Dose - How fast does one build up a tolerance?

[Baked.]

Well SWIM is going to drop for the 4th time and wants to know how fast his tolerance builds up? Like if he does it once every other week will it build up or will it stay about the same?

[Fitz Hugh Ludlow]

Based on my monkey's experience, tolerance to LSD and mushrooms occurs immediately and decays completely in a week to ten days.

If your monkey take a dose of good acid, count on needing @3X the amount to experience similar effects within 24-48 hours.

After two weeks, your simian friend should be ready for unimpeded tripping, but my monkey wouldn't recommend taking strong psychedelics, LSD especially, more than twice a month at the very most. These drugs are immensely powerful and, as such, should be treated with care and respect. But by all means, have a lovely time!

[Arthur Dent]

My towel agrees - his experience was that there was absolutely no point doing another trip for at least 5 days after the first one, as it would have close to zero (or actually zero) effect and be a complete waste of good tabs. Doing a tab the next day or the day after would literally give him no effects at all, not even a hint.

There was one time when he had a big batch and did it every weekend for four weeks. The first time was amazing, the 2nd and 3rd were lacklustre - mildly pleasant but still basically a waste. Then on the 4th weekend he took 5 tabs in one go to see if the tolerance could be 'kicked out. He ended up going a bit manic, suddenly shouting and screaming at nothing in particular, and in general having a bad time of it. This taught him to be a lot less foolish in future.

So the advice of 'once a month' is good, maybe even less than that. Particularly because if one does it too soon and doesn't get the full effects, then the tolerance timer is reset and an opportunity has been wasted. i.e. waiting 4 weeks might give one an OK time, but waiting 6 would be a great time.

[RaverHippie]

The only tolerance that occurs is psychological, just becoming more used to the substance. Giving it at the minimum week is a very realistic timeframe and my raver friend has never noticed the need to increasing the dosage off the same supply using that schedule

[Shampoo]

Originally Posted by RaverHippie

The only tolerance that occurs is psychological, just becoming more used to the substance.

To clarify, tolerance to psychedelics such as LSD is caused by an adaptation of proteins in the brain to overexcitation- namely the downregulation of 5-HT2A/C receptors. This also occurs outside of the brain, as LSD has also been shown to act as an agonist at 5-HT receptors in the peripheral nervous system.

Tolerance is not a purely psychological phenomenon, but a molecular relationship between the agonist molecule (LSD-25) and it's target proteins (5-HT receptors) which occurs in both the brain and body.

[Valseedian]

Originally Posted by Shampoo

To clarify, tolerance to psychedelics such as LSD is caused by an adaptation of proteins in the brain to overexcitation- namely the downregulation of 5-HT2A/C receptors. This also occurs outside of the brain, as LSD has also been shown to act as an agonist at 5-HT receptors in the peripheral nervous system.

Tolerance is not a purely psychological phenomenon, but a molecular relationship between the agonist molecule (LSD-25) and it's target proteins (5-HT receptors) which occurs in both the brain and body.

unless swim is getting his many drugs mixed up (he may be thinking of mdma, or another replaced amphetamine phenethylamine.... but he thinks it's lsd-25 ), LSD has a seretonin/dopamine/norepinephrin releasing action aswell as being a VERY potetn 5-ht(2) agonist... releasing tons of neurotransmitters, possibly causing permanent damage to the synapses/connections between nerves... (see seretonin stroming for other info on this).... so,not only is tollerance an effect of down-regulation, but possibly nerve damage, permanent damage to the seretonin transmitter, and your body's stores of seretonin and other neurotransmitters will be obviously depeleted after the first initial trip, and will take time to regain the cellular density of the neurotransmitters, after all, if your cells aren't dense with neurotransmitters, LSD's action isn't nearly as intense...

if swim is mistaken, please don't hurt him..

edit:
yup, I was thinking about MDMA, not lsd-25... sorry for the confusion, I didn't bother editing out what I'd written, as the rebuttles to follow actually provide some very usefull info.

[Jatelka]

Originally Posted by Valseedian

not only is tollerance an effect of down-regulation, but possibly nerve damage, permanent damage to the seretonin transmitter

No, absolutely not.

No evidence at all for this theory in relation to LSD (that I am aware of)

You may be getting confused with some research that relates to mdma (much of it highly flawed), that suggests long-term changes in serotonergic neurotransmission can occur

[Shampoo]

Originally Posted by Valseedian

LSD has a seretonin/dopamine/norepinephrin releasing action aswell as being a VERY potetn 5-ht(2) agonist... releasing tons of neurotransmitters, possibly causing permanent damage to the synapses/connections between nerves... (see seretonin stroming for other info on this)....so,not only is tollerance an effect of down-regulation, but possibly nerve damage, permanent damage to the seretonin transmitter, and your body's stores of seretonin and other neurotransmitters will be obviously depeleted after the first initial trip, and will take time to regain the cellular density of the neurotransmitters, after all, if your cells aren't dense with neurotransmitters, LSD's action isn't nearly as intense...

