Opiate and (meth)Amphetamine Tolerances: Reduction, Prevention, Information:

We all know how much tolerance sucks; it will burn holes in your pockets, prevents you from getting as high as you used to, and increases the chance you're going to overdose. Well, I'm just here to let you know it doesn't have to be like that. There is hope to stop yourself from gaining tolerance, and to even completely reverse it to the point where you're getting as high as you did the first time. Do you remember the first time you got high on your opiate/opiod of choice, or the first time you got spun as fuck on meth/amps? It was fucking beautiful, huh?

NDMA antagonists have been shown to reduce tolerance to morphine:

Co-administration of dextromethorphan, memantine or MRZ 2/579 between tests 1 and 2 dose-dependently (5-10 mg/kg) inhibited the development of morphine tolerance.

Although this study shows DXM along with memantine stops a user from gaining morphine tolerance, there is some evidence that DXM alone can stop an opiate tolerance and maybe even reverse it. Also, even if DXM is not very powerful at directly reducing tolerance without another NMDA antagonist, it can certainly potentiate the effects of opiates, and reduces the negative effects of them:

Preclinical and double-blind single-dose placebo-controlled studies demonstrated that MorphiDex (MS:DM), a 1:1 ratio of morphine sulfate (MS) to dextromethorphan hydrobromide (DM), provides significantly greater analgesia than an equal dose of immediate release MS, with a faster onset, and a duration of > or = 8 h. The analgesic effect of MS:DM compared to MS was evaluated in 2 double-blind, multiple-dose studies in 321 patients with cancer and other chronic pain: a crossover study that consisted of two 2-wk periods and a 4-wk parallel study. As specified in the study protocols, patients took sufficient MS or MS:DM to achieve satisfactory pain control. In the crossover study, the MS:DM group required half as much morphine as the MS group to achieve satisfactory pain control (80 mg and 162 mg, respectively). The interval between doses and the time from the last dose of the day to the first dose of the next day were significantly longer for MS:DM compared to MS. In the parallel study, MS:DM also provided pain control at a significantly lower dose. After four weeks of treatment, the mean daily dose of MS increased, while there was little change in the MS:DM mean daily dose (P = 0.025) to maintain satisfactory pain control. More patients preferred MS:DM to run-in MS than preferred MS to run-in MS (P = 0.026). The addition of DM to MS did not increase the incidence of adverse events, which were those commonly associated with opioid use. These studies confirm that MS:DM provides satisfactory pain relief but at a significantly lower morphine daily dose.

From here.

Note that DXM is not the best choice for reducing tolerance, it is just the cheapest and most available. Do not think that a "stronger" dissociative like ketamine or PCP will work better, because it is likely that DXM's tolerance reducing ability is linked to the specific sigma receptors with which it is an agonist of. NMDA antagonists also reduce tolerance to amphetamine. It should be noted that some doses of NMDA antagonists will only stop tolerance, not reverse it:

A rat warm-water tail-withdrawal procedure was used to examine the effects of chronic administration of the competitive NMDA receptor antagonist LY235959 in morphine tolerant rats. Morphine dose-dependently increased tail-withdrawal latencies from 55 degree C water. When morphine (10 mg/kg) was administered twice-daily for 7 days, the morphine dose-effect curves shifted 0.3-0.5 log unit to the right. When morphine was administered for an additional 7 days, the morphine dose-effect curve shifted 0.4 log unit further to the right. Co-administration of LY235959 (1, 3, 10 mg/kg) along with morphine prevented the development of tolerance observed during the second week of chronic morphine administration. Although the highest dose of LY235959 (10 mg/kg) partially reversed tolerance in five of seven rats, tolerance was not reversed by lower doses of LY235959. These data suggest that NMDA receptor antagonists may effectively prevent the progressive development of morphine tolerance at doses that are not sufficient to reverse pre-established morphine tolerance.

From here.

