Lysergamides How do I reset LSD Tolerance after 7 Years of once a week Nootropic macro dose use

[VastIllumination]

Hi, It's been a while since I've been on BlueLight and it's great to be back. I have some questions regarding the best approach and advice for resetting a LSD tolerance that I've built up from once a week macro dosing 99%+ DS-3.0 LSD over the past 7 years. Overall, I feel amazing in every way. I'm objectively 5x more productive on a daily basis (given the amount I accomplish in a given day). I've had significant positive transformations in my cognitive abilities and creative designs for med tech platforms I built for work.

What is the Best approach to reducing my tolerance?
I'm at the point where 500ug feels closer to 120ug when I first started dosing. If I push it up to 550ug at this tolerance level I will get a pretty nice psychedelic experience, but then my tolerance will be set higher around 550ug and so on. So even though I'm having zero negative effects on my life from taking these doses once a week with my current level of tolerance. I'm looking for recommendations for the best way to reset my tolerance in half or completely.

One of the reasons I haven't attempted this yet, is the level of performance increase I get each week for my job that isn't there on the few weeks I skipped over the years. I get such benefits from the nootropic use, I would have to endure a couple weeks or lower productivity it seems to accomplish a proper abstinence based reset approach.

My Main Questions for resetting such a strong LSD tolerance:

• Given my level of tolerance, how long should I abstain from LSD use before my tolerance is completely reset, or half reset?
• If I were to stop dosing for 3 or 4 weeks, how far would my tolerance have dropped by then?
  • What dose should I take after 3-4 weeks of abstinence to get effects similar to 200ug (Without tolerance)?
    • I'm weary that I may over/under dose not knowing where my tolerance is at after 3-4 weeks.
  • Does anyone have experience with stopping weekly use after 5+ years and how long it took to fully reset tolerance?

It now requires 400-500ug to have an LSD experience comparable to what 150ug would accomplish a couple years ago. After dosing once I'm incredibly productive all week from the afterglow. I haven't experienced any "burnout" or issues with memory, concentration or emotional stability, in fact all of those attributes have improved significantly during the entire once a week dosing process. As far as other drug use, I do not consume any alcohol or hard drugs only Cannabis (daily) and MDMA 5-6 times a year. I do not feel any physical addiction or desires regarding LSD, I set aside a day on the weekend to trip and don't dwell thinking about it much in the week until that day takes place. Sometimes I wait til much later in the night without feeling any compulsion to take it earlier. After 350+ macro doses during the 7 years, I've yet to have a bad trip experience - something I can't say about mushrooms in comparison. I'm sure the buffer of the tolerance helps reduce the overall tripping balls intensity, but It's been a beautiful weekly process non the less.

Tolerance Build up Year by Year:
For the first 2 years I took doses between 100ug - 130ug. The 3rd year I start dosing closer to 175ug, by the 4th year it was closer to 200ug-220ug, each of these getting close to what 125ug originally felt like. By the 5th year I started dosing 300ug+ (Which still felt like 150ug at the time) that's when my tolerance started to increase at a faster rate. By year 6 it was 400ug and now 500ug. A reference point of my tolerance: I've never come close to ego death, even at 520ug I can talk and think clearly in social environments with the tolerance.

LSD Neuroplasticity:
My background is in neuroscience and I have extensively researched the neuroplastic effects of 5HT-2a/1a psychedelic activation as well as the overall safety of LSD-25 use. Please refer to the collection of important LSD studies listed in the next post.

Significant Improvements in Cognitive Performance, ADHD-Reduction, Daily Productivity, Procrastination Reduction, Memory Recall, and creative brainstorming, design and finding instant solutions to problems:
Since I started the once a week nootropic dosing I've accomplished multiple successful startup companies, including grad level medical research where I had to design every aspect of the software/platform from the ground up and write up all the development blueprints. Each time I would dose, I deeply monitor any negative or positive changes in the days afterwards. Spacing macro doses out a week apart over the 7 years honestly created no noticeable side effects, everything I saw was clear benefits - with many people I know telling me "Keep doing what ever you are doing" without knowing about my LSD use - given the improvements they have seen in my cognitive and productive abilities. I am able to process a list of everything I need to get done during my weekly LSD trips and then accomplish all of the goals during the week. I truly wish I had started this nootropic regiment back when I was in college, I would have achieved so much more. I'm substantially outperforming what I was able to accomplish on prescribed Ritalin/Focalin without having to deal with any of the nasty side effects of stimulations. For instance I was able to complete writing a 50 page med tech thesis within 13 days of non-stop work - something I couldn't fathom ever attempting to accomplish previously. It seems to have completely removed any traces of my ADHD, where I can now work 12 hours days without losing focus or getting burnt out and sitting down to write a 5 page report just flows instantly as if its no effort at all. Where in contrast I used to struggle and take additional hours to accomplish these tasks prior to this dosing regiment. Overall I'm consistently in a good mood, feeling stable, patient and excited for life - truly better than I've ever felt.

