Thank you for elucidating this paper. Greatly appreciated.
Do we currently have a clear understanding of why different signaling biases result in the various subjective effects of, for example, LSD versus LSA? Or do we only know that this is the case without further insight into how and why it happens?
We don't have a full picture yet no -- the neuron is a complex system embedded in a larger complex system (the cortex), so unravelling these things is extremely difficult. Computational systems biology models are likely to be useful in this regard I think.
In recent years I've occasionally found reports of users ingesting amounts of LSD that are just enormous in comparison to the usual dosage range- amounts measured in milligrams rather than micrograms. Some is anonymous folklore from drug forum websites, including stories about distributors being initiated with a "thumbprint" of pure powder LSD, etc. Jesse Jarnow also includes a story about a young woman well-known as an LSD distributor (complete with Federal trafficking conviction) who related a story of taking such a massive dose once. Robert Hunter had to pull himself together after ingesting an unknown but undoubtedly massive quantity of LSD.
The most verifiable report I found was that of a drug agent who was exposed to a massive amount in a raid and eventually retired on a disability claim. His story is told in the "Hallucinogens" episode of the National Geographic TV program "Drugs, Inc." https://www.imdb.com/title/tt2166771/?ref_=ttep_ep_4
The narration claims that the agent suffered "brain damage" as a result, but no specific details were added. The agent allowed himself to be filmed, and he seemed lucid and communicative during his appearance. He didn't present with an especially disordered affect, either, although it sounded like he was still grappling with some significant HPPD aftereffects. At any rate, in the stories I read, everyone survived without lasting physical impairments, however extravagant or traumatizing the effect on consciousness might have been.
My question is: how might the human brain and body metabolism possibly cope with such a megadose? Is there a ceiling on effect, from neurotransmitter saturation? How long would a >5,000 microgram LSD trip last, in terms of primary effect? Would other aspects of serotonin metabolism be affected, beyond uptake in the brain and brainstem structures?
This does not explain "long LSD" - like long COVID :)
As I rose up the ranks of the scientific and corporate world I started to wonder: where did all the acid heads go? Very few people who regularly dropped acid avoided dropping out.
Criminalization is a social sorting filtering process. In many institutional realms, criminalization works to cull those identified as heretical or "unreliable," The overly (or overtly) noncomformist. That's arguably the most important impact of user criminalization. It's a means of ascribing categorical social status to a population, and to the individuals who make up that population. In this case, the status of "pariah."
As for those LSD users who have found it necessary to conceal their use, or history of use- how could you possibly know?
I have made no secret of my own LSD use (many years ago). Neuroscience was part of my degree and doctorate so my background was a fascination with the mind-body conundrum. LSD was interesting but did not go anywhere philosophically and scientifically and, although it may be useful medically, it just altered the loading of data and emotional reaction to it. It got boring. As I became more prosperous, from my 30s and later, I would sometimes go to dinner parties where joints were offered around, my friends would freely talk about drunken, stoned parties etc. but even in private people would say they never took heroin or LSD. The two things were linked in their minds.
that isn't surprising, given that most folks haven't tried either one, and consider experimentation with either of substance unacceptably risky. In the US, there's some regional variation, but even in the parts of the country with populations more sympathetic to psychedelics use, most people haven't tried LSD and have a negative view of it.
Which brings us back to "long LSD". Are LSD users less prone to becoming part of my social group, do they die young, where do they go? At university they were possibly more reckless than other people and had a tendency to drop out but they were not less able. Did LSD have a life long effect? It is interesting that I have lost touch with any of them.
