I have a medical background, get literally physically sick when I see my friends do too much MDMA or coke when we are out. I also love problem solving. They asked me to put those three things together to come up with a plan for them where they can do different drugs without causing any damage.

Here's the goals I listed:

*Figure out the biochemical/pharmacological process of several chemicals to know:

*how long and at what amount will cause a tolerance to build up

*how long is needed to reverse that tolerance back to baseline

*how much and/or how long until irreversible damage occurs

*what supplements can decrease the damage

Hopefully with that knowledge one could create a plan to cycle through various chemicals that hit different receptors in such a way that you could rotate through those chemicals and not get any long term damage or tolerance buildup. This has been a lot harder than I anticipated. Either there isn't a lot of information known (like how long can you do 4 lines of cocaine once a week before building up a tolerance, weekly, once a month?). Also, it seems like even if different receptors are stimulated or chemical re-uptake inhibited, there is a lot of cross pathway activation between various receptors that the different chemicals work on. Here are my notes so far...anyone want to help me out with information so I can keep my friends from frying their brains and making me sad?

Chemicals are grouped into effect categories because similar effects are often due to similar mechanisms and therefore you'd only want one from that category per overall cycle

High Mechanism and Tolerance Notes:

I. Empathogenic roll (MDMA, 4-FA, 5/6 APB/MAPB, Borax)

A. stimulate the release of and/or inhibit the reuptake of dopamine, serotonin (5-HT), and norepinephrine. These three are mainly released via TAAR1 and VMAT2. These flood the synapse and keep it from being reuptaken.

B. Serotonin: Need to give body time to build it back up, 6 weeks minimum.

C. Dopamine: replenished to near full levels after a day

D. Epinephrine: replenished to near full levels after a day

E. Norepinephrine

F. Oxytocin

G. Prolactin

H. Cortisol

I. Binds to 5-HT1 and 5-HT2 weakly

II. Stim (4F-MPH, amphetamines, 3-FPM, B2)

A. Binds to the receptors for dopamine and norepinephrine in the brain and epinephrine in the adrenal gland. Additionally, it blocks the activity of the transporters that remove catecholamines from the synapse to end the response, and actually allows for some reverse transport of endogenous catecholamines out of the neuron into the synapse so that they can bind their receptors as well.

B. Dopamine is strongly elevated: replenished to near full levels after a day

C. Norepinephrine:

D. Epinephrine: replenished to near full levels after a day

III. Psych (acid, shrooms, derivatives of both, 5-MeO-MiPT)

A. 5-HT2A and 5-HT2C agonism (tolerance is most likely due to 5-HT2A receptor)

B. Takes about 12 days to get back to baseline

IV. GHB

A. GHB interferes with GABA neurotransmitter production rates, which essentially sets off a chain reaction that offsets dopamine, glutamate and norepinephrine production outputs. These combine to produce euphoria and sedation.

B. Suppresses dopamine. This may cause increased dopamine storage, and later increased dopamine release when the GHB influence wears off [Chin and Kreutzer, 1992]. This effect could account for the middle-of-the-night wakings common with use of higher GHB doses, and the general feelings of increased well-being, alertness and arousal the next day.

C. Prolactin: Other compounds which lessen dopamine activity in the brain (such as the neuroleptic Thorazine) have been shown to result in prolactin release. Although prolactin tends to counteract many of the beneficial effects of GH, the sixteen-fold increases in GH probably overwhelm the five-fold increases in prolactin.

V. Alcohol

A. suppresses dopamine

VI. Opioids

A. bind to the μ-opioid receptor (MOR)

1 three types (1, 2, 3)

2 G-protein coupled receptor

3 mediate acute changes in neuronal excitability via suppression of presynaptic release of GABA

B. and the δ-opioid receptor (DOR)

1 G-protein coupled receptor

VII. Kratom

A. contains 7-hydroxymitragynine which has been shown to be 13x stronger than morphine as an antinociceptive agent in mice.

B. Both mitragynine and 7-HMG are selective full agonists of the μ-opioid receptor; 7-HMG appears to have higher affinity.[7] The stimulant effects appear be mediated via prevention of activation of serotonin 5-HT2A receptors and postsynaptic α2-adrenergic receptors.

C. Rhynchophylline is a non-competitive NMDA antagonist found in kratom

VIII. Cannabis

A. CB1, CB2 receptors

B. positive allosteric modulator (PAM) for μ-opioid and δ-opioid receptors

IX. Cocaine

A. Dopamine is strongly elevated: replenished to near full levels after a day

B. Inhibits monoamine uptake in rats with ratios of about: serotonin:dopamine = 2:3, serotonin:norepinephrine = 2:5

Various reuptake and binding affinities: https://www.reddit.com/r/Stims/comments/1w8w1b/various_release_reuptake_and_binding_affinities/

Supplement Notes (inhibit negative effects):

Empathogens (MDMA, 4-FA, 5/6 APB/MAPB, Borax)

Take an SSRI between the 5th and 6th hour after dropping. The SSRI will bond stronger than dopamine which is what causes a descent amount of the nuerotoxicity. Research shows rats getting it up to 6 hours after get no toxicity, but every hour waited after that increases toxicity.

Follow instructions on https://rollsafe.org/

Stims (4F-MPH, amphetamines, 3-FPM, B2)

Psych (acid, shrooms, derivatives of both, 5-MeO-MiPT)

Lysergamines need about 14 days to return to normal effect

Tryptamines need about 7 days to return to normal effect

GHB

Some people think that GHB might lower potassium levels and should therefore be taken with potassium supplementation. Some research papers have identified such an effect, others have not. If you want to play it safe, take a potassium supplement equal to 10% of the GHB dose.

Alcohol

Doesn’t seem to be very neurotoxic at moderate use levels

NAC, N-acetyl Cysteine, 200 mg 30 minutes before alcohol, not after (worse than nothing). Taking Vit C and Vit B1 have been shown to improve NAC effect. Focus on taking vodka, gin, rum

Opioids

Kratom

Cannabis

Cocaine

NAC, N-acetyl Cysteine 200 mg L-tyrosine 1-2 hours before (also augments or makes ride smoother anecdotally). I usually use 500mg-1g as needed. You can't really take too much of either (unlike L-Dopa or 5-HTP) because your body puts a metabolic rate limiting factor on those two supplements, meaning it only uptakes what it needs to balance out your neurotransmitters.

Nitrous

Vitamin B12, 0.5mg for a day or two after using nitrous