Significant Anxiety Reduction:
5 year ago, after a couple months of once a week dosing of 100ug - 130ug, I no longer experienced any anxiety (state or trait). Things that used to make me anxious to the core, like presenting in front of a board of executives at some of the largest hospitals didn't phase me at all. Where in the past I used to get increasingly anxious the closer it got to presenting, after macro dosing once a week I wouldn't have a worry in my mind when going into and carrying out presentations. I was able to present clearly without rushing, it is truly life changing. I can understand the power this can have on people in hospice dealing with the anxiety of death. The same anxiety reduction took place in social situations as well which is truly remarkable. As I continued dosing over the years it maintained a strong baseline of anti-anxiety effects without dropping out and seems to have improved over the years even as my tolerance has increased.

Thanks in advance

 

[VastIllumination]

(STUDIES) Important LSD Neuroplasticity & Nootropic Studies & Articles:

Psychedelics Promote Structural and Functional Neural Plasticity (Study Link 2018):
Results: "Serotonergic psychedelics increase neuritogenesis, spinogenesis, and synaptogenesis. Psychedelics promote plasticity via an evolutionarily conserved mechanism. TrkB, mTOR, and 5-HT2A signaling underlie psychedelic-induced plasticity."

Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics (Study Link 2021)
Results: "A single administration of a psychedelic produces rapid changes in plasticity mechanisms on a molecular, neuronal, synaptic, and dendritic level. The expression of plasticity-related genes and proteins, including Brain-Derived Neurotrophic Factor (BDNF), is changed after a single administration of psychedelics, resulting in changed neuroplasticity. The latter included more dendritic complexity, which outlasted the acute effects of the psychedelic. Repeated administration of a psychedelic directly stimulated neurogenesis and increased BDNF mRNA levels up to a month after treatment. "

Neuroscience research suggests LSD might enhance learning and memory by promoting brain plasticity (Study Link 2022)
Results: "The study found that LSD increased markers of neuroplasticity in human brain organoids, increased novelty preference in rats, and improved memory performance in humans. “Notably, we found significant LSD-induced changes in the mTOR pathway, a protein kinase involved in multiple neural plasticity events, acting as a hub between plasticity, learning, and memory.”

LSD allows more information to flood into the brain by altering activity in the thalamus (Study Article 2019)

Lysergic Acid Diethylamide–Assisted Therapy in Patients With Anxiety With and Without a Life-Threatening Illness: A Randomized, Double-Blind, Placebo-Controlled Phase II Study (Study Link 2021)
Results: "LSD treatment resulted in significant reductions of State-Trait Anxiety Inventory-Global scores up to 16 weeks after treatment (least-square mean [standard error] change from baseline difference (p = .007). Similar effects were observed for ratings of comorbid depression on the Hamilton Depression Rating Scale, 21-item version (p = .0004) and the Beck Depression Inventory (p = .02). Positive acute subjective drug effects and mystical-type experiences correlated with the long-term reductions in anxiety symptoms."

LSD Produces ‘Harmonic’ Order In The Brain, Says Neuroimaging Study (Study Article Link 2018)

Study finds LSD reverses the deficiency in avoidance learning in impaired rats (Study Link 2014)

New study shows LSD's effects on language (Study Link 2016)
Results: “This indicates that LSD seems to affect the mind's semantic networks, or how words and concepts are stored in relation to each other. When LSD makes the network activation stronger, more words from the same family of meanings come to mind. The effects of LSD on language can result in a cascade of associations that allow quicker access to far away concepts stored in the mind.”

(LSD SAFETY STUDIES)

Therapeutic Use of LSD in Psychiatry: A Systematic Review of Randomized-Controlled Clinical Trials (2020) (N = 567) (Study Link)

• Results: “As a recreational drug, LSD at 25μg, 50μg, 100μg, or 200μg does not entail physical dependence as withdrawal syndrome, as do most of these substances (opioids, cocaine, cannabis, and methamphetamine). Their safety has recently led to considering LSD as one of the safest psychoactive recreational substances. Classical hallucinogens in general, and LSD in particular, exhibit very low physiological toxicity, even at very high doses, without any evidence of organic damage or neuropsychological deficits (36, 37) associated with their use. (38–42).”

Safety and Efficacy of Lysergic Acid Diethylamide-Assisted Psychotherapy for Anxiety (2014) (Study Link)

• Results: “Neither the experimental dose (200 μg of LSD) nor the active placebo (20 μg of LSD) produced any drug-related severe adverse events, that is, no panic reaction, no suicidal crisis or psychotic state, and no medical or psychiatric emergencies requiring hospitalization. Interestingly, fewer reports of anxiety were received during experimental sessions with 200 μg (22.7%) than with active placebo (50%), and the mean intensity of anxiety was comparable between the groups.”