Nope, incorrect almost all around.

Why don't we review the relevant information...

First of all, LSD-25 has not been shown to significantly positively effect the release of neurotransmitters- especially not via the monoamine transporters SERT/DAT/NET.

LSD-25 acts as a potent agonist at the 5-HT1A/B/D, 5-HT2A/B/C, 5-HT5A/B, 5-HT6, 5-HT7/7L receptors, as well as the D3 and D4 receptors.

It also has a modest (but likely inconsequential at recreational doses) affinity for the 5-HT6, 5-HT4L, Alpha-adrenergic, Beta1/2-adrenergic, D1/2/5 and H1 receptors.

Some evidence suggests that it may also act through the DARPP32 pathway in later stages, though the reports on this are not well substantiated.

As you can see, none of those receptors or proteins are are involved in the "releasing of tons of neurotransmitters."

If anything, 5-HT1A, which is a somatodendritic autoreceptor, would inhibit the release of serotonin if activated by a potent agonist such as LSD-25 (Ki of LSD-25 for somatodendritic 5-HT1A = 1.1nM). Furthermore, should recreational doses of LSD-25 have any real effect at the D2 receptor (unlikely based on it's Ki of 120nM), it would also inhibit DA release as it is also a presynaptically situated autoreceptor.

Additionally, as there is no cross-tolerance between LSD-25 and dopaminergic agonists or DAT protein agonists/antagonists, its action on DA is likely quite minimal (additionally, DA antagonists have been shown to have little or no impact on the effects of LSD-25). Seeing as excessive DA release is one of the primary sources of neurotoxicity in many recreational psychoactives, its absence here is further evidence for a lack of neuotoxicity as a result of LSD-25 use.


Please provide evidence for your claims that:

A. Acute LSD-25 administration results in nerve damage.
B. Acute LSD-25 administration causes permanent damage to the 5-HT "transmitter" (I assume you are referring to SERT, the serotonin transporter).
C. Intracellular stores of 5-HT/DA/NE are significantly "depleted" after acute LSD-25 administration.
D. Lack of NT density in presynaptic neurons abolishes or inhibits the activity of LSD-25.


In terms of cellular density, the only reduction in cellular density is in that of the 5-HT/DA/NE receptors which it acts as a potent agonist at; this is the process of downregulation, as stated before.

Originally Posted by Valseedian

unless swim is getting his many drugs mixed up (he may be thinking of mdma, or another replaced amphetamine phenethylamine.... but he thinks it's lsd-25 )
...
if swim is mistaken, please don't hurt him..

If you are unsure of what you are posting, especially if you are correcting another member's post, do your research before you begin typing! This is simple- do not post information (especially regarding pharmacology/pharmacokinetics) that you are not sure of, it can be misleading and perpetuate false-information and myths.

Reputation Comments on this post:

	A perfect rebuttal Sir! Informative, well written and factually correct
	Thankyou for this excellent refutation of false information. Your contributions are invaluable.

[Valseedian]

Originally Posted by Shampoo

Nope, incorrect almost all around.

Why don't we review the relevant information...

First of all, LSD-25 has not been shown to significantly positively effect the release of neurotransmitters- especially not via the monoamine transporters SERT/DAT/NET.

LSD-25 acts as a potent agonist at the 5-HT1A/B/D, 5-HT2A/B/C, 5-HT5A/B, 5-HT6, 5-HT7/7L receptors, as well as the D3 and D4 receptors.

It also has a modest (but likely inconsequential at recreational doses) affinity for the 5-HT6, 5-HT4L, Alpha-adrenergic, Beta1/2-adrenergic, D1/2/5 and H1 receptors.

Some evidence suggests that it may also act through the DARPP32 pathway in later stages, though the reports on this are not well substantiated.

As you can see, none of those receptors or proteins are are involved in the "releasing of tons of neurotransmitters."

If anything, 5-HT1A, which is a somatodendritic autoreceptor, would inhibit the release of serotonin if activated by a potent agonist such as LSD-25 (Ki of LSD-25 for somatodendritic 5-HT1A = 1.1nM). Furthermore, should recreational doses of LSD-25 have any real effect at the D2 receptor (unlikely based on it's Ki of 120nM), it would also inhibit DA release as it is also a presynaptically situated autoreceptor.

