O-Desmethyltramadol (O-DSMT) is an opioid that has primarily been used indirectly due to it being a primary metabolite of the analgesic tramadol. Since the 2010s it has occasionally been used on its own as it has been sold through the grey market/research chemical market.
It has a longer duration than tramadol and more typical opioid-like effects, although it still impacts monoaminergic systems to an extent that might somewhat influence the effect profile.
O-Desmethyltramadol = O-DSMT; Desmetramadol; O-Demethyltramadol
Molecular formula: C15H23NO2
Molecular weight: 249.354 g/mol
- Light: 15 – 30 mg
- Common: 30 – 50 mg
- Strong: 50 – 70+ mg
Some people report using doses in the hundreds of milligrams, including via more intense routes of administration like intravenous. Because too little information exists about higher doses and non-oral routes, it is best to stick with common oral doses.
It does seem true that some users fail to receive any notable effects at common doses and have to use over 100 mg to receive a positive experience. Despite this, common doses are still recommended as they will usually be sufficient in someone without a tolerance.
A few reports of rectal administration exist. When using via this route nausea might be reduced and it may be somewhat more potent vs. oral use, so dosing needs to be adjusted accordingly.
Oral use is usually preferred to intranasal.
- Total: 5 – 7 hours
- Onset: 00:30 – 01:00
O-DSMT has not been studied for medical uses, but it likely has efficacy in the same conditions as typical opioids like oxycodone and morphine. Also, based on research with tramadol, there’s some evidence indicating how much benefit people receive from tramadol is at least partly dependent on how much O-DSMT they produce (Kirchheiner, 2008 ; Stamer, 2007 ; Poulsen, 1996).
An animal study in rats did find O-DSMT had analgesic effects and those were blocked by a MOR antagonist (Valle, 2000). The effects were seen with the (R) enantiomer, as the (S) enantiomer produced no antinociception or respiratory depression at 2 to 10 mg/kg IV.
- Mood enhancement
- Physical euphoria/pleasant physical sensations
- Impaired respiration
- Reduced heart rate and blood pressure
- Cognitive impairment
Users who are seeking a classic opioid effect tend to prefer O-DSMT to tramadol, which makes sense when considering its pharmacology. Often it’s said to be pretty good in people who are relatively opioid naive and/or those who don’t have an opioid tolerance, whereas people who regularly use the strongest opioids may not find it very effective. It’s been compared favorably to codeine, tramadol, and kratom by a number of users.
It does not usually produce a substantial “rush” of euphoria and is therefore weaker in that respect than certain opioids, but it can reliably offer a relaxed, chill, and pleasantly sedated state. Relative to tramadol is can bring someone to a nodding-like state of relaxation and impaired consciousness, although too few reports of its effects exist to know if it as frequently produces a “nod” as other opioids.
Cognition will usually be somewhat impaired, leading to slowed thinking or brain fog. This is partly due to the sedating effect of O-DSMT not being counteracted by monoaminergic effects like it would be with tramadol and as a result, if someone is trying to receive mood enhancement and anxiolysis while still being functional, tramadol is sometimes a preferred drug.
Some mental stimulation is sometimes reported at light to common doses, especially early in the effect period, though this is less common than with tramadol.
Feelings of warmth and general coziness or fuzziness are often reported with common to strong doses and it can also be moderately numbing for sensations, though not nearly to the extent seen with dissociatives.
Itchiness is sometimes reported like with other opioids. It can be annoying, but in a fair portion of people the sensation is not very unpleasant and can even become pleasant upon itching. This may be combated by using an antihistamine with O-DSMT, though ones that affect the brain to a substantial degree, like DPH and hydroxyzine, will potentiate the sedative effects.
A strong sensation of labored breathing can be induced with strong doses. If you’re taking a common dose and notice a change in the sensation of respiration you most likely aren’t in any physical danger, but with an overdose the sensation of labored breathing is a sign of danger, which is why common doses are recommended.
Among the after effects are minor to moderate headache, edginess/irritability, decreased motivation, and insomnia for up to a few hours after it ends, so it’s better to dose earlier in the day if you don’t want sleep to be affected. By the following day the after effects are usually minor to non existent.
O-DSMT has two stereocenters, giving four potential stereoisomers, and it is sold as a mixture of enantiomers, R,R-O-DSMT and S,S-O-DSMT. The R enantiomer is thought to be the primary active substance since it has a very high affinity for the mu opioid receptor (MOR) and studies on tramadol confirmed the S enantiomer of that substance is largely less active than the R enantiomer.