Safety pharmacology of acute LSD administration in healthy subjects (2022) (N = 83) (Study Link)

• Results: “The single-dose administration of LSD is safe in regard to acute psychological and physical harm in healthy subjects in a controlled research setting… Maximal ratings of > 50% good drug effects were reached in 37%, 91%, 96%, and 91% of the LSD administrations at 25, 50, 100, and 200 µg. Maximal ratings of > 50% bad drug effects were reached in 0%, 9%, 27%, 31% at 25, 50, 100, and 200 µg, respectively. Mean ratings of Oceanic Boundlessness were 10%, 25%, 41%, and 44%, and mean ratings of Anxious Ego-Dissolution were 3.4%, 13%, 20%, and 22% at 25, 50, 100, and 200 µg, respectively.”

 

[pupnik]

one month should get you fine and dandy.
you can play around with some ephedra or ephedrine to get some of the sympathomimetic ADHD benefits in the interim.
it's not the same but wont aggravate the 5ht receptors
thanks for the links.

I seems to me that there is a bit of confusion in trying to correlate the psychedelic experience and the plastogenic effects

Because brain exposure to these compounds is often of short duration due to rapid metabolism, it will be interesting to assess the kinetics of psychedelic-induced plasticity.

the relationship may be more of an evolutionary adaptation:

• enhanced axon branch and dendrite branch growth correlates with more potential connections, and not necessarily with activation (especially as the neurons in vitro are not active)
• enhanced spine growth correlates with new memory formation, but I do not see why that would occur in vitro at all, since no activity was happening.
• the psychedelic experience effects relate to increased (lower threshold of activation) reactivity of primary cortical neurons and thalamic neurons keeping the corticao-thalamic loop running longer than the usual 3 cycles of feedback. Longer loop cycles lead to frame stacking and other psychedelic effects (altered sense of time passing, intensification of sensation and feelings, strobing and trails...)
• This one LSD allows more information to flood into the brain by altering activity in the thalamus (Study Article 2019) - is what I have been talking about for years https://www.pnas.org/doi/10.1073/pnas.1815129116

btw, you may be interested in my signature perception demo link at the bottom of my posts - increase the feedback loop duration from 3 to 8 or 9 and watch how perception begins to ramify

 

[cosmosmariner]

It is possible that with chronic use, your 5HT2A receptors are down regulated. One thing you could try is St. John’s Wort, which has been shown to upregulate 5HT2A receptors. A six-week course might help. Let us know. I’m sure there are a lot of people here who would like to know.

 

[VastIllumination]

It is possible that with chronic use, your 5HT2A receptors are down regulated. One thing you could try is St. John’s Wort, which has been shown to upregulate 5HT2A receptors. A six-week course might help. Let us know. I’m sure there are a lot of people here who would like to know.

Thank you for the suggestion, that would be amazing if St John's Wort could upregulate 5TH2A without having to abstain for a month. I'll look into trying it. Just curious if there is any data on what level of tolerance reduction I can expect from a couple weeks of st johns wort use.

Currently, I'm in a weird place where I know taking 500ug isn't going to hit me like a true 500ug dose, which would likely be way too intense. Each time I know it will work, but I have to trust that I'm not getting a true 500ug experience when I dose, knowing it will be closer to a feeling of 125-150ug. When I dose 500ug before going to a social event, I find myself second guessing the tolerance wondering if I'm going to get hit with a much stronger experience, but it always feels like 125-150ug.

I'm just trying to figure out where I should place future doses with the St John's Wort regiment so I don't heavily overdose/under dose myself.
If this works as a method to continue to prevent substantial deregulation of 5HT2A that would be an incredible find. Thank you.

 

[VastIllumination]

one month should get you fine and dandy.
you can play around with some ephedra or ephedrine to get some of the sympathomimetic ADHD benefits in the interim.
it's not the same but wont aggravate the 5ht receptors
thanks for the links.

I seems to me that there is a bit of confusion in trying to correlate the psychedelic experience and the plastogenic effects


the relationship may be more of an evolutionary adaptation:

• enhanced axon branch and dendrite branch growth correlates with more potential connections, and not necessarily with activation (especially as the neurons in vitro are not active)
• enhanced spine growth correlates with new memory formation, but I do not see why that would occur in vitro at all, since no activity was happening.
• the psychedelic experience effects relate to increased (lower threshold of activation) reactivity of primary cortical neurons and thalamic neurons keeping the corticao-thalamic loop running longer than the usual 3 cycles of feedback. Longer loop cycles lead to frame stacking and other psychedelic effects (altered sense of time passing, intensification of sensation and feelings, strobing and trails...)
• This one LSD allows more information to flood into the brain by altering activity in the thalamus (Study Article 2019) - is what I have been talking about for years https://www.pnas.org/doi/10.1073/pnas.1815129116

btw, you may be interested in my signature perception demo link at the bottom of my posts - increase the feedback loop duration from 3 to 8 or 9 and watch how perception begins to ramify

Great post, thank you for the deeper insights into neuroplasticity, it's fascination to start breaking down how LSD impacts axon branching and dendrite growth and their effects on cognitive and bodily processes. Fascinating point that growth of new connections doesn't always determine high activation of those new pathways, although it sets up a biological faculty where enhanced activation could take place.

