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Death may occur when opiates are combined with other depressants such as benzodiazepines, barbiturates, gabapentinoids, thienodiazepines, alcohol or other GABAergic substances.[1]

It is strongly discouraged to combine these substances, particularly in common to heavy doses.

Summary sheet: Tramadol
Tramadol (Racemate).svg
Chemical Nomenclature
Common names Tramadol, Tramal, Tadol, Tramacur, Tramundin
Substitutive name Tramadol
Systematic name 2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol
Class Membership
Psychoactive class Opioid
Chemical class Phenyl / Cyclohexane
Routes of Administration

WARNING: Always start with lower doses due to differences between individual body weight, tolerance, metabolism, and personal sensitivity. See responsible use section.

Bioavailability 70 - 75%
Threshold 25 - 50 mg
Light 50 - 100 mg
Common 100 - 250 mg
Strong 250 - 300 mg
Heavy 300 mg+
Total 6 - 10 hours
Onset 15 - 60 minutes
Peak 2 - 6 hours
Offset 2 - 4 hours

DISCLAIMER: PW's dosage information is gathered from users and resources for educational purposes only. It is not a recommendation and should be verified with other sources for accuracy.

Tramadol (also known as Ultram, Ralivia or Tramal) is a synthetic opioid analgesic which is commonly prescribed to treat moderate to severe pain. It was first launched and marketed as Tramal by the German pharmaceutical company Grünenthal GmbH in West Germany. It would take another 20 years for it to be launched in English-speaking countries such as the UK, US and Australia.[2]

Tramadol is a reuptake inhibitor of norepinephrine and serotonin and a weak μ-opioid receptor agonist.[3][4] Tramadol is metabolised to O-Desmethyltramadol (O-DSMT), a significantly more potent opioid.

Tramadol is marketed as a racemic mixture of both R and S stereoisomers. This is because the two isomers compliment each other's analgesic activity. It is often combined with paracetamol as this is known to improve the efficacy of tramadol in relieving pain.[citation needed]

Unlike most opioids, tramadol has been established to lower the seizure threshold in humans.[5] This makes its effects and interactions relatively unpredictable. As a result, high doses or combinations with other psychoactive substances are strongly advised against.

History and culture

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For a period of time it was believed tramadol was not a purely synthetic drug after its apparent discovery in the roots of the pin cushion tree.[6] These reports later proved to be erroneous; the tramadol had been excreted by cows treated with the drug, resulting in the tramadol having seeped into the roots through their urine.[7]


(+/-)Tramadol, or 2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol, is an atypical synthetic opioid. Tramadol is loosely analogous to codeine, but is not a morphinan opiate. Instead, tramadol contains two rings that include a cyclohexane ring bonded to a phenyl ring at R1. This phenyl ring is substituted at R3 with a methoxy group (CH3O-). At the same location (R1) the cyclohexane ring is bonded to the phenyl ring, an additional hydroxy group is found. Tramadol features a second substitution on its cyclohexane ring at R2. Here, the ring is bonded to a dimethylamine group connected through a methyl bridge.

Tramadol is unique as it is found in a racemate (combination) of its stereoisomers. These are two molecules that share the same chemical structure, but are three-dimensional mirror images of each other. Tramadol is produced as a racemate of its two isomers because the combination is proven to be more effective. The picture seen above is the R- enantiomer of tramadol, switching the dashed and solid wedges seen on the molecule skeleton results in the S- enantiomer. It is produced as a hydrochloride salt.[8]


The R- and S- enantiomers of tramadol act on different receptors in a complimentary manner. The R- enantiomer is a selective agonist of the mu receptors and inhibits serotonin reuptake while the S- enantiomer inhibits noradrenaline reuptake. Tramadol acts as an opioid receptor agonist,[9][10] serotonin releasing agent,[11][12][13][14] norepinephrine reuptake inhibitor,[15] NMDA receptor antagonist,[16] 5-HT2C receptor antagonist,[17] (α7)5 nicotinic acetylcholine receptor antagonist,[18] TRPV1 receptor agonist,[19] and M1 and M3 muscarinic acetylcholine receptor antagonist.[20][21]

The euphoric effects of this compound stem from the way in which opioids bind to and activate the μ-opioid receptor. This occurs because opioids structurally mimic endogenous endorphins which are naturally found within the body and also work upon the μ-opioid receptor set. The way in which opioids structurally mimic these natural endorphins results in their euphoria, pain relief and anxiolytic effects. This is because endorphins are responsible for reducing pain, causing sleepiness, and feelings of pleasure. They can be released in response to pain, strenuous exercise, orgasm, or general excitement.

Subjective effects

The effects listed below are based upon the subjective effects index and personal experiences of PsychonautWiki contributors. These effects should be taken with a grain of salt and will rarely (if ever) occur all at once, but heavier doses will increase the chances of inducing a full range of effects. Likewise, adverse effects become much more likely on higher doses and may include serious injury or death.

Physical effects

Cognitive effects

Experience reports

There are currently no anecdotal reports which describe the effects of this compound within our experience index. Additional experience reports can be found here:

Toxicity and harm potential

Tramadol has a low toxicity relative to dose. As with all opioids, long-term effects can vary but can include diminished libido, apathy and memory loss. It is also potentially lethal when mixed with depressants like alcohol or benzodiazepines and generally has a wider range of substances which it is dangerous to combine with in comparison to other opioids. It should not be taken during benzodiazepine withdrawals as this can potentially cause seizures.

It is strongly recommended that one use harm reduction practices when using this drug.

Tolerance and addiction potential

As with other opioids, the chronic use of tramadol can be considered moderately addictive with a high potential for abuse and is capable of causing psychological dependence among certain users. When addiction has developed, cravings and withdrawal symptoms may occur if a person suddenly stops their usage.