When someone uses tramadol they will generate O-DSMT via O-demethylation, which is historically how most people have come into contact with the substance.
One study found that, like tramadol, it is cross-reactive with the EMIT II+ immunoassay for PCP (Hull, 2006). Tramadol itself is already pretty weak as a cross-reactive substance and O-DSMT is even weaker, so it doesn’t seem very likely that someone would test positive for PCP after using O-DSMT.
In the 2010s tramadol was detected in soil in the far north of Cameroon. Although this was taken as a sign that it may be a naturally occurring drug, more comprehensive research found local farmers and users had been a source of contamination in the region, in large part due to animals being given the substance and then excreting it, leading to its presence in the soil and plants. The same situation was seen with some of tramadol’s metabolites, O-DSMT included, but like with tramadol it is no longer thought these drugs occur naturally (more information is available on the tramadol page).
The strongest pharmacological evidence pertaining to O-DSMT shows it is a MOR agonist and that property fits with its reported effects in humans. It’s also the basis for tramadol having long been described as dual-action analgesic: tramadol inhibits pain as an SNRI and as an opioid because of its metabolism to O-DSMT.
Tramadol is easily classified as an SNRI because it has core actions of inhibiting serotonin and norepinephrine. This is mostly absent with O-DSMT. Bamigrade (1997) reported R,R-Tramadol significantly blocked serotonin uptake at 5 μM in vitro, while S,S-Tramadol and O-DSMT had no significant impact. Another in vitro study looking at noradrenergic activity showed tramadol significantly increased extracellular norepinephrine levels by 25% at 1 μM, while even at 10 μM O-DSMT only had a weak facilitatory effect of 17% (Driessen, 1993). Given how drastic the potency difference is between opioid activity and monoamine reuptake inhibition activity for O-DSMT, it effectively loses the SNRI characteristic of tramadol.
Further confirming the importance of MOR, Sevcik (1993) tested the impact of the tramadol and O-DSMT enantiomers on locus coeruleus activity using rat brain slices in vitro. With differing potencies, all four drugs could significant reduce locus coeruleus activity. The effect of R,R-O-DSMT was nearly abolished just with 0.1 μM of the opioid antagonist naloxone, while additional use of rauwolscine (an adrenergic antagonist) was required to block the impact of R,R-tramadol and S,S-O-DSMT. The (R) enantiomer of O-DSMT was unaffected by rauwolscine and even the (S) enantiomer only showed partial attenuation, with full attenuation being seen once naloxone was present.
Over time some additional actions of O-DSMT have been indicated. Tramadol and O-DSMT both inhibit TRPA1(transient receptor potential ankyrin 1) at relevant concentrations, though tramadol is more potent (Miyano, 2015). TRPA1 is involved in sensation and blocking it has some antinociceptive effects, although not in a way that clearly explains most of what tramadol or O-DSMT do.
Racemic O-DSMT has a 19 nM affinity for MOR, compared to the substantially higher 12,000 nM affinity seen with tramadol (Volpe, 2011). The (R) enantiomer of O-DSMT has a much higher affinity (3 nM vs. 674 nM). Other studies have given similar affinity values for the drug.
Direct inhibition of Substance P, which is involved in pain transmission, was seen in vitro, with O-DSMT inhibiting the activity of Substance P to 71% of its normal level at a low concentration of just 0.1 μM (Minami, 2011). Substance P is a neurotransmitter released within afferent nerve fibers into the spinal cord and it plays a role in the excitatory synaptic input required to ultimately produce pain sensation.
There may be a serotonergic component to the analgesia offered by O-DSMT, although that could very well be indirect given the pain transmission system is complex and monoamines are involved throughout key parts of it, therefore disturbing monoamine activity could reduce the impact of O-DSMT but in an indirect manner. Yanarates (2010) demonstrated in mice that a spinal serotonergic lesion induced by 5,7-DHT significantly blocks the antinociceptive effect of tramadol and O-DSMT. Specifically administering a 5-HT7 antagonist also blocked the antinociception, whereas ketanserin and ondansetron did not attenuate the effects, suggesting a role of 5-HT7, but not 5-HT2 and 5-HT3 receptors.
