A Briefer on Tolerance

A. Introduction. MDMA is an exciting and promising clinical compound which has shown promise in the treatment of serious mental health conditions such as PTSD. It has also been explored for a variety of indications ranging from obsessive compulsive disorder (OCD) to intimate couples therapy. There are, however, certain limitations on the use of MDMA in a clinical context. MDMA’s neurotoxic and cardiotoxic effects have been widely discussed in scientific literature and are explored in ‘Briefer on MDMA toxicity.’ However, MDMA tolerance is also a critical and largely underexplored issue. Anecdotally, this is often described as a permanent or long term ‘loss-of-magic.’ (https://www.vice.com/en/article/y3pejk/losing-the-magic-mdma). Tolerance to MDMA has also been demonstrated in relevant preclinical literature and in some human studies. In this briefer, we hope to better understand the incidence of MDMA tolerance, suggest some possible mechanisms for its development and finally, explore whether these mechanisms may provide a framework for understanding the tolerance phenomenon in psychiatric compounds generally.

B. Incidence of MDMA Tolerance. MDMA has been noted to produce tolerance effects in a wide variety of informal settings (https://erowid.org/chemicals/mdma/mdma_effects_lossofmagic1.shtml). While some users report loss of drug effect after as few as 10 lifetime sessions, others maintain that even a regular regimen of dosing does not produce tolerance effects. On the peer-reviewed front, [ Green et al. ] found consistent subjective reports of tolerance in long-term MDMA users, consistent with neurotoxicity. [ Steinkellneret al. ]’s review of amphetamine toxicity also found evidence of consistent tolerance in users. [ Parott et al. ] demonstrated chronic tolerance to MDMA with repeat use (https://pubmed.ncbi.nlm.nih.gov/15671132/). [ Kirkpatrick et al. ] noted tolerance effects of MDMA as well(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161650/#:~:text=The%20drug%20produced%20very%20similar,a%20number%20of%20methodological%20differences).

C. Possible Mechanisms of MDMA Tolerance. Despite the anecdotal examples of tolerance and the subsequent implications for longer term treatment, no conclusive mechanisms for MDMA tolerance have been identified. MDMA tolerance in model animals has, however, been demonstrated in a number of peer-reviewed studies. [ Fantegrossi et al. ] found that prolonged MDMA self-administration progressively weakens response in rhesus monkeys and eventually fails to maintain self-administration (https://pubmed.ncbi.nlm.nih.gov/16555062/). Some studies have identified impaired serotonin release via 5HT-(2A/C)-receptor desensitization as one potential mechanism. [ Jones et al. ] found that pre-treatment with MDMA in rodents created dose-dependent emergence latency which was attenuated with a 5HT-2C antagonist, suggesting de-sensitization of this receptor (https://pubmed.ncbi.nlm.nih.gov/20477756/). [ Baumann et al. ] found that single doses of MDMA were sufficient to significantly reduce hormone secretion and 5-HT release when challenged with i.v administration of MDMA (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2390896/). This is consistent with (Benningfield & Cowan, 2013; Di Iorio et al.; Urban et al.) who all showed changes in expression of 5HT receptors in humans exposed to MDMA.

However, there has also been significant work linking the somewhat unique chronic tolerance of MDMA to the neurotoxic profile of MDMA. In a review of potential dangers of using MDMA for psychotherapy, [ Karlsen et al. ] posits neurotoxicity as a potential link to the chronic shift in MDMA’s dose response curve (https://onlinelibrary.wiley.com/doi/full/10.1111/j.1742-7843.2007.00159.x). [ Jones ] found abnormal 5HT signaling to be a root cause of MDMA tolerance, consistent with loss of SERT terminals from direct toxicity. [ Parrott et al. ], in one of the most definitive studies of chronic MDMA toxicity, concluded that distinct underlying mechanisms related to serotonergic neurotoxicity were responsible for MDMA’s chronic tolerance given the lack of convenient parallels in amphetamines with a similar pharmacologic profile (https://journals.sagepub.com/doi/10.1177/0269881105048900).

