Metabolisation of smoked methamphetamine hydrochloride (Ice) and ambiguous scientific research into this subject.

[Jabberwocky]

So, I've read dozens of scientific papers on all aspects of amphetamine and remain confused about one very simple thing related to smoking: when and where does smoked crystalised methamphetamine hydrochloride convert to pure methamphetamine and when does it further metabolise into amphetamine.

You'd think this would be a basic answer evident in a grad paper on meth metabolisation. However I have noticed that almost every paper on smoked meth uses the terms METHAMPHETMINE HYDROCHLORIDE (METH-HCL - formula C10H16ClN) and METHAMPHETAMINE (METH - formula C10H15N) interchangeably even when it seems highly likely they are talking about METH-HCL at one point (for example what is in the pipe) but pure METH at another point (for example when they are talking about blood plasma levels or bioavailability).

My understanding is that people people put the crystaline form of METH-HCL (i.e. C10H16ClN) their pipe and heat it until it liquidises and undergoes a phase change becoming METH-HCL vapor. METH-HCL is not broken down when it is vaporised although it does decompose when it is overheated and burnt. I was mistaken about this for a long time and believed that what you sucked in was pure METH (i.e. C10H15N) converted from METH-HCL (i.e. C10H16ClN).

Now, in the lungs the molecule METH-HCL enters the blood (or does it change at this point?) and begins it's journey to the brain. At this point the literature invariable refers to the effects of METH and no longer makes any reference to METH-HCL. But nowhere does it explain if, when, or how the inhaled METH-HCL might have been converted to METH. It just says "METH" does this or that in the brain. Then it jumps another mysterious gap and starts talking about the metabolisation of "METH" in the liver and how X% excretes unchanged and at a rate depending on Ph of your system.

For the life of me I can't work out from any of these papers if it is C10H16ClN having psychoactive effects in the brain and whether it is C10H16ClN being excreted unchanged. However it is very clear that C10H16ClN does change at some point because smoking meth leads to the production of various metabolites including mainly Amphetamine (presumedly as C9H13N) and 4-hydroxymethamphetamine (C9H13NO).

Anybody who can clarify the if, when, and how of conversion of METH HCL to METH and in which form it has it's psychoactive effects and is excreted in a simple way will know more than almost 100 % of scientists writing about meth.

 

[CFC]

The psychoactive effects come from the free base. I think it will be helpful for you to read about deprotonation. I'm no expert but I can offer a brief explanation: the dissociation constant (pKa) for meth is about 10, which means that once you've inhaled your water soluble meth hcl into your alveoli, a certain amount will naturally begin to break apart and free base (deprotonate) in the blood stream (your blood's pH is 7-7.5 ish).

If meth had a lower dissociation constant (a lower pKa), then it would more willing to give up it's proton (deprotonate) and thus more of the free base would be 'released' to interact with plasma proteins or cross membranes into cells. For example amphetamine has a slightly lower pKa (9.9 iirc), which means more will be free in the blood to act. However it's less lipid soluble than meth, hence why meth is still more psychoactive for a given amount.

Edit: in specific terms, you'd expect about 6% of a dose of methamphetamine to be free based in serum vs. about 7% for amphetamine at any given moment once it's in circulation. That can vary a bit tho depending on organ/fluid compartment.

You might want to redirect this to N&PD.

 

[Jabberwocky]

Thanks @CFC. You know, i have never once encountered the term depronate in dozens of papers on meth metabolisation.

i wonder if it such a basic concept and so obvious to journal readers in this field there is no need to even mention it or whether indeed authors actually are really sloppy about differentiating METH-HCL from METH in their writing.

I think it’s the latter because they are often really anal about defining and detailing other things.

 

[Xorkoth]

Want me to move this to N&PD? You'll get better answers and discussion there I think.

 

[Xorkoth]

Moved from OD to NPD

 

[CFC]

Thanks @CFC. You know, i have never once encountered the term depronate in dozens of papers on meth metabolisation.

i wonder if it such a basic concept and so obvious to journal readers in this field there is no need to even mention it or whether indeed authors actually are really sloppy about differentiating METH-HCL from METH in their writing.

I think it’s the latter because they are often really anal about defining and detailing other things.

It's not a basic concept for most people, though it is one of the basics you have to learn about when you study pharmacology. Many of the people involved in writing papers about drug use from the perspective of addiction don't come from a pharmacology background though. So it's possible some can get a bit muddled or confused using different terms interchangeably if they're not completely clear what those terms relate to in the systems they're discussing.

