Fenethylline

[serotonin2A]

There are a few companies that are actively working on development of psychedelic drugs. They aren't large drug companies -- they would almost certainly never recoup their investment. I know that people like to bash big-pharma, but they wouldn't survive if they invested in research programs that will never make any profit.

Physicians who want to prescribe a psychedelic will probably have to receive special training. The regulations probably wouldn't dictate the specific environment, but the training program would outline best practices, and physicians who deviate considerably from those norms would potentially put themselves in professional and legal jeopardy.

 

[Cotcha Yankinov]

I see... It seems like a psychedelic used monthly to hold someone's depression at bay or used twice in a cancer patient would have little potential for profit, but if the regulations may not dictate a particular psychotherapeutic environment, perhaps there is potential for recouping investment with daily microdosing?

Is it going to be more economically viable for a small drug company to bring a psychedelic to market as opposed to a big drug company (maybe small companies aren't as affected by lawsuits following side effects of their drugs?), or are the smaller companies just more able to accept a loss of profit and not have their shareholders bail?


Are there any particular compounds that show promise? I'm curious about the optimal functional selectivity/receptor affinity...

 

[serotonin2A]

The studies to date indicate that the therapeutic effects of psilocybin are linked to mystical experiences. So microdosing would not be effective in the current therapeutic model. More importantly, I think there is a general perception that chronic dosing with a 5-HT2B agonist should be avoided.

The individuals/companies trying to develop this treatment are doing so because they want to help people and their primary motivation is not to make money.

No one will probably start looking at other compounds until psilocybin is approved.

 

[Cotcha Yankinov]

I could certainly see mystical experiences playing a critical role in helping cancer patients and such, but do you think that microdosing a psychedelic ligand with negligible 5-HT2B activity would have use in conditions involving default mode network dysregulation/rumination? Maybe the decrease of DMN strength noted with LSD is only at real doses, and an opposite effect may be noted at lower doses?

Has microdosing ever been examined outside of an informal setting? I just hear lots of anecdotal success stories.

 

[serotonin2A]

I'm skeptical whether there is such a thing as default mode network rumination -- I definitely wouldn't say they have unequivocally proven that their interpretation is correct.

But assuming that their interpretation about psychedelic effects and the DMN is correct, then it is important to consider that the psychedelic effects of psilocybin and LSD are a direct consequence of DMN inhibition. Given that fact, microdosing would do nothing for depression because non-psychedelic doses do not disrupt the DMN.

Placebos work about 30% of the time in antidepressant studies. LSD is an extremely potent psychoactive drug that can produce a range of effects at low doses that some depressed individuals may feel is beneficial (alertness, reduction of fatigue, altered affect). However, I'm not sure that makes LSD any more of an antidepressant than low doses of amphetamine.

 

[Cotcha Yankinov]

Re: "I'm skeptical whether there is such a thing as default mode network rumination"

Are you not convinced that the DMN or a "socio-affective self referential" circuit plays a role in mediating rumination, or just that psychedelics may not be effective specifically because of their effects on the DMN?

It seems really hard to rule out the "low dose of amphetamine improving depression" kind of scenario with low doses of psychedelics. But maybe decreasing the rumination for a few months (even with a placebo) can allow for some synaptic remodeling?


"But assuming that their interpretation about psychedelic effects and the DMN is correct, then it is important to consider that the psychedelic effects of psilocybin and LSD are a direct consequence of DMN inhibition."

I'm confused, are you saying that the psychedelic effects are downstream of the DMN inhibition, or just that if their interpretation is correct then the psychedelic effects are downstream of the DMN inhibition?

I guess an alternative theory is that the DMN inhibition is downstream of the psychedelic experience, and that the noted correlation between the strength of subjective effects, the decrease in DMN power and decreased "returns to the past" are causally linked with a chain of "subjective effects -> DMN inhibition -> decreased return to the past". Although I suppose they could all intertwine a bit.


I'm mostly reading into this particular study https://www.ncbi.nlm.nih.gov/m/pubmed/26979587/

"Consistent with the previously proposed role of the default-mode network (DMN) in autobiographical memory recollection and ruminative thought, decreased resting-state functional connectivity (RSFC) within the DMN correlated with decreased mental time travel to the past.

These results are discussed in relation to potential therapeutic applications of LSD and related psychedelics, e.g. in the treatment of depression, for which excessive reflection on one's past, likely mediated by DMN functioning, is symptomatic."

 

[serotonin2A]

^ fMRI measures blood flow and blood oxygenation. fMRI studies make an assumption that these measures can be used as a readout of neural activity, but not everyone is convinced that fMRI is actually indirectly measuring neural firing. Adding psilocybin to the mix makes the situation even worse because it has direct vascular effects and seems to decouple blood flow regulation from neural activity. Furthermore, the DMN proponents are making certain assumptions, which may not be accurate, about the mental state of subjects undergoing resting state fMRI scans.

The group performing resting state fMRI studies with psilocybin and LSD have proposed that the psychedelic effects occur because the DMN is inhibited. Based on their interpretation, the psychedelic effects cannot be downstream from the DMN, otherwise the entire concept of the DMN becomes meaningless. If the therapeutic effects of psilocybin and LSD stem from DMN inhibition and a resulting increase in network entropy, then microdosing would not mimic the therapeutic effects because sub-threshold doses are inherently too low to alter DMN function (otherwise they would be active doses).

 

[Cotcha Yankinov]

Thanks for the explanations.

So if we put aside fMRI imaging while a patient is presently on a psychedelic and instead consider a controlled study utilizing pre-treatment + post-treatment imaging with sufficient time to allow vascular effects to normalize, do you think there may be enlightening findings correlating changes in regional volume/metabolism post-treatment to a decrease in symptoms?

Maybe those findings could be taken into consideration with studies on mindfulness/vipassana or use mindfulness as another arm?

For example, while we still have the issue of whether or not fMRI is a good readout of neural activity, mindfulness neuroimaging may help sort through the direct vascular effects of psychedelics if you consider mindfulness as primarily a method to reduce DMN strength (which is of course an oversimplification, and we're still assuming that fMRI tells us something useful about neural activity).

It would then be interesting if some of the findings in people that meditate translated over to people who used psychedelics, although properly controlled studies would be needed instead of the present findings of ie thicker right anterior insula in people who meditate (although I'm not sure as to how to interpret the causality of the below study, there is a correlation between meditation experience and such changes but it could just be that those people had a tendency towards meditation)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1361002/

I recall one study showed increased volume of BA25 after 6 weeks of mindfulness (in elderly with insomnia), and I think there might be some other studies that hint its really mindfulness making the changes that correlate with improvements. Maybe analogous findings could be shown with psychedelic therapy.

 

[Parabolan]

Analysis of seized captagon pills revealed zero fenethylline presence.. it was amphetamine, meth, ephedrine, caffeine, an antibiotic, an antihistamine, and a coupla anti malaria vaccines.

A small portion of seized pills contained caffeine and ephedrine only..