5-HT2C antagonism may not play a role in tramadol or O-DSMT’s analgesia, but O-DSMT has been shown to at least bind to that site and could be causing some effect as a result. In vitro research using rat 5-HT2C expressed in Xenopus oocytes showed O-DSMT inhibited serotonin-evoled calcium-activated chloride currents, with even 0.1 μM of O-DSMT reducing the current to 74.9% of control (Horishita, 2006).
An in vitro study has shown inhibition of muscarinic M1 receptor activity (Nakamura, 2005), although in humans the effects of tramadol and O-DSMT largely don’t align with those of an antimuscarinic and this effect, if present in humans, may be minimally relevant at any typical dose.
- Racemate Tramadol
- MOR: 2.1 μM
- DOR: 57.6 μM
- KOR: 42.7 μM
- NE uptake inhibition: 0.78 μM
- Serotonin uptake inhibition: 0.9 μM
- MOR: 1.3 μM
- DOR: 62.4 μM
- KOR: 54.0 μM
- NE uptake inhibition: 2.51 μM
- Serotonin uptake inhibition: 0.53 μM
- MOR: 24.8 μM
- DOR: 213 μM
- KOR: 53.5 μM
- NE uptake inhibition: 0.43 μM **** (most potent NE blocker of the listed drugs)
- Serotonin uptake inhibition: 2.35 μM
- MOR: 0.0034 μM
- DOR: NR
- KOR: NR
- NE uptake inhibition: NR
- Serotonin uptake inhibition: NR
Note: This is an outlier study in multiple respects, giving tramadol and O-DSMT high affinity for δ and κ opioid receptors, not just MOR. For now this claim should be viewed with skepticism. More research is needed.
- MOR (hot ligand: DAMGO): 1.6 μM
- DOR (hot ligand: Naltrindole): 0.0094 μM
- KOR (hot ligand: U69,593): 0.014 μM
- MOR (hot ligand: DAMGO): 0.0086 μM
- DOR (hot ligand: Naltrindole): 2.9 μM
- KOR (hot ligand: U69,593): 0.450 μM
Half-life: 6.7 hours (Grond, 2004) or 9 hours (Dayer, 1994)
Tmax: 3 hours
Cmax (after 100 mg of tramadol): ~25% of the tramadol concentration, which would be around 0.075 μg/mL. This will vary significantly based on CYP2D6 phenotype and may be affected by OCT phenotype.
AUC: ~25% that of tramadol (Grond, 2004). This will vary significantly based on CYP2D6 phenotype.
Renal impairment doubles the half-life of O-DSMT (Miotto, 2016).
Whereas tramadol’s effects are impacted by genetic differences in at least a couple areas, namely CYP2D6 and OCT1, the impact of genetics on O-DSMT may be reduced. When people receive opioid effects from tramadol that is mostly because they are converting it, with the help of CYP2D6, to O-DSMT. Taking O-DSMT bypasses that and should give a more consistent effect profile if pure opioid-like properties are what the user desires.
Organic cation transporter 1 (OCT1)
Because O-DSMT itself is still going to be metabolized and uptake into the liver for that metabolism can vary based on OCT1 status, there can still be some inter-individual variability there. OCT1 mediates the uptake of the drug into the liver, as it’s a transporter expressed on the membranes of hepatocytes. Polymorphisms are common, like with CYP2D6. For example, around 9% of Europeans have a “poor transporter” profile correlating with higher levels of drugs taken up by OCT1, which probably extends to O-DSMT, allowing those users to get stronger effects per dose.
There’s some evidence OCT1 really is relevant in the effects of tramadol and likely, by extension, O-DSMT. Stamer (2016) demonstrated a poor transporter phenotype correlated with nausea/vomiting and Tzvetkov (2011) found miosis was increased in poor transporters. Both findings point to reduced OCT1 activity causing more opioidergic effects because O-DSMT is not being metabolized as quickly.
Tzvetkov (2011) also reported in vitro membrane penetration was strong for tramadol even when OCT1 was absent, suggesting differences in OCT1 will specifically affect the pharmacokinetics of O-DSMT, whose penetration is low without OCT1.
Multiple studies have show a person’s OCT1 profile affects the pharmacokinetics of O-DSMT (Stamer, 2016 ; Tzvetkov, 2011 ; Matic, 2016).
There is very little history specifically related to O-DSMT because it has not been marketed on its own by pharmaceutical companies and comparatively little research has been conducted on it relative to tramadol.