So a month of abstinence should reset even 7 years of once a week use, that sounds doable. Although, I've read posts of people who said it takes months to years to reset after that long - are there any case studies here where people tested out the speed of tolerance reduction after 5+ years. I may go back to using l-tyrosine (precursor of dopamine) supplements for productivity during the abstinence period.

One other question: After the month period should I expect a 200ug dose to hit like a true 200ug dose? I assume I should avoid MDMA during the abstinence period as well?

Response to the your great posts on the science:

There are a couple studies that show substantial increases in communication networks between brain regions that generally do not communicate or did at much lower degrees. There are also studies that show single doses of 5HT2A psychedelics can increase neuroplasticity by 10%- 40%, even though they only bind for a limited amount of hours.

• Algernon Pharmaceuticals Confirms DMT Increased Growth of Neurons by 40% in single dose Preclinical Study at Sub Hallucinogenic Dose (Press Release Link 2021)
• The Doors of Expression: LSD Alters Epigenetics and Protein Induction (2022 Study Link)
• A Single Dose of Psilocybin Increases Synaptic Density and Decreases 5-HT2A Receptor Density in the Pig Brain (2021 Study Link)
• Homological scaffolds of brain functional (Psilocybin increases networks between brain regions) (Study Link 2014)

• Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo (2021 Study Link)
• People Who Take Psychedelics Tend to Be Healthier Than Non-Users, New Study Suggests (2021) (Article) (Study)
• Alcohol Is Worse for Mental Health than Psychedelics: (2010 Article with Link to Study)
  “In a study of 130,000 American adults, including 19,299 psychedelics users, researchers failed to find evidence that taking psychotropic substances results in serious mental health problems. Alcohol, on the other hand, continues to drive rates of depression and suicide higher because it easily aggravates smaller mental health issues into something larger.”

Really appreciate all the help

 

[afk]

How have you not lost the magic of an LSD trip after all these years with that frequent dosing? Or do you only care about the nootropic benefits? I used to trip every weekend for 3-4 months and completely lost the magic, needed to take a full year off and even then I felt like it was missing something. Maybe I was just nostalgic but when I trip now it feels just like it did when I was 19.

I feel with psychedelics there is a physiological tolerance as well as a “mental or psychological tolerance” so to speak, as if your brain can expect the effects and is super familiar with the headspace. Kind of how stoners simply can’t get high like they used to even after extended breaks. Very interesting thread regardless.

 

[AussieJoe]

We never lost the 'magic' of LSD trips ...every weekend strong doses for 8 years 1972-1980 ...brilliant times ....as far as tolerance went well there really wasnt much after waiting a week ...back again and again for another psychedelic adventure .BUT if you didnt wait a week and dosed a couple of days later you would have to double up to get the same weekend experience. Common sense kicked in ....why waste good acid just wait till the weekend. I would think though a small break maybe a month or 6 weeks if you are expeiencing this dosage tolerance.Also keep in mind the strength of your blotters may vary these days as well....degradation of product...few variables to consider.Give it a break and test it out ...my logic tells me tolerance should drop right down afterall you are not consuming.Would like to hear how it works out for you .

 

[Hexagon Sun]

Super interesting thread. Please report back your st john experiences.

Another classical family of compounds for resetting general tolerances are the dissociatives. So in theory, you could get some DMXE, for example. In my experience the tolerance resetting is discrete at most but you dont lost anything trying. Also, probably you are going to love the susbstance itself. Its a different paradigm that psychedelics but if you like one, probably you are going to like the other family too as they are somehow intrincated and compatible, even synergistic.

You will regain some tolerance after 1 month, but to really come back to baseline, you are probably needing more time, like 2-4 months maybe more. The cool thing about 5ht psychs is that sooner or later, you pretty much come back to baseline

 

[VastIllumination]

You will regain some tolerance after 1 month, but to really come back to baseline, you are probably needing more time, like 2-4 months maybe more. The cool thing about 5ht psychs is that sooner or later, you pretty much come back to baseline

Hi thanks Hexagon. How much tolerance reduction do you think I should see after 1 month, like dose to non-tolerance effect ratio?

Would it be 3:2 like if I took a 300ug dose and had effects close to 200ug (without tolerance) or 2:1.5 or otherwise?

 

[pupnik]

@VastIllumination
I think one month should do you fine, however, do not expect to be re-virgin-ated.
all that spine plasticity is evidence of new memory formation. (the spines are left where dendrites of active cortical neurons sense a charge at the point of contact with an active branch of a pyramidal neuron (which may have up to 100000 branches) these are very fine and faint and do not seem to show up on the photos in your link (Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo (2021 Study Link))

This means that when you get stoned again, some previously strange things will be familiar (from the memory that formed when previously stoned (those spines)).