We both have our own circles of friends, of course. Neither of them can be considered a "random sample", and there are several valid reasons to account for why not. Psychedelics can feel like a sufficiently worthwhile or intriguing path to get a young college student to "drop out" and "follow their bliss for a while, so to speak. I mean, I did that. But I also eventually returned to college and graduated. I also think that--for reasons I've already mentioned--illicit psychedelics use encourages people to work as independent professionals rather than assimilating into corporate culture or getting jobs that require security clearances. That pressure may have lessened. But if it did, it was only recently. To mention my own anecdotal experience, I personally know- or have known- doctors, lawyers, and architects. And believe me, nothing rules out accountants. But I spent a total of around 25 years living in Northern California, and that's the region of the US most friendly to psychedelic cultures (although smaller outposts abound, from Hawaii to Maine.) Maybe your friends are hiding out in one of those enclaves. But there's no way of knowing. I mean, it does end badly for some of us. Other folks go through rough patches that sometimes last for quite a span of time. So there's that, too.
Along with my Real World friends and acquaintances with LSD experience, I've run across plenty of successful professionals online. There are clearly a number of them on Substack, posting on psychedelic matters and sometimes ingesting the substances on a continuing basis.
No, it does keep that proton in the bound state, and a protonated amine is actually a major molecular recognition point for aminergic gpcrs. In the 5HT2B pdb structure that is discussed 5TVN this is also clear and the ammonium at N6 forms a strong interaction with Asp135.
I guess the question is where this proton is picked up. It's not the "same proton" as in the tartrate salt. The protonated form is unlikely to pass the BBB, so reprotonation occurs either inside the brain or within the binding site itself.
Nice write up! How feasible do you think it would be to concoct (protein engineering perhaps?) a LSD-esque DMT molecule that has the same binding properties? Perhaps including ergoline structure in it. Just curious if it even makes sense.
I'd suggesting avoiding using the ergoline structure since it's likely to be very difficult to match the signalling patterns with such a bulky group in the binding site. A bulky group on DMT that sits outside the binding site but acts as an anchor and increases the residence time is more feasible imho. But even then I think it's a tough ask.
Thank you for elucidating this paper. Greatly appreciated.
Do we currently have a clear understanding of why different signaling biases result in the various subjective effects of, for example, LSD versus LSA? Or do we only know that this is the case without further insight into how and why it happens?
We don't have a full picture yet no -- the neuron is a complex system embedded in a larger complex system (the cortex), so unravelling these things is extremely difficult. Computational systems biology models are likely to be useful in this regard I think.
These compounds remain such a fascinating mystery, thanks.
In recent years I've occasionally found reports of users ingesting amounts of LSD that are just enormous in comparison to the usual dosage range- amounts measured in milligrams rather than micrograms. Some is anonymous folklore from drug forum websites, including stories about distributors being initiated with a "thumbprint" of pure powder LSD, etc. Jesse Jarnow also includes a story about a young woman well-known as an LSD distributor (complete with Federal trafficking conviction) who related a story of taking such a massive dose once. Robert Hunter had to pull himself together after ingesting an unknown but undoubtedly massive quantity of LSD.
The most verifiable report I found was that of a drug agent who was exposed to a massive amount in a raid and eventually retired on a disability claim. His story is told in the "Hallucinogens" episode of the National Geographic TV program "Drugs, Inc." https://www.imdb.com/title/tt2166771/?ref_=ttep_ep_4
The narration claims that the agent suffered "brain damage" as a result, but no specific details were added. The agent allowed himself to be filmed, and he seemed lucid and communicative during his appearance. He didn't present with an especially disordered affect, either, although it sounded like he was still grappling with some significant HPPD aftereffects. At any rate, in the stories I read, everyone survived without lasting physical impairments, however extravagant or traumatizing the effect on consciousness might have been.
My question is: how might the human brain and body metabolism possibly cope with such a megadose? Is there a ceiling on effect, from neurotransmitter saturation? How long would a >5,000 microgram LSD trip last, in terms of primary effect? Would other aspects of serotonin metabolism be affected, beyond uptake in the brain and brainstem structures?
This does not explain "long LSD" - like long COVID :)
As I rose up the ranks of the scientific and corporate world I started to wonder: where did all the acid heads go? Very few people who regularly dropped acid avoided dropping out.
