fluorinated amphetamines' increased toxicity

[hydroazuanacaine]

if you search, google will turn up a lot of results about fluorinated amphetamines being more neurotoxic and/or more cardiotoxic than plain amphetamine. these results are largely reddit posts and the closest thing to a study being cited is talking about a 4-fa study about serotonin neurotoxicity that's never actually linked to and that people argue about the results of.

i recently discovered 2-fa and 2-fma. they are like amphetamine light, and i like them very much. especially 2-fa, which is so cool and gentle it's hard to believe it's an amphetamine. 2-fma is a little bit more like classic dextroamphetamine in that it has some more umph to it, but still not on the same level adderall. so 2-fma is good for when you need the drug to last a few hours while you get something done; 2-fa when your project is only an hour or two. they feel even less toxic than adderall, but i know that doesn't mean anything.

is there any legitimacy to these online repetitions of fluorinated amphetamines being more toxic than amphetamine in general? i realize there is no definite answer because 2-fa and 2-fma have not been studied like amphetamine. i'm hoping people like @sekio could weigh in and let me know if there is a foundation to these rumors that i should look into? or if people are simply repeating what they heard and it's not supported by anything meaningful?

thank you!

 

[polymath]

The dosage in milligrams is higher for fluoroamphetamines than for normal d-amphetamine and d-methamphetamine, so it's more likely to cause other toxic effects in addition to the stimulant effect that they're used for. This could be MDMA-like serotonergic toxicity, 5-HT2B agonism or simply more sympathomimetic side effects compared to the CNS stimulation. Not sure how much this has actually been studied, but there has to be some source where it's shown that 4-FA is not as toxic as the 4-chloro and 4-bromo compounds.

Edit: as another interesting observation, para-chlorotranylcypromine doesn't seem to be neurotoxic, despite inhibiting monoamine oxidase and probably also affecting monoamine release and reuptake.

Effect of 2-(p-chlorophenyl)cyclopropylamine on 5-hydroxyindole concentration and monoamine oxidase activity in rat brain. | Semantic Scholar

Semantic Scholar extracted view of "Effect of 2-(p-chlorophenyl)cyclopropylamine on 5-hydroxyindole concentration and monoamine oxidase activity in rat brain." by R. Fuller et al.

www.semanticscholar.org

 

[checktest]

Here's a study for comparative 4-fa and 4-ca to amp, along with some cathinones, in a liver cell viability assay. Mentions some of the serotonergic toxicity in references. As noted, 2-fa was not included but left for study.

Para-Halogenation Affects Monoamine Transporter Inhibition Properties and Hepatocellular Toxicity of Amphetamines and Methcathinones - PMC

Halogenated derivatives of amphetamine-type stimulants are appearing on the drug market, often with altered pharmacological profile and sometimes different legal status compared to the non-halogenated substances. The aim of the present study was to ...

www.ncbi.nlm.nih.gov

The classification and different types of cell death is interesting, for the limitations of the assay.

Figure - PMC

Halogenated derivatives of amphetamine-type stimulants are appearing on the drug market, often with altered pharmacological profile and sometimes different legal status compared to the non-halogenated substances. The aim of the present study was to ...

www.ncbi.nlm.nih.gov

Same issues. This study didn't even want to give 150 mg doses of 4-fa due to concerns.

Frontiers | Safety Profile and Neurocognitive Function Following Acute 4-Fluoroamphetamine (4-FA) Administration in Humans

Availability of novel psychoactive substances (NPS) exponentially increased over the last years. Risk evaluations of NPS are hampered by the lack of pharmaco...

www.frontiersin.org

More real life cases 4-fa, but prone to misrepresentation due to amount of use.

Redirecting

linkinghub.elsevier.com

I wonder if part of the issue is dose control because of the relative tolerability at a mg basis (or less presence of some effects), leading to off-target effects.

How much is inhibiting monoamine oxidase protective for some neurotoxic/oxidative effects? I mean a lot was based on MPTP

I think they were looking at tranylcypromine derivatives for some oncology purposes because of some demethylase activity.

Definite NET reuptake and minor DA release for tranylcypromine. I was on it and surprised it didn't have much more toxicity. Still curious long term

 

[polymath]

Here's a study for comparative 4-fa and 4-ca to amp, along with some cathinones, in a liver cell viability assay. Mentions some of the serotonergic toxicity in references. As noted, 2-fa was not included but left for study.

Para-Halogenation Affects Monoamine Transporter Inhibition Properties and Hepatocellular Toxicity of Amphetamines and Methcathinones - PMC

Halogenated derivatives of amphetamine-type stimulants are appearing on the drug market, often with altered pharmacological profile and sometimes different legal status compared to the non-halogenated substances. The aim of the present study was to ...

www.ncbi.nlm.nih.gov

Looking at this quote

All substances depleted the cellular ATP content at lower concentrations (0.25–2 mM) than cell membrane integrity loss occurred (≥0.5 mM), suggesting mitochondrial toxicity. The amphetamines and 4-chloromethcathinone additionally impaired the mitochondrial respiratory chain, confirming mitochondrial toxicity. The following toxicity rank order for the para-substituents was observed: chloride > fluoride > hydrogen. In conclusion, para-halogenation of stimulants increases the risk for serotonergic neurotoxicity. Furthermore, para-halogenation may increase hepatic toxicity mediated by mitochondrial impairment in susceptible users.

it seems that the neurotoxicity happens because of this mitochondrial effect after the molecules enter the neuron through the serotonin transporter. The kidney cells in the experiment were artificially modified to contain monoamine transporters, which they otherwise wouldn't have, on their cell membrane. Did I get this correctly?