 

[Jabberwocky]

It’s always worrying when you realise how many “experts” publishing in authorative addiction journals have no training at all in biology/chemistry/pharmacology etc etc

 

[CFC]

It’s always worrying when you realise how many “experts” publishing in authorative addiction journals have no training at all in biology/chemistry/pharmacology etc etc

Even for those that do, we don't really know exactly how this all works. I'm sure in the 20 years since I studied this, gaps in the knowledge base have been filled. But much is inferred or assumed no matter how professional people try to sound when writing up.

For example it's likely methamphetamine (base) forms little micelles with some of the constituents of blood, which would likely have some pharmacological effect, or pops in and out of various new bonds with alternative proton donors (eg citrates, acetates etc) and/or larger molecules, plasma proteins, bile salts etc, forming different complexes while making its way through the body, temporarily becoming 'active' and 'inactive' from moment to moment, which would be in the nature of many things derived thru acid-base reactions (which tend to happen very fast compared to other kinds of reactions). And that's before you even get to the 'metabolism' side of the equation that normally preoccupies most researchers, and all the different kinds of methylations, deaminations and so on.

 

[4meSM]

Crystal meth isn't just methamphetamine hydrochloride, various protonated meth molecules and chloride ions interact with each other forming a particular 3D crystal structure. As you heat it you break those weak bonds which in turn breaks apart the crystal, the gas phase likely consists of isolated meth hydrochloride molecules though.
Meth vapour is a mixture of two different phases (liquid and gaseous) and there's an equilibrium between them. As soon as the vapour enters your body, specially at the lungs and mucous membranes, the equilibrium will shift towards the liquid phase. When this happens, meth hcl will come in contact with water and it will react immediately (as CFC explained) via an acid-base reaction (which is also an equilibrium).

I don't think meth hcl continues to exist in the bloodstream, there's just way too much liquid so it's going to dissociate almost completely.
In its free form (meaning the part which isn't bound to plasma proteins) there's going to be a mixture of the freebase and the protonated forms with different counter ions. You can actually calculate the % of freebase with the Henderson–Hasselbalch equation.

 

[sekio]

Crystal meth isn't just methamphetamine hydrochloride

uhm, it is?

As you heat it you break those weak bonds which in turn breaks apart the crystal, the gas phase likely consists of isolated meth hydrochloride molecules though.

as I understand it, heating methamp.hcl will cause the freebase to dissasociate from the HCl and the vapor becomes a mixture of meth and hydrochloric acid

When this happens, meth hcl will come in contact with water and it will react immediately (as CFC explained) via an acid-base reaction (which is also an equilibrium).

more accurately it will dissolve in the water in the lungs/blood

 

[4meSM]

as I understand it, heating methamp.hcl will cause the freebase to dissasociate from the HCl and the vapor becomes a mixture of meth and hydrochloric acid

You know I actually have some doubts about this.
If heating crystal meth causes the freebase to dissociate then how would you explain the condensation on the inside of the pipe? It doesn't look like the freebase at all.
HCl prefers to exist as a gas so once it's formed it would probably get lost, I can't see it reacting with the freebase again (especially in those conditions).
And apparently the freebase is very unpleasant to smoke and tastes nothing like regular crystal meth (from what I've heard). Could the "environment" of the smoke really change the experience that much ?

Nicotine is an interesting example, IIRC it can be present both as a freebase and as a salt (or as protonated nicotine, not sure about the counter ion) in tobacco smoke, yet only the freebase exists in gas state while the protonated version is present as an aerosol.


What happens upon heating crystal meth is not entirely clear, or at least I wasn't able to find a whole lot about it.
I personally think the hydrochloride salt may be carried as an aerosol (kinda like what happens with nicotine), although the salt is also considered "volatile" at the temperatures at which it is commonly smoked. But since meth "smoke" presumably contains a mixture of different phases there may very well be an equilibrium between the freebase (as a gas) and the salt.


I did find a few old papers though, here are some interesting quotes from this book : Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants - Donald G. Barceloux

"Both methamphetamine and methamphetamine hydrochloride easily volatilize with heat; consequently, methamphetamine may volatilize during the dry - down or evaporation phase of extraction. Unlike cocaine hydrochloride, methamphetamine hydrochloride volatilizes at 300 – 305 ° C (572 – 581 ° F) without pyrolysis..."
"Unlike most methamphetamine salts, the vapor pressure of methamphetamine hydrochloride is suffieciently high to allow the efficient smoking of this salt, regardless of the size of the crystals."