When things are not familiar, the wonder of strangeness imbues a special quality for first timers, and probably this continues through a few early forays into psychedelic mindspaces.
But when you already have memories of these strange places, they are just not that strange anymore.
At that point, it is more like you have come home to something familiar.

However you can work with tolerance and get your money's worth.

 

[Viraldrome]

I have a perma tolerance that doesn't go down after a month off. I don't use it weekly but monthly, and for around a decade, and its steadily crept up over the years and now i'm up to 400 mics, where 10 years ago i did 200. Isnt it like being a heavy drinker? I mean even if if you quit and stop drinking for 5 years, pretty sure if you start again you will still have large tolerance. I understand thats your ruined liver, but we are probably damaging something too.

There is no way to dance around it, weekly use is way too much. Its surprising you can trip at all. People who do it rarely don't have your issues. Guess you have to decide if its something you want to still be able to do years from now, in which case i would reduce use to very occasionally. That's probably how i will go, instead of monthly only a few times a year, but a huge dose. Do report back on st johns wort though if you try.

 

[VastIllumination]

@VastIllumination
I think one month should do you fine, however, do not expect to be re-virgin-ated.
all that spine plasticity is evidence of new memory formation. (the spines are left where dendrites of active cortical neurons sense a charge at the point of contact with an active branch of a pyramidal neuron (which may have up to 100000 branches) these are very fine and faint and do not seem to show up on the photos in your link (Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo (2021 Study Link))

This means that when you get stoned again, some previously strange things will be familiar (from the memory that formed when previously stoned (those spines)).

When things are not familiar, the wonder of strangeness imbues a special quality for first timers, and probably this continues through a few early forays into psychedelic mindspaces.
But when you already have memories of these strange places, they are just not that strange anymore.
At that point, it is more like you have come home to something familiar.

However you can work with tolerance and get your money's worth.

Pupnik, always appreciate your responses. Overall my trips are fairly psychedelic still at this point, I get some pleasant visuals that are a little more faint but mostly I enjoy the expansion of mental thought processes and thinking. I'm able to clearly think through many aspects of needed self reflection and goals for the upcoming week, year, life etc each trip - which still come in strong. Something interesting to note, even if I take lower doses where the visuals are weaker, the nootropic effects still take place the upcoming week.

Although, the times where I increased my weekly dose by 50-100+ug, like when I was regularly taking 400ug and went up to 500ug one week. I would get thrown into far more incredible worlds of all encompassing visuals and geometric patterns of colors dancing and wrapping around my body (Mostly CEV - Some OEV). No ego loss, but images also glowed with white light and became 3d in depth to large extents.

In those moments the "Special" profound experience and feeling was definitely there and this was after 6 years of weekly dosing. So even if I can't completely re-virginify being able to get back to that psychedelic space at lower doses would be nice. If I take larger doses like that weeks in a row, by the 3rd/4th week I would have to reup the dose even more to get the same effect to like 550ug - 575ug. I generally avoid this because it would shoot my tolerance up at a much faster rate and it would be nice to reset back at a lower dose with those effects rather than going above 600ug.

 

[pupnik]

@VastIllumination
I find that if my mind stumbles into the concept of "what is presence?"
i.e. being here and now, or "i am here"
then a chain of physical sensations will become established that somehow ramifies into visual enhancement as well,
with psychedelics, even the air takes on a gel like fragmentation into prismatism, and tiny points of light elaborate into mandalas.

 

[pupnik]

I have a perma tolerance that doesn't go down after a month off. I don't use it weekly but monthly, and for around a decade, and its steadily crept up over the years and now i'm up to 400 mics, where 10 years ago i did 200. Isnt it like being a heavy drinker? I mean even if if you quit and stop drinking for 5 years, pretty sure if you start again you will still have large tolerance. I understand thats your ruined liver, but we are probably damaging something too.

There is no way to dance around it, weekly use is way too much. Its surprising you can trip at all. People who do it rarely don't have your issues. Guess you have to decide if its something you want to still be able to do years from now, in which case i would reduce use to very occasionally. That's probably how i will go, instead of monthly only a few times a year, but a huge dose. Do report back on st johns wort though if you try.

the every week thing is really for just one tab
if it stops being effective then you need a longer break - but if you up the dose you definitely need a longer break
keep dose down to go more often
I guess 2 tabs with a two week break min.

 

[pupnik]

by the way,
although I have been encouraging up to 1/4 tab every third day.
with 5 days off it is twice as strong.
also with 5 days off, 1/8 tab is twice as strong.
I may be spacing out more between the spaced out days going forward.