Here's an extremely helpful thread from bluelight:

Amphetamine tolerance is caused by excess Ca++ influx through the NMDA receptor gated calcium channels on the outer membranes of the dopamine cells bodies in the ventral tegental area, one of two areas in the brain with concentrations of dopamine producing neurons.

As alluded to above, taking an appropriate NMDA (partial) antagonist will prevent the development of a tolerance for the effects of an amphetamine or amphetamine-like stimulant. Also, by preventing excess Ca++ influx into the neuron, an NMDA antagonist will prevent associated brain alterations and damage (excitotoxicity).

Studies have indicated that amphetamine tolerance is prevented by exogenous or endogenous agents that are able to inhibit excess Ca++ influx into the neuron through the gated calcium channels on the neuronal membrane that have NMDA subtype glutamate receptors .Glutamate , the body’s major excitatory neurotransmitter, opens the gated calcium ion channels upon attaching to the NMDA receptor. A number of other receptors are also expressed on these calcium channels, which, when stimulated, either facilitate or inhibit glutamate’s action.

It is also important that agents that inhibit calcium channel activity not also cause deficient Ca++ influx. For example, ketamine is a full NMDA receptor antagonist, that prevents excess Ca++ influx and amphetamine tolerance. But being a full NMDA antagonist, ketamine in excessive doses results in deficient Ca++ influx. This could be one of the reasons it leaves K-user in a state of disassociation.

So, basically you can stop amphetamine tolerance and even reduce it if you can stop the Ca++ influx. How can you do this? Quite easily, actually. From the same post that I quoted earlier:

Magnesium is also an NMDA antagonist. Most people are deficient in magnesium, and stress reduces magnesium levels. Whether or not one takes amphetamines, magnesium supplementation is very important for mood, general well-being and keeping stress levels under control. It is also important to take magnesium in efficient form, with adequate bioavailability. The best type is magnesium glycinate (chelated) with bioavailability at around 80%. Second best is magnesium carbonate with (I don't remember exactly) bioavailability at little above 30%. Supplemented magnesium should be at 500 mg/day level. Also there is a study which shows that children who use amphetamine-type stimulants have bad magnesium/calcium balance. Calcium levels stay the same with amphetamine usage, but magnesium levels drop.

There are a few theories regarding just how exactly NMDA antagonists are able to reduce tolerance. One of these ideas, regarding neuroplasticity , is the idea that NMDA receptors are responsible for tolerance, physical dependence, and sensitization, and so thusly NMDA antagonists are able to reduce and prevent tolerance:

RESULTS: The effects of NMDA receptor antagonists on the development of tolerance to opiate analgesia and the development of opiate physical dependence do not appear to be due to confounding behavioral effects produced by high doses of NMDA receptor antagonists, "side-effects" of a particular drug or drug class, blockade of associative learning processes, or state-dependency. Results on tolerance and sensitization to the locomotor effects of morphine are more mixed and controversial; however, there is evidence suggesting that NMDA receptor antagonists may inhibit these phenomena in a similar manner. CONCLUSIONS: NMDA receptor antagonists appear to inhibit the neural plasticity underlying some forms of opiate tolerance, sensitization and physical dependence, suggesting that NMDA receptors are involved in the development of these drug-induced changes in behavior. Further research will help to determine the neural mechanisms responsible for these phenomena, and the therapeutic potential for drugs acting on the NMDA receptor complex in the treatment of pain and addiction.

Taken from here.

For those of you in extreme pain daily, or just most of the time, I highly sympathize with you, as I have my own chronic pain problems. However, there is evidence to suggest that hyperalgesia is related to opiate tolerance, the idea of which will most likely not surprise some of you who are in pain and have a huge natural or perhaps "unnatural" opiate tolerance:

A model proposing that N-methyl-D-aspartate (NMDA) receptor and opioid receptor mechanisms overlap and interact within the same dorsal horn nociceptive neurons makes several predictions. First, hyperalgesia should be associated with opioid tolerance. Second, both hyperalgesia and tolerance to opioid-analgesia should be blocked by an NMDA-receptor antagonist. Results from our laboratory and others support these predictions and point to several clinical implications. One is that, in addition to preventing tolerance and dependence, combining NMDA-receptor antagonists with both opioid and nonopioid analgesics may increase their analgesic potency. Preclinical animal studies demonstrate these advantages and underscore the practicality of the combined administration of nontoxic NMDA-receptor antagonists with various types of analgesic drugs.