"Smoking of methamphetamine in a pipe reduces the bioavailability of the drug both by deposition of active compound in the pipe apparatus and through thermal decomposition. Following insertion of a pipe in an aluminum block heated to about 300 ° C, approximately 25% of the dose remained in the pipe after the completion of the smoking of a 30 - mg dose of methamphetamine hydrochloride by healthy volunteers. During this in vitro study, the recovery of intact methamphetamine base from pipes at temperatures of 400 ° C (752 ° F), 600 ° C (1,112 ° F), and 800 ° C (1,472 ° F) was approximately 98%, 88%, and 62%, respectively. The amount of amphetamine formed as a result of the complete pyrolysis methamphetamine was about 1%. The recovery of intact methamphetamine hydrochloride was slightly less than methamphetamine base with the recovery being 81%, 62%, and 38% for these temperatures, respectively."

Governments are also concerned with the possibility of tweakers leaving their nasty meth residue everywhere they go, which could contaminate the clothes of innocent children and depreciate property values (mostly from the manufacture of the drug).
So there are a few somewhat recent articles about the volatilization of meth and that kind of stuff. The issue is that pretty much all of them involve experiments carried out in aqueous systems/solutions, crystal meth has a low volatility at room temperature. The idea is that the hydrochloride salt will be partly converted to the freebase when dissolved in water (even at pH=4, which is still relatively acidic) and since the latter isn't hydrosoluble it will then begin to evaporate slowly in a pH dependent manner

 

[unodelacosa]

as I understand it, heating methamp.hcl will cause the freebase to dissasociate from the HCl and the vapor becomes a mixture of meth and hydrochloric acid […]
more accurately it will dissolve in the water in the lungs/blood

These two statements seem at odds. Bonding methamphetamine freebase oil to an acid forms a drug salt, thus making it water-soluble so it can easily and rapidly enter the bloodstream, as you pointed out. So if it dissolves in the water in the lungs, wouldn't that imply it stays bonded to the acid molecule in question, here: Hcl? I thought the liver removed the acid molecule, as it's accustomed to doing, what with our stomachs containing hydrochloric acid.

Methamphetamine.hcl melts around 174-175°C and boils around 214-215°C (I see different data posted on this thread, though…) which is a sufficient temperature difference enough to afford an easy opportunity for vaporizing methamphetamine.hcl. The drug is heated until the first phase change from solid to liquid. At that point, a slight-but-effective vacuum is introduced in the form of taking a hit. As the user breathes in, atmospheres are removed from inside the pipe and effectively methamphetamine.hcl's boiling point is reduced, facilitating vaporization as the top layer of liquid meth changes phase to a gas.

Do note: people commonly say "smoking meth" when they in fact mean "vaporizing meth"; it kind of drives me nuts, but then I do understand that the monosyllabic “smoke” is preferable to the word “vaporize”, even if it's a misnomer of sorts. You know, nothing is actually combusted and no true smoke is typically produced or you've long since destroyed the molecule with heat.

I was under the impression that it stayed as a salt until hitting the liver where it's stripped of its hcl finally, enters the blood plasma in its base form and is sufficiently lipophilic now to cross the BBB. However, there are some metabolic processes that the lungs perform as well, and I cannot speak on whether this affects methamphetamine.hcl. Indeed, I agree with @Perforated that the literature available on the subject is generally shoddy and inconsistent, oddly so.

 

[sekio]

If heating crystal meth causes the freebase to dissociate then how would you explain the condensation on the inside of the pipe? It doesn't look like the freebase at all.

the vapor is a mixture of HCl and methamphetamine, it can quite easily recombine as it cools to form meth.HCl again

in fact the visible "smoke" from a meth pipe is likely an aerosol of tiny droplets/particulates of meth.HCl - if it was pure vapour the temperature would be 200+C!

Bonding methamphetamine freebase oil to an acid forms a drug salt, thus making it water-soluble so it can easily and rapidly enter the bloodstream, as you pointed out. So if it dissolves in the water in the lungs, wouldn't that imply it stays bonded to the acid molecule in question, here: Hcl? I thought the liver removed the acid molecule, as it's accustomed to doing, what with our stomachs containing hydrochloric acid.

As soon as the meth.HCl vapour hits the liquid in the lungs it will dissociate to "methamphetaminium" (protonated methampetamine) and chloride which will go their seperate ways. Depending on local pH some of it will also exist as a freebase bound to fats and serum protiens.

The liver has nothing to do with it.