 

[cryptix420]

My .02 is that you're using all this research to justify what you intuitively know is excessive use of LSD - and I can't stand behind that. Taking something as potent as LSD so frequently simply isn't a good idea for a myriad of reasons, IMO. It's important to try and access the benefits of psychedelics without actually using them, via yoga, meditation, or other beneficial lifestyle practices.

Chronic LSD administration depletes magnesium, btw - along with who knows what else. Don't get me wrong, I love acid just as much as the next guy, huge fan.



But if you're intent on abusing it, perhaps check out a Bacopa product called Cognance at Nootropics Depot:

Why Should I Take Cognance?​

Over the years, the concept of microdosing has really taken off; yet for the average person, it is quite an inaccessible concept to partake in (for now). Although the legislative environment is changing, wide spread microdosing accessibility is still a ways off. Luckily, we had the foresight many years ago to look towards one of the most famous natural nootropics, Bacopa monnieri. It contains the precursor for a fantastic molecule called ebelin lactone, which just so happens to be a positive allosteric modulator of one of the main receptor targets of microdosing: 5-HT2A! Through a patented extraction and processing method, we were able to, for the first time ever, concentrate massive amounts of ebelin lactone! This has never been done before, so you are among the first to try out this unique molecule! Ebelin lactone is perhaps one of the only high affinity natural 5-HT2A positive allosteric modulators. The effects you can expect from Cognance are a distinct mood boosting effect, backed up by increases in overall cognitive function, focus, and even creativity!* This is, of course, not all down to 5-HT2A receptor activation. In fact, Cognance has another special trick up its sleeve. The ebelin lactone content of Cognance also acts as an M1 muscarinic acetylcholine receptor positive allosteric modulator. This is quite an important and seemingly elusive target for cognitive enhancement, and thus it is quite special to see it here alongside ebelin lactone’s 5-HT2A activity!*

What is Cognance?​

Cognance is an incredibly unique patented extract of Bacopa monnieri. First, we create a very potent bacoside extract, similar to our bacopa 24% bacosides product, but even more potent. We then put this extract through a two stage hydrolysis process, which mimics the natural metabolism of bacopa extracts in the human body. The first hydrolysis stage turns the various bacosides into two main compounds, jujubogenin and pseudojujubogenin. These compounds then undergo a second acid hydrolysis, which converts the jujubogenin into ebelin lactone and pseudojujubogenin into Bacogenin A1. By perfecting this process, we have been able to consistently obtain ebelin lactone concentrations in excess of 10%, which is a massive achievement!

What we end up with at the end of the patented extraction process, is a bacopa extract that has been “pre-metabolized”. This means you don’t have to rely on your body to metabolize the bacosides in bacopa. This has some major advantages! First and foremost, the bacosides like bacoside A3, bacopaside C, bacopaside II and bacopaside X do not absorb very readily, if at all. Let’s take a look at why this is the case:

Figure 1: The molecular structure of bacoside A3. Sugar groups are circled in red.

The bacosides have very bulky sugar groups hanging off of it. This increases the molecular weight of the molecule quite a bit, and when combined with its sheer size, this makes it very hard for the bacosides to be absorbed. The molecular weight limit for most bioavailable compounds (as determined by Christopher A. Lipinski) is 500 g/mol, but bacoside A3 (as pictured above in Figure 1.) clocks in at a whopping 929.10 g/mol. This is almost double the Lipinski rule of 5 limit of 500 g/mol!

Removing these sugar groups is not particularly difficult, and with a bit of effort, the sugar groups are ripped off in our digestive tract during the initial hydrolysis process. This then yields jujubogenin with a molecular weight of 472.7 g/mol, right under the 500 g/mol limit according to the Lipinksi rule of 5! Unsurprisingly, jujubogenin now all of a sudden absorbs fairly well and even makes it past the blood brain barrier (BBB). The same can be said for pseudojujubogenin, which without the bulky sugar groups, now also has a molecular weight of 472.7 g/mol, and is fairly bioavailable.

During the first stage of R&D on this extraction process, we purposefully cut the hydrolysis process off at the point where there was a lot of jujubogenin and pseudojujubogenin present. We then bioassayed this extract and it felt characteristically like regular Bacopa monnieri, just a lot more potent and quicker acting. The calming and for some individuals, lethargy inducing effects, were there in spades.* Due to already having ripped off the sugar groups outside of the body, the extract got to work a lot faster. However, we had our sights set on scrubbing these calming/lethargy effects out, and for that we had to push the hydrolysis process along quite a bit more!

In the secondary hydrolysis process, we are mimicking the low pH environment of the stomach, using the low pH to drive the secondary hydrolysis process which converts jujubogenin to our target compound, ebelin lactone! This is where some more complex chemical changes take place, as can be seen in our proposed multi-step acid hydrolysation process as drawn out by our lab director:

Figure 2: Proposed mechanism of ebelin lactone production via acid hydrolysis.