Tolerance to many of the effects of tramadol develops with prolonged and repeated use. The rate at which this occurs develops at different rates for different effects, with tolerance to the constipation-inducing effects developing particularly slowly for instance. This results in users having to administer increasingly large doses to achieve the same effects. After that, it takes about 3 - 7 days for the tolerance to be reduced to half and 1 - 2 weeks to be back at baseline (in the absence of further consumption). Tramadol presents cross-tolerance with all other opioids, meaning that after the consumption of tramadol all opioids will have a reduced effect.

Dangerous interactions

Although many psychoactive substances are safe to use on their own, they can quickly become dangerous or even life-threatening when combined with other substances. The following lists some known dangerous combinations, but may not include all of them. A combination that appears to be safe in low doses can still increase the risk of injury or death. Independent research should always be conducted to ensure that a combination of two or more substances is safe to consume.

  • Stimulants - It can be dangerous to combine depressants with stimulants due to the risk of accidental excessive intoxication. Stimulants mask the sedative effect of depressants, which is the main factor most people use to gauge their level of intoxication. Once the stimulant effects wear off, the effects of the depressant will significantly increase, leading to intensified disinhibition, motor control loss, and dangerous black-out states. This combination can also potentially result in severe dehydration if one's fluid intake is not closely monitored. If choosing to combine these substances, one should strictly limit themselves to a pre-set schedule of dosing only a certain amount per hour until a maximum threshold has been reached.

Serotonin syndrome risk

Combinations with the following substances can cause dangerously high serotonin levels. Serotonin syndrome requires immediate medical attention and can be fatal if left untreated.

Legal status

  • Austria: Tramadol is legal for medical use under the AMG (Arzneimittelgesetz Österreich) and illegal when sold or possessed without a prescription under the SMG (Suchtmittelgesetz Österreich).[citation needed]
  • Sweden: As of May 2008, Sweden has chosen to classify tramadol as a controlled substance in the same way as codeine and dextropropoxyphene. This means that the substance is a scheduled drug. But unlike codeine and dextropropoxyphene, a normal prescription can be used at this time.[24]
  • United Kingdom: On June 10th, 2014, tramadol was made a Class C drug under the Misuse of Drugs Act.[25]
  • United States: Tramadol is a Schedule IV controlled substance in the United States.[26]

See also

External links


  1. Risks of Combining Depressants (Tripsit) |
  2. Tramadol as an analgesic for mild to moderate cancer pain |
  3. Induction of 5-hydroxytryptamine release by tramadol, fenfluramine and reserpine (ScienceDirect) |
  4. p-Methylthioamphetamine and 1-(m-chlorophenyl)piperazine, two non-neurotoxic 5-HT releasers in vivo, differ from neurotoxic amphetamine derivatives in their mode of action at 5-HT nerve endings in vitro |
  5. Talaie, H., Panahandeh, R., Fayaznouri, M. R., Asadi, Z., & Abdollahi, M. (2009). Dose-independent occurrence of seizure with tramadol. Journal of medical toxicology, 5(2), 63-67.
  6. Occurrence of the Synthetic Analgesic Tramadol in an African Medicinal Plant |
  7. Kusari, S., Tatsimo, S. J. N., Zühlke, S., Talontsi, F. M., Kouam, S. F., Spiteller, M. "Tramadol- A True Natural Product?". Angewandte Chemie International Edition.
  8. 1: Dayer P, Desmeules J, Collart L. [Pharmacology of tramadol]. Drugs. 1997;53 Suppl 2:18-24. Review. French. PubMed PMID: 9190321.
  9. Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids ( / NCBI) |
  10. Influence of tramadol on neurotransmitter systems of the rat brain ( / NCBI) |
  11. Induction of 5-hydroxytryptamine release by tramadol, fenfluramine and reserpine ( / NCBI) |
  12. p-Methylthioamphetamine and 1-(m-chlorophenyl)piperazine, two non-neurotoxic 5-HT releasers in vivo, differ from neurotoxic amphetamine derivatives in their mode of action at 5-HT nerve endings in vitro |
  13. Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro ( / NCBI) |
  14. Actions of tramadol, its enantiomers and principal metabolite, O-desmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus |
  15. Influence of tramadol on neurotransmitter systems of the rat brain ( / NCBI) |
  16. The Effects of Tramadol and Its Metabolite on Glycine, γ-Aminobutyric AcidA, and N-Methyl-d-Aspartate Receptors Expressed in Xenopus Oocytes |
  17. The Inhibitory Effects of Tramadol on 5-Hydroxytryptamine Type 2C Receptors Expressed in Xenopus Oocytes |
  18. The Inhibitory Effects of Tramadol on 5-Hydroxytryptamine Type 2C Receptors Expressed in Xenopus Oocytes |
  19. The analgesic drug, tramadol, acts as an agonist of the transient receptor potential vanilloid-1 ( / NCBI) |
  20. Inhibition by tramadol of muscarinic receptor-induced responses in cultured adrenal medullary cells and in Xenopus laevis oocytes expressing cloned M1 receptors ( / NCBI) |
  21. The Inhibitory Effects of Tramadol on Muscarinic Receptor-Induced Responses in Xenopus Oocytes Expressing Cloned M3 Receptors |
  22. Talaie, H., Panahandeh, R., Fayaznouri, M. R., Asadi, Z., & Abdollahi, M. (2009). Dose-independent occurrence of seizure with tramadol. Journal of Medical Toxicology, 5(2), 63-67.
  23. Gillman, P. K. (2005). Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. British Journal of Anaesthesia, 95(4), 434-441.
  26. DEA Controlled Drugs |