 

[Rectify]

Methamphetamine is largely (about 50 percent) excreted as benzoic acid, about 1% as 4-OH-methamphetamine, a small amount of amphetamine, and about half as unchanged drug.

 

[Jabberwocky]

Methamphetamine is largely (about 50 percent) excreted as benzoic acid, about 1% as 4-OH-methamphetamine, a small amount of amphetamine, and about half as unchanged drug.

This is true and relatively frequently mentioned in scientific papers. What remains something of a mystery is the transformation pathway from methamphetamine hydrochloride to these metablolites.

In many papers they say 'subject consumed methamphetamine' blah blah 'subject excreted 50 % of consumed methamphetamine'. However, while it is pretty obvious the subject consumed METH.HCL it is ambiguous whether they extreted METH or METH.HCL because the research does not use terminology that differentiates the two substances or reference the one turning into the other.

 

[Rectify]

The subjects excreted freebase methamphetamine, because urine is basic IIRC.

 

[4meSM]

This is true and relatively frequently mentioned in scientific papers. What remains something of a mystery is the transformation pathway from methamphetamine hydrochloride to these metablolites.

In many papers they say 'subject consumed methamphetamine' blah blah 'subject excreted 50 % of consumed methamphetamine'. However, while it is pretty obvious the subject consumed METH.HCL it is ambiguous whether they extreted METH or METH.HCL because the research does not use terminology that differentiates the two substances or reference the one turning into the other.

Meth hydrochloride doesn't really exist as such in aqueous solutions, picture it as protonated meth and Cl- going separate ways. So it would be excreted as protonated methamphetamine since the freebase isn't water-soluble. It's true that urinary pH can vary a lot depending on your diet and a bunch of other factors, but it's usually slightly acidic (around pH5 to pH7).

This is partly why taking vitamin C or eating something acidic will decrease the duration of both meth and regular amphetamine, it decreases urinary pH allowing the kidneys to filter out more meth.
Lower pH -> higher % of protonated meth -> protonated meth will be chillin' in your bladder fully dissolved, waiting for you to pee it out.


The thing about ~50% of meth being excreted as benzoic acid seems kinda hard to believe. Mainly because the whole process involves multiple enzymatic steps : To form benzoic acid, meth needs to be converted to amphetamine and then to phenylacetone. The fact that meth has such a long half-life suggests that the first step (from meth to amp) isn't particularly fast. Just to be clear, I'm talking about human metabolism, the main metabolites can be different in other species.

One could also take a look at the metabolism of pharmaceutical amphetamines, I believe they have been more extensively studied due to the large number of prescriptions and the reduced stigma.
If half of the meth was in fact excreted as benzoic acid (and a very small % as amphetamine) it would then mean that close to 100% of dexedrine should be excreted as benzoic acid as well.

This is just the first picture I found, the % of each metabolite may vary (especially for the hydroxy metabolites).

 

[paracelsius]

You'd think this would be a basic answer evident in a grad paper on meth metabolisation. However I have noticed that almost every paper on smoked meth uses the terms METHAMPHETMINE HYDROCHLORIDE (METH-HCL - formula C10H16ClN) and METHAMPHETAMINE (METH - formula C10H15N) interchangeably even when it seems highly likely they are talking about METH-HCL at one point (for example what is in the pipe) but pure METH at another point (for example when they are talking about blood plasma levels or bioavailability).

By “pure” METH (as opposed to the hydrochloride salt) you mean free base METH right? The reason in papers you see people talk about methamphetamine or the hydrochloride interchangeably is that they’re no point really as far as its pharmacology is concerned. As @sekio mentioned, once the hydrochloride (ie the protonated METH you smoke with chloride as counterion) is absorbed in the plasma via lungs, it gets into equilibrium (MethHydrochloride <--------> free base Meth + HCl). Same thing happens once vaporized in the vapor phase.

Of course methamphetamine being a base (pKa~10.4) at normal physiological pH (7.4) the equilibrium is shifted to the left. So, most of it exists in the plasma in the form of protonated METH (with the counterion being chloride or other anions in the body). Actually pretty much all of it is in the form of protonated: for 1 non-protonated (free base) molecule you’ll have ~1000 molecules in protonated form (3 log units difference between pKa of meth and plasma pH). So essentially there is pretty much no free base METH ("pure METH") once absorbed. This is true for the free base as well. Once absorbed (by eating or vaping) it will quickly get converted to the protonated form. That’s why you’ll see scientists referring to METH HCl (pure crystal) and METH only once in solution. Correct way will be to call it methamphetaminium (protonated form of methamphetamine with Cl counterion or others anions in the body like phosphate, sulfate, carboxylate...etc but mostly Cl as it is the most abundant).