Edit: para-fluoroamphetamine is also predicted to have more chance of binding to the 5-HT2B receptor than regular amphetamine, as seen in these links:

http://www.swisstargetprediction.ch/result.php?job=308022317&organism=Homo_sapiens (4-FA)

http://www.swisstargetprediction.ch/result.php?job=677455118&organism=Homo_sapiens (AMPH)

 

[checktest]

Sorry for the delay.

Yeah, the human epithelial kidney cells were transformed with hSERT/NET/DAT for the transporter assays, while hepatoma cells were used for toxicity assays (this was more of a liver focus and the ease of some lipid monitoring in liver cells). The hepatoma HepG2 line is not like neurons in many ways, and there are extensive limitations to comparing them to specific neurotoxicity/neuronal effects beyond some general warnings.

This study didn't specifically monitor the amphetamine localization (say a radioisotope of the halogenated amphetamines and marker for transporters....etc....) to say specifically the route you implied, let alone definitive modification and possible mechanisms, but more correlated the toxicity with oxidative stress and lipid indicators, ATP and the like with application of the drugs and relative affinity. The extension of that transport is a possible route.

I'd be curious to see 2-fa and 2-fma in assays like https://www.sciencedirect.com/science/article/abs/pii/S0161813X16300651 as well as extended SAR for them https://www.researchgate.net/public...s_with_Transporter_Binding_Uptake_and_Release

I think I've seen that 1970s paper or whatever OP mentioned, but I don't know whether the techniques used would match modern approaches.

 

[polymath]

^ Thanks. Some other non-neuron type cells seem to contain serotonin transporters, including even the thrombocytes (platelets) in the blood (if those are counted as actual cells).

 

[checktest]

Yeah, I think most of the gut or intestinal mucosa has SERT to react to serotonin released from enterochromaffin cells. Let alone the enteric nervous system. And some cardiopulmonary cells in addition to platelets. Serotonin released in response to hypoxia, etc...

(Sometimes I wonder if part of the cardiac toxicity with some serotonergic agents is akin to a false hypoxia reaction, where stimulation of 5-ht2b and the like with adrenergic co-stimulation sends hearts / valve interstitial cells and some pulmonary cells to recover/grow /overgrow [as a response to perceived hypoxia and stressors] while tamping down on feedback that would limit growth / some cellular differentiation. Trying to push through more because of a reaction to 'hypoxia', even though the heart and early lungs aren't actually suffering some of that. Or recalling early development profiles. Competing vasoconstriction and other effects leading to PAH as well. Idk)

Some liver cells had sert but not quite sure which.

 

[Pfafffed]

Any further research turn up on possible neurotoxicity of fluorinated amphetamines? They're pretty widely used now.

 

[clubcard]

The only thing I can add is that the para position of the benzene ring can be hydroxylated in vivo in the case of amphetamine, that route isn't open to p-F amphetamine. I am interested to know if both isomers are equally toxic because someone handed me a lovely route to the raecemization of this class so resolution does not mean throwing away 50% of the product.

I DID find a reference to an amphetamine bioisostere in which the benzene was replaced by a 4-pyridyl moiety. I couldn't get the paper, sadly, but it would be interesting to know what that N: did.

 

[decalwire]

The dosage in milligrams is higher for fluoroamphetamines than for normal d-amphetamine and d-methamphetamine, so it's more likely to cause other toxic effects in addition to the stimulant effect that they're used for. This could be MDMA-like serotonergic toxicity, 5-HT2B agonism or simply more sympathomimetic side effects compared to the CNS stimulation. Not sure how much this has actually been studied, but there has to be some source where it's shown that 4-FA is not as toxic as the 4-chloro and 4-bromo compounds.

Edit: as another interesting observation, para-chlorotranylcypromine doesn't seem to be neurotoxic, despite inhibiting monoamine oxidase and probably also affecting monoamine release and reuptake.

Effect of 2-(p-chlorophenyl)cyclopropylamine on 5-hydroxyindole concentration and monoamine oxidase activity in rat brain. | Semantic Scholar

Semantic Scholar extracted view of "Effect of 2-(p-chlorophenyl)cyclopropylamine on 5-hydroxyindole concentration and monoamine oxidase activity in rat brain." by R. Fuller et al.

www.semanticscholar.org

View attachment 20960

This is brilliant, you have researched this one better. Thanks for sharing.

 

[clubcard]

Oh, and BTW we tried replacing the alpha methyl position (in old money) with a fluoromethyl with mephedrone, methylone and amphetamine. They all felt toxic at active doses. I would expect the potent 5HT2a ligands related to DOM, DOI, DOC and so on to be fairly safe BUT nobody knows for sure. Didn't Shulgin have some PET scans of deuterated analogues tested and the drug initially goes to the lungs which is odd. It's just a legal loophole in many countries BUT just look at things like Bromo-dragonfly. In Chemoffice I noted that the O of the m-MeO of the class overlaid the O of the amide in LSD. Given that many different substitutions are active (mono sec butyl for 1 example) suggests that space-filling is the reason why the diethylamine moiety is so potent.
Check out BOL-148 since the 2-Br is removed by NaBH4 in 74% yield and DEA itself can be made from DEF & NaOH.

 

[Skorpio]

Don't methoxy oxygens have an electron donating effect when compared to amide (carbonyl) oxygens electron withdrawing effect? If so why is it significant that the methoxy in bromo dragonfly overlays the amide oxygen in LSD?