cocaine and methylphenidate - are they cross tolerant

[TheMerryPrankster]

This is an old thread which I found while googling the question .

http://www.bluelight.org/vb/threads/606539-Cocaine-and-Methylphenidate-is-there-a-cross-tolerance

I mean no offense to any of the original 'commenteers', but all of the responses were unsubstantiated speculation, which rapidly veered off into subjective commentary regarding the respective relative highs of the substances being debated, and a further tangent regarding the purity (or lack thereof) of street cocaine , but nothing of substance (about the substance) outside of personal conjecture that pertained in any way to answering the question in question, so to speak, before the discussion mutated into everything but the query that thread title implied.

If anyone is actually reading this (I am interested the science, not the qualitative comparison of the highs) , let me try to pose said question in the manner in which I might have phrased it, were I the original poster. The salient fact that is absent in this thread is the critically important understanding of the 'semi-familial' relationship that exists on a molecular level between cocaine and methylphenidate .

As I understand it (as little more than a layman with a Google compulsion) methylphenidate is the closest Molecular relative of cocaine, paraphrased with jocularity in my words as being 'the halfway house on the highway between coffee and cocaine'. Apparently when injected intravenously, or even insufflated, the subjective similarities between these two compounds are palpably noticeable. Methylphenidate is molecularly as close to actually being cocaine as a molecule can be, without it actually being cocaine (which I am sure leaves methylphenidate feeling depressed and inadequate by comparison to its older, sexier and more popular chemical cousin - this could explain why people on coke have a huge ego, and why methylphenidate will never amount to more than a poor man's cocaine).

But I digress...

To accurately and unambiguously pose the question of cross tolerance between these two molecularly similar chemicals , I would do so in strict regard to the neurological receptors responses and interactive relationships with both substances in the brain as pertains strictly and solely to the issue of biochemical cross tolerance, factoring in the amount of each substance required to attain a threshold dose on a clean system, and comparing that to the respective dosages required to attain the same threshold on separate subjects, each of whom had imbibed a threshold dosage of the alternative substance 24 hours prior to retesting the original compound at its previously established threshold dose, and that If the drugs were in fact cross tolerant, then the dose previously ascertained as the threshold, would be reduced in potency because of that cross tolerance, and the injection would have no noticeable subjective effect.

Only I would possibly have broken the explanation down into more than one sentence...

A simplistic view (for those whose brains became unhinged during the previous paragraph), might be to ask whether if one takes methylphenidate, does the methylphenidate use some of the receptors that would normally be reserved for cocaine, and therefore if one used methylphenidate prior to using cocaine, would the effects of the cocaine be proportionately reduced.

If true, then the answer to the question would be "Yes", regardless of any qualitative opinions, or issues of purity. If not, then the answer would conversely be "No".

I may try - and occasionally succeed - to be something of a wordsmith, but I make no claim whatsoever to be an authority in the field of chemistry. So in composing this unnecessarily and possibly annoyingly verbose question, I have - owing to my ignorance in the field of organic chemistry - in no way answered any part of my own question.

But it is my earnest hope that I have reasonably successfully defined and presented it for someone else who is gifted with the knowledge that I lack, to do so.

But I imagine the chances of such a person actually stumbling across this relatively articulate and hopelessly inconcise drivel to be about as likely as accidentally running over a dodo.

 

[endotropic]

I think you'll have some trouble answering the question of "how much cross-tolerance" from a neurological perspective, because for most responses stimulants don't actually cause a tolerance. At the right dosing interval you'll actually find the opposite: cocaine sensitizes dopamine response to other stimulants - including methylphenidate.

Also keep in mind from a pharmacological perspective cocaine and methylphenidate are similar, but not identical. Methylphenidate is a potent DA/NE reuptake inhibitor with relatively little effect on 5-HT, while cocaine affects all three relatively equally.

 

[Solipsis]

There is a difference between A) tolerance produced by two drugs i.e. the reaction of your body to certain drugs causing that drug or similarly acting drugs (not necessarily structurally similar!) to have less effect thereafter... and B) the synergy produced by combining two drugs, or priming a drug by taking another one before it.

Synergy / drug-drug interaction can be a lot more complex and does not necessarily demonstrate that much other than the actions of the two drugs being either partially the same, or just complementary.

As for cross-tolerance, this happens when the actions of two drugs are at least partially pharmalogically similar, indeed involving the same receptors or transporters.
Usually this involves downregulation, as you more or less said transporters (not receptors - although yes both have drug binding sites) are probably reduced in number to attenuate future reactions.. though I think tolerance can be a lot more complex and have a strong psychological factor (cf setting based tolerance sometimes being very significant!)

edit: endotropic - is the reason for the above that transporter downregulation doesn't happen as fast? I think there is plenty of anecdotal evidence though that eventually you get tolerance from something like cocaine but at point probably also depletion and oxidative stress issues etc.

Methylphenidate is a dopamine and norepinephrin reuptake inhibitor.
Cocaine is a dopamine, norepinephrin and serotonin reuptake inhibitor, but mostly of the former two. edit: yes about the same order of magnitude though.

So yes they share a lot of pharmacological action, so simply said yes plenty of cross-tolerance should be expected since how the body reacts to exposure to one of these drugs affects these drug binding sites the other one acts on as well.

 

[endotropic]

Usually this involves downregulation, as you more or less said transporters (not receptors - although yes both have drug binding sites) are probably reduced in number to attenuate future reactions.. though I think tolerance can be a lot more complex and have a strong psychological factor (cf setting based tolerance sometimes being very significant!)

edit: endotropic - is the reason for the above that transporter downregulation doesn't happen as fast? I think there is plenty of anecdotal evidence though that eventually you get tolerance from something like cocaine but at point probably also depletion and oxidative stress issues etc.

I don't think duration of treatment can explain those findings, look at this primate study where they gave methylphenidate for a full year: Chronic treatment with extended release methylphenidate does not alter dopamine systems or increase vulnerability for cocaine self-administration: a study in nonhuman primates.

No change in DAT levels, no change in D2/D3 receptor availability. The MPH treated animals actually had more D2/D3 receptors than control animals after treatment ended.

 

[Solipsis]

Ah, I did not expect that. Apparently similar things are true for cocaine.

What about very short term tolerance effects though?

 

[dopamimetic]

I would guess they are. One will probably begin to feel the additional serotonergic effect from the cocaine more pronounced over time as tolerance increases, as MPH does not inhibit SERT.

No change in DAT levels, no change in D2/D3 receptor availability. The MPH treated animals actually had more D2/D3 receptors than control animals after treatment ended.

This is indeed interesting. Dunno about the receptor quantities, but for the DAT levels I would speculate it is true, stimulants always had a much shorter and somewhat easier recovery period for me than SSRIs, which feel a bit like they irreversibly up regulate SERT levels. Or, alternative possibility (or additional effect) - down regulate dopamine. As D2 agonists do help with SSRI after effects.