Anybody who can clarify the if, when, and how of conversion of METH HCL to METH and in which form it has it's psychoactive effects and is excreted in a simple way will know more than almost 100 % of scientists writing about meth.

As for binding/blocking of the Monoamines transporters in the brain which is the psychoactivity mechanism of stims, it is the protonated METH that binds and blocks them as you could imagine. Else, if that was the free base ("pure" METH) that is psychoactive, then you’ll have to smoke ~1000x more METH to feel the same effects (ie, you’ll need smoke 50grams of meth!!!!!??? to feel effects of 50 mg). And that is because concentration of free base is so low relative to the salt in the body/brain. Here is a pic of METH (protonated form) bound to the dopamine transporter DAT (notice the counterion is now a carboxylate part of the DAT protein: protonoted METH in green with NH2+ in blue and DAT carboxylate COO- in blue-red). Same things with the other 2 (NET and SERT).

[???how do you upload image???]

Another issue with METH tho (and related amps) is that it is a releaser of Dopamine, Norepinephrine and Serotonin, in addition to being a reuptake inhibitor of all 3. Not only it blocks the reuptake of already existing baseline DA, NE, SERT in the synapse, it enters the presynaptic neuron and dumps more DA/NE/SERT that have been stored in storage vesicles (excess reuptaken to regulate the level of neurotransmitters) into the synaptic cleft. So much so that it jacks up DA/NE/SERT concentration in the synapse by up to a whooping ~800% iirc! 8 times the baseline!!!). Huge dump! Which is why METH rush (and crash!) is so incredibly powerful.

The reason I mentioned that last point is that one theory I’ve seen on how METH does that, suggests that actually free base METH (not the protonated form!!) enters the presynaptic neuron, get transported to storage vesicles (by “fooling” the transport system “it is dopamine or ne or sert” ie act as a substrate) and once there gets converted to the protonated form and this raise the pH (decrease protons concentration inside the storage vesicles. Now, that fools the other transporters (vesicular monoamine transporters VMAT) and put them in reverse mode, basically “thinking” there is too much neurotransmitter on storage (and not enough in the synapse). So VMAT dumps stored Dopamine or NE or SERT by going in reverse mode (transporting them from inside the storage vesicles to the synaptic cleft) instead of normally transporting excess from the synapse to presynaptic neuron storage vesicles.. But that is only a theory, nobody really know for sure how METH does that!! Interesting drug!.. Hope that helps clarify a little bit..Good’day everybody

 

[unodelacosa]

By “pure” METH (as opposed to the hydrochloride salt) you mean free base METH right? The reason in papers you see people talk about methamphetamine or the hydrochloride interchangeably is that they’re no point really as far as its pharmacology is concerned. As @sekio mentioned, once the hydrochloride (ie the protonated METH you smoke with chloride as counterion) is absorbed in the plasma via lungs, it gets into equilibrium (MethHydrochloride <--------> free base Meth + HCl). Same thing happens once vaporized in the vapor phase.

Of course methamphetamine being a base (pKa~10.4) at normal physiological pH (7.4) the equilibrium is shifted to the left. So, most of it exists in the plasma in the form of protonated METH (with the counterion being chloride or other anions in the body). Actually pretty much all of it is in the form of protonated: for 1 non-protonated (free base) molecule you’ll have ~1000 molecules in protonated form (3 log units difference between pKa of meth and plasma pH). So essentially there is pretty much no free base METH ("pure METH") once absorbed. This is true for the free base as well. Once absorbed (by eating or vaping) it will quickly get converted to the protonated form. That’s why you’ll see scientists referring to METH HCl (pure crystal) and METH only once in solution. Correct way will be to call it methamphetaminium (protonated form of methamphetamine with Cl counterion or others anions in the body like phosphate, sulfate, carboxylate...etc but mostly Cl as it is the most abundant).

As for binding/blocking of the Monoamines transporters in the brain which is the psychoactivity mechanism of stims, it is the protonated METH that binds and blocks them as you could imagine. Else, if that was the free base ("pure" METH) that is psychoactive, then you’ll have to smoke ~1000x more METH to feel the same effects (ie, you’ll need smoke 50grams of meth!!!!!??? to feel effects of 50 mg). And that is because concentration of free base is so low relative to the salt in the body/brain. Here is a pic of METH (protonated form) bound to the dopamine transporter DAT (notice the counterion is now a carboxylate part of the DAT protein: protonoted METH in green with NH2+ in blue and DAT carboxylate COO- in blue-red). Same things with the other 2 (NET and SERT).

