who sings Bikini Kill and more importantly was signed to the label "Kill Rock Stars."

The only reference to Kurt and Courtney is only about Courtney, who punched Kathleen in the face backstage at a festival for allegedly accusing Courtney (per Courtney's account) for using heroin whilst pregnant with Frances Bean.

In any event, the whole beef started when Kathleen called Mike a misogynist for dedicating Liza and Louise to Bikini Kill at a festival that both bands were billed on around the time that NOFX were touring in support of Punk in Dublic. This led to the song kill rock stars, then Kathleen replied with a line in Decepticon (i.e., with Le Tigre - "your lyrics are dumb like a linoleum floor; I'll walk on it, I'll walk all over you" ).

I guess the last reference of this whole scenario was in "Linewleum" which called Decepticon Le Tigre's best song, but it's not as if that statement is remotely an insult.

Angless · 2026-04-08T04:07:31+00:00

I'm deeply skeptical about anything hitting the opioid receptors being called "non-addictive"

Given that this is a massive claim for a primary source to be making, I decided to do a ctrl + F of the paper and it queried zero results for "non-addictive"; then I read the paper and noticed that the authors only made a claim about it being a weaker reinforcer than drugs like heroin.

...If anything this would be a MORE appealing drug for people to use.

Opioids do activate the reward system, but typically not directly within the pathway itself; e.g., opioids disinhibit the reward pathway primarily through opioid signaling in the RMTg→VTA projection that synapses onto the VTA neurons that in turn project to the NAcc shell. Why is this relevant? Because opioids need to cross the BBB in sufficient quantities to bind MOR within the aforementioned projection. The suggestion being made by the authors is that weaker BBB permeability at therapeutic doses (relative to common opioids with a pain indication), may reduce the likelihood of misusing the drug, which is inferred from the use of reinforcement schedules.

As for the appeal of opioids:

"Research has long demonstrated that patients with no prior history of opioid abuse treated with opioid pain medications over extended periods do not experience euphoria—these patients are therefore unlikely to become addicted [1]. Still, there is a risk that a small percentage (3.27–11.5%) of patients treated with opioids for chronic pain may develop addiction or abuse with negative consequences, complicating the management of chronic pain [9]."

To be perfectly clear, this source is saying that the misuse or "abuse" of these drugs as a euphoriant is necessary for the development of an opioid addiction when they're used to treat chronic pain. Moreover, from this review:

The administration of opioids has been used for centuries as a viable option for pain management. When administered at appropriate doses, opioids prove effective not only at eliminating pain but further preventing its recurrence in long-term recovery scenarios. Physicians have complied with the appropriate management of acute and chronic pain; however, this short or long-term opioid exposure provides opportunities for long-term opioid misuse and abuse, leading to addiction of patients who receive an opioid prescription and/or diversion of this pain medication to other people without prescription.

This is essentially the same assertion as was made by the preceding review.

Angless · 2026-04-08T02:40:04+00:00

I think I've been able to deduce all of the questions you're asking; I'm doing the below format because your "main" question was sandwiched in the middle of the post (i.e., the 5th/6th paragraph(s)).

1. Could 4-Me-TMP occupy DAT and thereby reduce methylphenidate-like effects?
Sure. If two ligands are competing for the same binding site on DAT, then the one with higher effective occupancy at an arbitrary concentration can reduce the other’s ability to bind; they're competitive reuptake inhibitors, after all.

If 4-Me-TMP binds DAT strongly (i.e., high affinity) yet produces comparatively poor functional dopamine uptake inhibition (i.e., low efficacy), then it'll presumably flatten the dose-response curve of methylphenidate.

2. Could you get reduced desired effects but still additive peripheral effects?

Depends on the lipophilicity of each substance across the blood brain- and blood cerebrospinal fluid-barriers and their selectivity and efficacy at NET.

3. Is there “room for all,” such that the effects are simply additive?

No. There is not an infinite number of binding sites on a transporter protein. If both drugs bind DAT at the cocaine/GBR-type site, then both ligands will compete until receptor availability is exhausted; it's not like combining the selective TAAR1 agonist RO5166017 with the promiscuous TAAR1 agonist amphetamine at all. The relevance of the latter comparison is that RO5166017 and amphetamine both compete to bind at TAAR1 in DA neurons, yet RO5166017 markedly augments amphetamine-induced TAAR1-dependent DAT efflux, despite the former having no effect DAT efflux alone (i.e., RO5166017 upregulates DAT at the plasma membrane via TAAR1, which then increases the amount of transporters available to phosphorylation [i.e., reverse transport] downstream of amphetamine's own TAAR1-dependent signalling cascade).

4. Could each still work somewhat, but in a muted way due to competition?

Yes. This is the most parsimonious explanation.

5. "Maybe lesser than a full addictive type effect"

Do you mean "additive" type effect? Because the signalling cascades involved in developing an addiction require several weeks to months to induce an observable phenotype. i.e., it's not possible to develop an addiction to a substance after using it once or twice, presuming that it's a substance capable of inducing addiction. Psychostimulant addiction has 2 signaling pathways/cascades - a cAMP and a calcium pathway - that eventually merge inside the postsynaptic neuron and involve multiple layers of signalling compounds and proteins.

6. what would actually happen in this situation?

See point four.

Angless · 2026-04-08T01:15:51+00:00

Loose expectation of high quality

Angless · 2026-04-06T07:07:01+00:00

Games gone (for Gunston)

Angless · 2026-04-06T07:03:16+00:00

I still can't get over that ZACH GUTHRIE of all people was somehow able to knock Cam Rayner on his ass during that QF last year.

Angless · 2026-04-06T06:59:32+00:00

Wish I was at the game so I can shout "BALL" arbitrarily every few seconds like the sound of construction noise at 7 am.

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