It would indeed be extraordinary if – alone among the neurotransmitter systems of the brain – the endogenous opioid families were immune from dysfunction. Enkephalins are critical to “basal hedonic tone” i.e. whether we naturally feel happy or sad. Yet the therapeutic implications of a recognition that dysfunctional endogenous opioid systems underlie a spectrum of anxiety-disorders and depression are too radical – at present – for the medical establishment to contemplate. In consequence, the use of opioid-based pharmacotherapies for “psychological” pain is officially taboo. The unique efficacy of opioids in banishing mental distress is neglected. Their unrivalled efficacy in treating “physical” nociceptive pain is grudgingly accepted.
– Future Opioids, by David Pearce
Albert Camus wrote that the only serious question is whether to kill yourself or not. Tom Robbins wrote that the only serious question is whether time has a beginning and an end. Camus clearly got up on the wrong side of bed, and Robbins must have forgotten to set the alarm. There is only one serious question. And that is: Who knows how to make love stay? [emphasis mine] Answer me that and I will tell you whether or not to kill yourself.
– Still Life with Woodpecker by Tom Robbins
As eloquently argued by David Pearce in Future Opioids, the problem with opioids and other euphoriant drugs is not that they make you feel good, but that the positive feelings are short lived. In their stead, tolerance, withdrawal, and dependence ultimately set in after repeated use. We take the position that these negatives are not a necessary outcome of feeling free from physical or psychological malaise, for the brain has clever negative feedback mechanisms that prevent us from wireheading chemically. Rather, we believe that tackling these negative feedback mechanisms directly might be they key that unlocks never-ending bliss. Note that even if excellent anti-tolerance drugs were to be developed and commercialized for therapeutic use, we would still need to find solutions to the problems posed by wireheading. Specifically, disabling the negative feedback mechanisms in place that prevent us from feeling well all the time still leaves unsolved the problem of avoiding getting stuck in counterproductive patterns of behavior and becoming at risk of turning into a pure replicator (for proposed solutions to these problems see: Wireheading Done Right). Still, we strongly believe that finding safe and effective anti-tolerance drugs is a step in the right direction in the battle against suffering throughout the living world.
We thus provide the following list of promising anti-tolerance drugs in the hopes of: (1) piquing the interest of budding psychopharmacologists who may be weighting-in on promising research leads, (2) show a proof of concept against the fake and fatalistic truism that “what goes up has to go down” (cf. The Hedonistic Imperative), and last but not least, (3) provide hope to people suffering from physical or psychological distress who would benefit from anti-tolerance drugs, such as those who experience treatment-resistant anxiety, depression, chronic pain, or chemical dependence.
It is worth noting that this list is just a draft, and we will continue to revise it as the science progresses. Please let us know in the comment section if you are aware of compounds not included in this list (of special interest are tier 1 and tier 2 compounds).
Tier System
The list is organized by tiers. Tier 1 includes compounds for which there is evidence that they can reverse tolerance. Tier 2 deals with compounds that seem to either block or attenuate the development of tolerance, meaning that co-administering them with a euphoric agonist reduces the speed at which this euphoriant creates tolerance. Tier 3 includes potentiators. That is, compounds that enhance the effects of other substances without at the same time increasing tolerance to the extent that would be expected given the intensity of the subjective effects. Tier 4 lists compounds that, while not exactly tolerance-related, are still worth mentioning by virtue of reducing the intensity of drug withdrawals. And finally, Tier 5 includes euphoriants that have a favorable pharmacological profile relative to their alternatives, although will still produce tolerance long-term. Typically, a substance belonging to Tier X will also belong to Tier X + 1 and above (except for Tier 5) but we omit repetitions to avoid redundancy (e.g. proglumide not only reverses tolerance, but prevents tolerance, is a potentiatior, and reduces withdrawals).
Opioid System
Tier 1
- Ibogaine (see: Low dose treatment)
- Proglumide
- Naltrexone (specifically in Ultra Low Doses)
- Ibudilast (AV-411)
Tier 2
- Agmatine (may also help with chronic pain on its own)
- Curcumin (found in Turmeric; only works in high-availability forms)
- Thymoquinone (found in Nigella Sativa/black seed oil)
Tier 3
- DXM (specially potentiates the analgesia, which may be of use for chronic pain sufferers)
- Hydroxyzine (beware of its effects on sufferers of Akathisia/Restless Legs Syndrome; also bad in the long term for one’s cognitive capacity)
- L-Tyrosine
- Magnesium (possibly tier 2 but only weakly so)
Tier 4
Tier 5
- Tianeptine (its effects on the delta opioid receptor attenuates its tolerance when used in therapeutic doses)
- Mitragynine (thanks to its partial agonism rather than full agonism it is less dangerous in high doses relative to alternatives; specifically, mitragyne does not have dangerous respiratory depression properties on its own, so switching heroin addicts to it would arguably save countless lives)
GABA System
Tier 1
- Flumazenil (note: very dose-dependent)
Tier 2
Tier 3
See also.