[???how do you upload image???]

Another issue with METH tho (and related amps) is that it is a releaser of Dopamine, Norepinephrine and Serotonin, in addition to being a reuptake inhibitor of all 3. Not only it blocks the reuptake of already existing baseline DA, NE, SERT in the synapse, it enters the presynaptic neuron and dumps more DA/NE/SERT that have been stored in storage vesicles (excess reuptaken to regulate the level of neurotransmitters) into the synaptic cleft. So much so that it jacks up DA/NE/SERT concentration in the synapse by up to a whooping ~800% iirc! 8 times the baseline!!!). Huge dump! Which is why METH rush (and crash!) is so incredibly powerful.

The reason I mentioned that last point is that one theory I’ve seen on how METH does that, suggests that actually free base METH (not the protonated form!!) enters the presynaptic neuron, get transported to storage vesicles (by “fooling” the transport system “it is dopamine or ne or sert” ie act as a substrate) and once there gets converted to the protonated form and this raise the pH (decrease protons concentration inside the storage vesicles. Now, that fools the other transporters (vesicular monoamine transporters VMAT) and put them in reverse mode, basically “thinking” there is too much neurotransmitter on storage (and not enough in the synapse). So VMAT dumps stored Dopamine or NE or SERT by going in reverse mode (transporting them from inside the storage vesicles to the synaptic cleft) instead of normally transporting excess from the synapse to presynaptic neuron storage vesicles.. But that is only a theory, nobody really know for sure how METH does that!! Interesting drug!.. Hope that helps clarify a little bit..Good’day everybody

Here's what I don't understand… methamphetamine.hcl is soluble in polar solutions, and it's hydrophilic AF, right? Meanwhile, the freebase oil is non-polar in nature and thus: lipophilic. Compounds need to be sufficiently lipophilic to cross the blood brain barrier. So, are you saying that methamphetamine.hcl is capable of crossing the BBB despite generally being hydrophilic?

 

[paracelsius]

Here's what I don't understand… methamphetamine.hcl is soluble in polar solutions, and it's hydrophilic AF, right? Meanwhile, the freebase oil is non-polar in nature and thus: lipophilic. Compounds need to be sufficiently lipophilic to cross the blood brain barrier. So, are you saying that methamphetamine.hcl is capable of crossing the BBB despite generally being hydrophilic?

Good point. Yeah the protonated form of METH+ (METH.HCl) is very hydrophilic while the free base METH is lipophilic. In principle, charged/hydrophilic molecules do not cross BBB but lipophilic compounds like free base METH do. To understand how METH+ get transported to the brain you got to back to the equilibrium I mentioned (MethHydrochloride <--------> free base Meth + HCl).

1. Once absorbed in the blood, the lipohilic METH free base readily crosses the BBB (fast).
2. This shifts the equilibrium (in the blood) to the right (more MethHydrochloride gets converted to free base in the blood to compensate). Mass action principle of chemical equilibrium.
3. Once the free base is inside the brain, it gets converted to the charged form (MethHydrochloride for simplicty) again by virtue of Mass action.
4. Now, the charged form (MethHydrochloride in the brain) cannot get back out (too polar/hydrophilic) and goes on to interact with its target transporters, receptors..etc.
5. End results: one way transport of MethHydrochloride via the free base to the brain until the whole thing reaches equilibrium (Meth in brain/plasma/tissue..etc). Actually this happens pretty fast (minutes if not seconds). I am not sure about the ratio METH concentration (in brain) versus METH(plasma) at steady-state but iirc it is somewhere near 5:1 (got to check that out tho). I am sure someone has measured it, at least for dextrometh since it is an approved drug.

Now you may ask: how does METH+(ie MethHydrochloride) eventually get out the brain and excreted?

As the drug (protonated METH) gets slowly metabolized (this is slow process! T1/2 anywhere from 12 to 72 hours) and excreted, you go on reverse: shift the equilibrium to the left since you are now removing the MethHydrochloride! from plasma by converting it to metabolites and pissing/sweating/shitting (pardon the term!) them off. Free base then crosses BBB back to the blood to compensate (mass action again). Gets converted to METH+ that either get pissed off unchanged or as metabolites. So more free base gets out the brain..etc etc until all the drug is cleared from the system..hope that helps (check out transport of weak bases on pubmed)..Good'day y'all