Additionally, as there is no cross-tolerance between LSD-25 and dopaminergic agonists or DAT protein agonists/antagonists, its action on DA is likely quite minimal (additionally, DA antagonists have been shown to have little or no impact on the effects of LSD-25). Seeing as excessive DA release is one of the primary sources of neurotoxicity in many recreational psychoactives, its absence here is further evidence for a lack of neuotoxicity as a result of LSD-25 use.


Please provide evidence for your claims that:

A. Acute LSD-25 administration results in nerve damage.
B. Acute LSD-25 administration causes permanent damage to the 5-HT "transmitter" (I assume you are referring to SERT, the serotonin transporter).
C. Intracellular stores of 5-HT/DA/NE are significantly "depleted" after acute LSD-25 administration.
D. Lack of NT density in presynaptic neurons abolishes or inhibits the activity of LSD-25.


In terms of cellular density, the only reduction in cellular density is in that of the 5-HT/DA/NE receptors which it acts as a potent agonist at; this is the process of downregulation, as stated before.
If you are unsure of what you are posting, especially if you are correcting another member's post, do your research before you begin typing! This is simple- do not post information (especially regarding pharmacology/pharmacokinetics) that you are not sure of, it can be misleading and perpetuate false-information and myths.

the information I'd come up with was actually to do with MDMA, Swim remembered that the possibility of neurotoxicity was one of the only functional differences in the actions of the two (MDMA and LSD) but couldn't remember which was which.. sorry for the mis-information again.

[doubledama]

SWIM also thinks once a week is closest interval you should trip at, but recommends one does not trip every week aka 52 weeks a year as its just not healthy. As with any drug, SWIM feels the first few times you use it will be the highest highs you ever reach, but SWIM doesnt think this is a "tolerance" so to speak.

[Baked.]

See, the thing is, SWIM did LSD for the first time about 4 weeks ago. He took 3 hits and his trip was great but it wasn't too visual. The second time SWIM took 4 hits which was 2 weeks later and SWIM's trip was extremely visual and a ton of fun. Yesterday, SWIM took 6 hits and his trip wasn't all too visual, just a little more then the first trip when he did 3. Why is this?

[Arthur Dent]

Originally Posted by Baked.

See, the thing is, SWIM did LSD for the first time about 4 weeks ago. He took 3 hits and his trip was great but it wasn't too visual. The second time SWIM took 4 hits which was 2 weeks later and SWIM's trip was extremely visual and a ton of fun. Yesterday, SWIM took 6 hits and his trip wasn't all too visual, just a little more then the first trip when he did 3. Why is this?

Could be lots of reasons.

Was it all purchased at the same time and is from the same batch? If not, then differences in the acid is the obvious one. Even if they were the same batch, there can be variances in the doses within a batch (at least there can be with blotter tabs.)

But even more than that, there are loads of variables that affect a trip - no two trips are ever really alike, it depends hugely on "set and setting", how you are feeling, what you are doing, who you are with, whether it's day or night, etc etc.

Reputation Comments on this post:

Good suggestions

[RaverHippie]

Thanks for the correction, forgot to think about down regulation of the receptors when it comes to LSD. But that's always at the top of my mind whenever the discussion is near MDMA and it completely makes sense too.

[sirmoonie]

SWIM agrees with the above. Tolerance is amazingly fast compared to other drugs. Then again, LSD is like no other. SWIM once tried tripping every day for a week, and by the third or fourth day, almost no effects at all. SWIM didn't know much then, and figured he had just taken taken a weak hit or two, so kept trying for a few days and ended up wasting a lot of hits (which were hard to come by at the time).

But, also unlike other drugs, if SWIY waits a few weeks, in SWIM's experience you are back at square one for effects. SWIM had memorable trips months after his first one, and almost equal to it. In fact, in some ways, even better than SWIM's first trip because SWIM and his insane buddies knew how to work the acid better after awhile.

Also, SWIM noticed a cross tolerance between LSD and shrooms, for whatever that is worth.

[slownerveaction]

It's interesting to read this thread and think about the Kis, EC50s, and whatever other metrics we have for deciding what something is doing.

Shampoo, have you looked much at systems biology and modern feedforward network theory? I appreciate your methodical deconstruction of a really uninformed post, for certain. I just want to step up a level from that and ask you, from one scientist to another, if you really think that knowing the thermodynamic or kinetic midpoint of a binding event really describes the behavior of it, so reduced. Well-tuned sigmoid fitting functions have upwards of five variables describing the shape of the curve, after all.