It appears to have first shown up on its own in the 2000s and then it became a somewhat popular substance around the 2010s, with grey market/research chemical vendors selling it online. Analysis of commercial incense products purchased in 2008 and 2009 revealed O-DSMT was present alone (n=1) or with caffeine (n=2) in three of 140 samples (Dresen, 2010).
Bodily samples analyzed by Sweden’s STRIDA project, which began in 2010, showed 9 of 103 drug samples were positive for tramadol or O-DSMT (Helander, 2013). 3 exclusively contained O-DSMT, 4 had both, and 2 were positive just for tramadol.
In Germany, a user of an alleged kratom product called “Krypton” tested positive for O-DSMT and kratom alkaloids, but not for tramadol (Arndt, 2011).
Analysis of 251 samples submitted to Sweden’s STRIDA from 2010 to 2015 revealed a single case of powder containing O-DSMT, yet another “Krypton” branded sample suspected to contain either kratom alkaloids or O-DSMT had no detectable psychoactive substance in it (Backberg, 2018).
O-DSMT continues to be used, but it is not a very popular opioid, in part because of limited availability and a somewhat high price, according to user reports. It has occasionally shown up in products, such as those alleged to contain kratom, perhaps to increase the strength of the mixture, but overall it is not a prevalent substance.
Legality (As of January 2019)
Note: This list is not exhaustive. Always check your local laws to verify how O-DSMT is treated in your region.
Australia: Not specifically controlled
United Kingdom: Class A
United States: Uncontrolled
Few detailed reports of its overdose effects are available but there is good reason to suspect it more readily leads to a stereotypical opioid-like overdose than tramadol. This would include effects like impaired consciousness, coma, respiratory depression, nausea, constipation, slowed heart rate and/or blood pressure, and miosis.
Because there may still be a small amount of monoaminergic effects, atypical overdoses may produce tachycardia, hypertension, and non-hypoxic seizures, but there is far more reason to anticipate typical opioid effects instead.
It is reasonable to suspect O-DSMT can be fatal when large doses are used or when it is combined with other depressants, such as alcohol, benzodiazepines, and barbiturates. Case reports do not exist, but that is more likely due to a relatively low level of use than to a strong safety profile. Given this, avoiding depressant combinations and strong+ doses is highly recommended.
Typically in the tramadol overdoses that exist, which are rare, tramadol itself is the dominant drug in the body and the concentration of O-DSMT is lower. But in some instances where the tramadol-related death is linked with respiratory depression, cardiac arrest, and bradycardia, for example, metabolism to O-DSMT has been blamed. So it’s possible that an opioid-like fatality from tramadol is much more likely in extensive or ultrarapid CYP2D6 metabolizers.
A series of fatalities involving kratom alkaloids and O-DSMT occurred in the late 2000s and early 2010s, though all the fatalities also involved additional drugs (Kronstrand, 2011).
Seizures may less of an issue in overdose compared to tramadol, though this has not been confirmed. The (S) enantiomer of O-DSMT did have the ability to cause seizures in rats, but minimal research was done because similar doses also caused a lot of respiratory depression (Potshka, 2000).
Some human and animal evidence points to a risk of liver toxicity (Arafa, 2018), though tramadol has been used for decades in humans, including long-term, and no clear evidence of a severe impact on liver health exists. Despite what has been shown, hepatotoxicity may not be a real concern in humans when used moderately, though more research is needed for a definitive answer.
Tolerance can develop very fast with daily use, especially when compulsively using it multiple times per day. The best effects may be hard to obtain after just a few days of heavy use, which is a major cause of people becoming highly dependent on the substance since they continue chasing the progressively harder to obtain positive effects.
Within a week of beginning heavy daily use, and especially within a few weeks, withdrawal will be an issue upon stopping administration. The withdrawal effects match those seen with other opioids, although they may tend to be weaker in intensity when compared to what occurs with diamorphine, for example.
Among the withdrawal effects are sweating, vomiting, a strong ill flu-like feeling, runny nose, chills, lethargy, and headache. At least 3 to 5 days of a moderate to strong ill/flu feeling should be expected.
Though more reports are needed to confirm how O-DSMT compares to other opioids, the mental effects are reportedly less severe than what’s seen with the classically strongest opioids, meaning withdrawal could be less depression and despair-inducing.