Taken from here.

This study is suggesting that NDMA antagonists are able to reduce and prevent tolerance because opiate receptors and NMDA receptors overlap in their mechanisms. If one has an idea of how NDMA receptors and opiate receptors work, this makes sense:

The signal from opioid receptor activation is transduced through ion channels for potassium, calcium, and enzyme systems in the cytosol and cell membrane (protein kinase C, adenylate cyclase, phospholipase A2, nitric oxide synthase, and possibly metabotropic glutamate receptors). Analgesia occurs as intracellular K+ increases, Ca++ decreases, and cyclic AMP (cAMP) decreases.

From here.

This is starting to make sense now, isn't it? There is further proof that opiate tolerance(and amphetamine tolerance as well) has something strongly to do with a Ca++ influx. This study suggests that nimodipine, a calcium channel blocker, can increase the analgesic effects of morphine and/or reduce tolerance:

The ability of nimodipine, a calcium-channel blocker, to enhance morphine analgesia and/or modify the development of tolerance was studied in patients with cancer pain who had needed successive increments of morphine for periods ranging from 21 to 780 days. Assessment of daily morphine consumption was the primary effect parameter. Nimodipine succeeded in reducing the daily dose of morphine in 16 of 23 patients (oral, n = 13; intrathecal, n = 3), and failed to modify it in 2 patients. Total oral daily dose was reduced by nimodipine (120 mg/day) from 282.6 +/- 47.7 mg to 158.7 +/- 26.2 mg (n = 15, P < n =" 3)" n =" 2).">

Specifically regarding amphetamines, amphetamines seem to throw off the magnesium-calcium ratio (the two are heavily related and are almost always absorbed together):

Dextroamphetamine can increase blood levels of magnesium, which causes significant lowering of the calcium to magnesium ratio in the blood. The change in this ratio may in part explain the effectiveness of stimulants like dextroamphetamine in hyperactive boys.

1 Another magnesium-amphetamine interaction involves supplements of magnesium hydroxide, which are known to cause retention of amphetamines in the body.

2 This could theoretically result in increased blood levels of these drugs. Finally, animal studies have suggested that magnesium supplements can increase learning and enhance the behavioral response to stimulants.

3 For these reasons, the use of magnesium along with amphetamines may enhance the effectiveness of these drugs in the treatment of ADD, but controlled studies of this possibility are needed.

References:

1. Schmidt ME, Kruesi MJ, Elia J, et al. Effect of dextroamphetamine and methylphenidate on calcium and magnesium concentration in hyperactive boys. Psychiatry Res 1994;54:199–210.

2. Hurwitz A. Antacid therapy and drug kinetics. Clin Pharmacokinet 1977;2:269–80.

3. Reviewed in Schmidt ME, Kruesi MJ, Elia J, et al. Effect of dextroamphetamine and methylphenidate on calcium and magnesium concentration in hyperactive boys. Psychiatry Res 1994;54:199–210.

In conclusion, while there are many theories regarding opiate/amphetamine tolerance and the relate to NMDA antagonists/Ca++ influx(et cetera), there is no concrete idea of the "why" or the "how". There are some basic ideas, but the for those of you not interested in the science of it all, and would rather just focus on the practical purposes, there is plenty of information on lowering and stopping tolerances. This is by no means meant to be an end-all post, but rather a general and basic primer for tolerance. There will be new and better information coming out all the time, so be sure to research this yourself.

Love,

-Rizzo