While the first hydrolysation step (bacosides to pseudojujubogenin & jujubogenin) is likely to occur fairly efficiently in the digestive tract, this secondary acid catalyzed hydrolysis step is a whole lot less likely to result in efficient conversion in the digestive system. Due to this, it is unlikely we are consistently converting high amounts of bacosides to ebelin lactone. This is a shame, because the chemical changes that lead to ebelin lactone, also lead to drastically enhanced bioavailability and BBB permeability! In addition to this, ebelin lactone is a 5-HT2A and muscarinic acetylcholine M1 receptor positive allosteric modulator, and according to data appears to lack GABAergic effects. This is what led us to the conclusion that concentrating high amounts of ebelin lactone would scrub the lethargy inducing effects, and in fact lead to a more uplifting and even stimulating bacopa extract.* We weren’t wrong! When we produced the second fully converted R&D batch, we discovered that during beta-testing a lot of long-time bacopa users around the office were no longer able to identify it as bacopa. Cognance is completely different, very clean, unique and totally lacking any sort of lethargy.* This truly is bacopa reimagined!

Cognance Benefits & Uses​

• Promotes cognitive function*
• Enhances mood*
• Promotes focus*

Bacopa Reimagined​

Now that you know the ins and outs of the extraction and conversion process, you are probably wondering what a high ebelin lactone bacopa extract feels like. For those who have experience with real microdosing (genuine sub-threshold effects), the effects will be recognizable, and subtle! Subtle is the name of the game here. Cognance is not going to blow you away and send you on a spiritual journey. That is not the intent of microdosing, and it is not the intent of Cognance. However, what it will provide is a very unique sense of mental clarity, focus, and creativity paired with a very natural feeling lift in mood.* These acute effects are perceptible by most when utilizing the standard 100 mg dose. However, if you want less subtle and more noticeable effects, you can bump up your dosage to 200 mg. What we are targeting here is predominantly the 5-HT2A receptors, so let’s talk about those a little more!

The 5-HT2A receptor is one of the 15 known serotonin receptors, and plays a major role in regulating the CNS, neuroplasticity, mood, creativity and focus. The 5-HT2A receptors are particularly densely distributed throughout regions of the brain that are heavily involved in cognition and mood. Thus, it is no surprise that 5-HT2A receptor dysfunction has been identified as a common thread amongst individuals with less than ideal cognitive function and mood. When 5-HT2A receptors are activated, highly complex signaling cascades occur that then end up influencing glutamatergic, cholinergic, GABAergic and even dopaminergic activity. It also forms receptor complexes (heterodimers & heteromers) with dopamine D2, cannabinoid CB1, glutamate mGluR2 and serotonin 5-HT1A. These complex reactions with other neurotransmitter systems certainly makes 5-HT2A a very important and far reaching neuromodulator, which has major implications for both cognition and mood. No wonder 5-HT2A has become such a legendary, although somewhat enigmatic, receptor target! This is why we were so excited to have found ebelin lactone, and even more excited when we figured out a clever method of producing production amounts of it! By taking Cognance, you can experience many of the beneficial effects of elevated 5-HT2A activity, such as elevated mental clarity, a lift in mood and deep calm focus!*

However, while 5-HT2A is an incredibly exciting receptor target, M1 muscarinic acetylcholine receptors are just as fascinating. However, they are less talked about, and certainly underappreciated! Similar to 5-HT2A, M1 is also a G-protein coupled receptor, and both 5-HT2A and M1 use very similar signaling proteins. It is then perhaps not surprising that M1 and 5-HT2A receptors have many overlapping effects when it comes to cognitive function. A lot of research has started to point to M1 receptors being one of the main cholinergic receptors involved in cognitive function. Due to this, there has been a major effort to find selective M1 agonists; or even better, positive allosteric modulators. This effort has turned out to be incredibly hard, so it is quite spectacular that nature has given us a compound which just so happens to be a selective positive allosteric modulator of M1.

The M1 positive allosteric modulation effects, combined with the 5-HT2A positive allosteric modulation effects, gives Cognance an incredibly unique, yet very clean nootropic effect.* We believe that this is a new chapter in the nootropic scene, and we hope that this process has illustrated that nature harnesses some of the most profound neuromodulators on the planet! Of course, sometimes requiring clever human intervention to liberate these fantastic molecules! We have achieved that with Cognance, and look forward to working alongside nature again to develop a full series of cutting edge herbal extracts.

 

[perpetualdawn]

Thanks for dropping all this gold @VastIllumination - the linked studies, but especially your own experience with your dosing regime. The experience you have shared is extremely valuable.

We've known for a while that drugs like LSD are really safe, and potentially health-promoting, but the more recent studies (like you've linked to) have been showing that there's this potential for drugs like LSD to be really powerful as nootropics via the neuritogenesis, spinogenesis, synaptogenesis. It's becoming more and more undeniable that we're sitting on an absolutely incredible tool in these psychedelics.