Dopamine System
Insufficient datapoints for a tier system. Here are the few promising leads:
See also.
Tanks to Adam Karlovsky for help compiling these lists.
Another lead for reducing opioid tolerance: TRPV1 antagonists [studies on rodents…]:
> … blockade of TRPV1 with its antagonist SB366791 potentiates the analgesic effects of systemic morphine in mice with bone cancer [31]. Similarly, another TRPV1 antagonist, capsazepine, can also strengthen morphine antinociception in mice [32]. Moreover, a growing body of evidence suggests that TRPV1 is closely linked to the adverse effects of opioids, especially opioid tolerance and opioid-induced hyperalgesia [33]. Intrathecal or intraperitoneal pretreatment with the TRPV1 antagonist SB366791 or capsazepine reduces morphine tolerance and the associated thermal hyperalgesia [29].
> … chronic morphine treatment induces opioid tolerance and tolerance-associated thermal hyperalgesia, concomitant with the increase in TRPV1 expression in the spinal cord, DRG, and sciatic nerve of rats [29]. Repeated co-treatment of capsazepine (a TRPV1 antagonist, 2.5 mg/kg i.p.) with morphine alleviates the development of opioid tolerance evaluated by the hot-plate test in naive mice [32]. Similarly, oral administration of AMG0347, another TRPV1 antagonist, reverses thermal and tactile hypersensitivity induced by repetitive morphine administration in naive mice and rats [30]. – a review by Wang et al., 2022, https://doi.org/10.3390/ijerph19042387
“Median Nerve Stimulation as a Nonpharmacological Approach to Bypass Analgesic Tolerance to Morphine: A Proof-of-Concept Study in Mice” — https://www.jpain.org/article/S1526-5900(20)30084-5/fulltext
Nitric oxide (NO) synthase inhibitors seem to attenuate tolerance to μ-opioid receptor agonists like morphine (at least in rodents): https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=nitric+oxide+synthase+inhibition+opioid+tolerance (credits to David Pearce: https://www.opioids.com/).
Perhaps somewhat related, the short acting K-opioid receptor antagonist Aticaprant.
Imidazenil, is a benzo that doesnt cause tolerance.
David Pearce talked about LIH383, an opioid that doenst cause tolerance either.
Maybe we can add 9me-bc for the dopamine system
I sent you a message on reddit. I can also help expand this list exponentially
Send me an email – I don’t find your message 😛
There’s another lead for further research: the following study finds that palmitoylethanolamine doubles the time that tolerance to morphine builds up: “Delay of Morphine Tolerance by Palmitoylethanolamide, “https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4385605/. This has “only” been shown for rats, though. (Also, for the record, I wish they did the study on informed humans w/ their consent rather than experimenting on rats.)
Fantastic! I hadn’t heard of palmitoylethanolamide! I’ll certainly add it to the list next time I update it! Thank you! (Please keep them coming!).
This info is so good and so important, much thanks for doing this! Also, I would sure love it if you could do an update including what you have learned since posting this. I am sure other would really appreciate that too.
All the best and continued big thanks for all you do for us!
Hi, do you know of any anti-tolerance drugs for the serotonin system? Great article btw.
Thank you!
Unfortunately I am not aware of any anti-tolerance drug for the serotonin system. I’ll make sure to update this article if I ever do find one. It would probably be of extreme significance indeed, and I hadn’t thought of it. So thanks for the suggestion 🙂
There are a few threads on reddit listing (ultra) low dose dopamine inhibitors like resperidone and other antipsychotics will increase the sensitivity of dopamine function. If you do a quick search you will find research confirming this.
Also heard mentioned that low dose MDMA will sensitize the serotonin system, but less sure about this one.
I can’t believe ketamine was not mentioned. There’s dozens of studies on it, showing it reduces tolerance (or, as they say in the studies, the need for analgesia) to opioids. It’s tier 1.
Is that so? I think it could be possibly a tier 2 or tier 3. I don’t think it *reverses* opioid tolerance, does it?
This all got a bit heady for me in terms of the scientific vocabulary, but I know good writing and thinking when I see it. Thanks for the honesty and moralizing-free take on the opioids, etc. Keep up the good work. It almost makes me dare to be encouraged in spite of the stubborn puritanical group-think that keeps serving up horror like The War On Drugs, with the resultant bulging prisons and many people in pain now being denied medication because other people have decided to take it just to, God forbid, FEEL better.
Thank You!
signed,
Still A Hippy Between My Ears..