D. Tolerance Profile of Amphetamines and Phenethylamines. While the chronic tolerance profile of MDMA appears to be relatively unique to the molecule, drugs in the amphetamine and more broadly phenethylamine class are also prone to diminishing or differential effects with repeat use. Methylphenidate. A literature review by [ Handelman et al. ] found that about 24% of patients developed tolerance to methylphenidate (Ritalin), in some cases requiring a dose of over 60 mg to maintain the effect (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9332474/). A link to the original study can be found at https://ps.psychiatryonline.org/doi/epub/10.1176/appi.ps.53.1.102. [ Sproson et al. ] separately found that methylphenidate attenuated pre-synaptic dopamine function and had some notable tolerance building effects. [ Cunill et al. ] found a negative correlation between the length of treatment and the efficacy of pharmacological treatment. This may show evidence some sort of chronic tolerance for stimulant medication for up to 26 weeks (https://pubmed.ncbi.nlm.nih.gov/26446868/). Amphetamine/Adderall. Somewhat surprisingly, there has not been substantial recent work on evaluating the tolerance of amphetamine and amphetamine-derived compounds (Adderall), especially with respect to extended use. However, some evidence for tolerance does exist. [ Turner et al. ] found that chronic oral amphetamine treatment of rodents showed drug tolerance and reduced hyper-locomotor activity (https://eprints.whiterose.ac.uk/127130/2/Turner%20et%20al%202018b%20for%20repository.pdf). Despite the relative lack of newer publications, papers published during the mid-late 20th century have shown evidence of amphetamine tolerance. [ Lewander (1971) ] showed that chronic administration of amphetamine sulfate drives tolerance and desensitization in rodents (https://link.springer.com/article/10.1007/BF00403992). Furthermore, [ Leith and Barrett ] showed that d-amphetamine drives not only tolerance to itself but also cross-tolerance to other amphetamines due to decreases in polysynaptic receptor sensitivity in rodents (https://pubmed.ncbi.nlm.nih.gov/6791199/). In terms of human studies, tolerance effects have been noted as well, especially by [ Strakowski et al. ] who found a modest decrease in d-amphetamine effects with chronic dosing (https://www.nature.com/articles/1395696.pdf). Lastly, although amphetamine-derived compounds have produced conflicting accounts of tolerance in the literature, the latest version of the Merck Manual unequivocally states that amphetamines are tolerance-forming with repeat use (https://www.merckmanuals.com/professional/special-subjects/illicit-drugs-and-intoxicants/amphetamines).

E. Tolerance Profile of SSRIs. Selective serotonin reuptake inhibitors (SSRIs) are a class of compounds widely used for the treatment of depression. Notable tolerance is so widespread that a specific term (“tachyphylaxis”) is widely used by academics and clinicians to describe it. In a definitive review of tachyplylaxis, [ Targum, MD ] found that up to 33% of depressed patients who achieved remission of symptoms experienced a recurrence between 14 and 54 weeks after starting treatment. Other referenced studies found a tachyphylaxis rate of around 25% in a longitudinal study (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4008298/). [ Fava et al. ] found that fluoxetine loss-of-effect could be attenuated by doubling the daily dose, suggesting a pharmacologic tolerance as a possible mechanism of tachyphylaxis (https://pubmed.ncbi.nlm.nih.gov/7852252/). More specifically, [ Balter ] and [ Mann ] have found that downregulation of 5HT-1A receptors may be an variable implicated in loss-of-effect (https://pubmed.ncbi.nlm.nih.gov/6521674/, https://pubmed.ncbi.nlm.nih.gov/6315778/). [ Santarelli et al. ] found that neurogenesis was critical for the antidepressant effects of SSRI’s, suggesting that chronic administration of these substances may alter the process of hippocampal neurogenesis (https://pubmed.ncbi.nlm.nih.gov/12907793/). This theory was further developed by [ El-Mallakh ] who suggested that drug-resistant depression was the result of neuroplastic processes related to dendritic arborization following chronic antidepressant use (https://pubmed.ncbi.nlm.nih.gov/21459521/).

F. Conclusions. Though underreported, tolerance to typical regimens of medication used to treat chronic mental illness has been shown in relevant literature. While the tolerance profile of amphetamine-like compounds (such as Adderall) is somewhat conflicting and understudied, tachyphylaxis is a well-known problem related to SSRIs, with several possible causes including downregulation of relevant CNS receptors and broader neurostructural changes. Additional work will have to be done to further elucidate the mechanisms and to possibly uncover relevant mechanistic analogues.