It's very interesting to read your personal experience with actually dosing it regularly enough to potentially be seeing vast effects in vivo + IRL of this sort. I always think it's no coincidence that silicon valley popped up at the epicenter of the american psychedelic movement, and the ongoing intertwining of tech and the psychedelic culture (via "that thing in the desert" etc) is fascinating.

A few questions if you don't mind me picking your brain:

• Why have you settled on LSD as your go-to (vs other psychedelics)?
• You mention occasional MDMA use. I'm pretty shy of it myself because it has always seemed very artificial, temporary, recreational and little to no long-term benefit. But I always wonder if I'm missing something there. Do you find MDMA confers any kind of long-term benefits to you, similar to what psychedelics can do but in different domains, or do you use it purely recreationally?
• You've talked a lot about how you've seen this dosing really enhance your performance professionally and intellectually. Have you seen changes in your social interactions, happiness, romantic life, other soft things like that?

I don't have specific advice for you on resetting your tolerance because I've never taken it that far, but sounds like a break won't hurt.

 

[VastIllumination]

My .02 is that you're using all this research to justify what you intuitively know is excessive use of LSD - and I can't stand behind that. Taking something as potent as LSD so frequently simply isn't a good idea for a myriad of reasons, IMO. It's important to try and access the benefits of psychedelics without actually using them, via yoga, meditation, or other beneficial lifestyle practices.

Chronic LSD administration depletes magnesium, btw - along with who knows what else. Don't get me wrong, I love acid just as much as the next guy, huge fan.

But if you're intent on abusing it, perhaps check out a Bacopa product called Cognance at Nootropics Depot:

Hi Cryptix420, thank you for your post. I truly haven't encountered any negative effects from once a week macro dosing of LSD over the 7 years. After each session I closely evaluate any negative or positive effects in the days/week after, it was always positive. The only small side effect I would get is the day after tripping, I would go to sleep an hour or 2 earlier than normal - that's really the only side effect I had. My 5HT2a receptors are still functioning well, I feel incredible during the day in terms of focus, energy, wellbeing and contentedness. Last week I upped the dose by 15ug and had one of the most incredible trips of my life. Breathtaking visuals dancing and forming complex sacred geometry all around me.

I've had my magnesium levels checked multiple times over the past 7 years and it was always normal. I'm going to be getting blood work again in a couple months for a check up, so I'll report back. Although, I've never had issues with magnesium, nor any low magnesium side effects during the trip. I've heard some people take magnesium when they trip on LSD to avoid little spasms and tenseness. I've never had that problem or any low magnesium symptoms.

The study you linked references a single Non-Clinical study from 1983 as the basis of the magnesium depletion claim. Have you seen any post 1990s studies looking into this? I wasn't able to find any.

Are you recommending Cognance as replacement for LSD use or a way to upregulate 5HT2a receptors to reduce tolerance from LSD? If i took Cognance during a period of taking a break from LSD, would its 5HT-2a agonism lengthen the time it takes to reset my tolerance?

(Study showing repeated LSD administration increased the stimulation of neurogenesis and neuroplasticity)

Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics (Study Link 2021)
Results: "A single administration of a psychedelic produces rapid changes in plasticity mechanisms on a molecular, neuronal, synaptic, and dendritic level. The expression of plasticity-related genes and proteins, including Brain-Derived Neurotrophic Factor (BDNF), is changed after a single administration of psychedelics, resulting in changed neuroplasticity. The latter included more dendritic complexity, which outlasted the acute effects of the psychedelic. Repeated administration of a psychedelic directly stimulated neurogenesis and increased BDNF mRNA levels up to a month after treatment. "

 

[VastIllumination]

How have you not lost the magic of an LSD trip after all these years with that frequent dosing? Or do you only care about the nootropic benefits? I used to trip every weekend for 3-4 months and completely lost the magic, needed to take a full year off and even then I felt like it was missing something. Maybe I was just nostalgic but when I trip now it feels just like it did when I was 19.

I feel with psychedelics there is a physiological tolerance as well as a “mental or psychological tolerance” so to speak, as if your brain can expect the effects and is super familiar with the headspace. Kind of how stoners simply can’t get high like they used to even after extended breaks. Very interesting thread regardless.

Even 7 years in it hasn't lost the magic. Most of my trips are fairly visual, transcendental and deeply special. Last week I upped my dose by 15ug and had one of the most incredible psychedelic experiences I've had in a while. Surrounded by moving fractals and rainbow colored geometric patterns that looked like thousands of glowing biological organisms multiplying and dancing. One of those experiences where I kept my eyes closed for hours not wanting to leave the beautiful imagery and fractal space.

I Woke up feeling great the next day and built 3 weeks worth of work on my schedule within this last week with ease. Each year my productivity appears to improve from the last and this is no different. It seems like higher doses within reason given the range I'm taking due to my tolerance lead to even more productivity and instant solutions with work during the week.