Criminalization is a social sorting filtering process. In many institutional realms, criminalization works to cull those identified as heretical or "unreliable," The overly (or overtly) noncomformist. That's arguably the most important impact of user criminalization. It's a means of ascribing categorical social status to a population, and to the individuals who make up that population. In this case, the status of "pariah."
As for those LSD users who have found it necessary to conceal their use, or history of use- how could you possibly know?
I have made no secret of my own LSD use (many years ago). Neuroscience was part of my degree and doctorate so my background was a fascination with the mind-body conundrum. LSD was interesting but did not go anywhere philosophically and scientifically and, although it may be useful medically, it just altered the loading of data and emotional reaction to it. It got boring. As I became more prosperous, from my 30s and later, I would sometimes go to dinner parties where joints were offered around, my friends would freely talk about drunken, stoned parties etc. but even in private people would say they never took heroin or LSD. The two things were linked in their minds.
that isn't surprising, given that most folks haven't tried either one, and consider experimentation with either of substance unacceptably risky. In the US, there's some regional variation, but even in the parts of the country with populations more sympathetic to psychedelics use, most people haven't tried LSD and have a negative view of it.
Which brings us back to "long LSD". Are LSD users less prone to becoming part of my social group, do they die young, where do they go? At university they were possibly more reckless than other people and had a tendency to drop out but they were not less able. Did LSD have a life long effect? It is interesting that I have lost touch with any of them.
We both have our own circles of friends, of course. Neither of them can be considered a "random sample", and there are several valid reasons to account for why not. Psychedelics can feel like a sufficiently worthwhile or intriguing path to get a young college student to "drop out" and "follow their bliss for a while, so to speak. I mean, I did that. But I also eventually returned to college and graduated. I also think that--for reasons I've already mentioned--illicit psychedelics use encourages people to work as independent professionals rather than assimilating into corporate culture or getting jobs that require security clearances. That pressure may have lessened. But if it did, it was only recently. To mention my own anecdotal experience, I personally know- or have known- doctors, lawyers, and architects. And believe me, nothing rules out accountants. But I spent a total of around 25 years living in Northern California, and that's the region of the US most friendly to psychedelic cultures (although smaller outposts abound, from Hawaii to Maine.) Maybe your friends are hiding out in one of those enclaves. But there's no way of knowing. I mean, it does end badly for some of us. Other folks go through rough patches that sometimes last for quite a span of time. So there's that, too.
Along with my Real World friends and acquaintances with LSD experience, I've run across plenty of successful professionals online. There are clearly a number of them on Substack, posting on psychedelic matters and sometimes ingesting the substances on a continuing basis.
Since LSD is taken as a tartrate, i.e., the position-6 Nitrogen is protonated, is it then still the protonated molecule that winds up at receptors?
No, this proton is highly labile.
No, it does keep that proton in the bound state, and a protonated amine is actually a major molecular recognition point for aminergic gpcrs. In the 5HT2B pdb structure that is discussed 5TVN this is also clear and the ammonium at N6 forms a strong interaction with Asp135.
I guess the question is where this proton is picked up. It's not the "same proton" as in the tartrate salt. The protonated form is unlikely to pass the BBB, so reprotonation occurs either inside the brain or within the binding site itself.
You say LSD is just right, does this mean it is perfect or is there potential to improve it further?
Depends what you mean by improve? Always possible to create new analogues, but they'll likely be much less potent.
Improve potency, duration etc.
Nice write up! How feasible do you think it would be to concoct (protein engineering perhaps?) a LSD-esque DMT molecule that has the same binding properties? Perhaps including ergoline structure in it. Just curious if it even makes sense.
Thanks!
You mean a drug that has the effects of DMT but the duration of effects of LSD????
Exactly. I assume the ergoline structure is what increases its affinity to the receptor so maybe it is feasible?
I'd suggesting avoiding using the ergoline structure since it's likely to be very difficult to match the signalling patterns with such a bulky group in the binding site. A bulky group on DMT that sits outside the binding site but acts as an anchor and increases the residence time is more feasible imho. But even then I think it's a tough ask.
Thanks! That was insightful