|Summary sheet: Codeine|
|Routes of Administration|
Codeine (also known as 3-Methylmorphine) is a naturally-occurring opioid substance of the morphinan class found in extracts of the poppy, particularly Papaver bracteatum. Members of this group produce effects such as sedation, cough suppression, and euphoria when administered.
Codeine is the second most predominant alkaloid in opium (up to three percent). Although codeine can be extracted from natural sources, a semi-synthetic process is the primary source of codeine for pharmaceutical use. It is considered the prototype of the weak to midrange opioids (tramadol, dextropropoxyphene, dihydrocodeine and hydrocodone.
Codeine is currently the most widely used opiate in the world, and is one of the most commonly used drugs overall according to numerous reports by organizations including the World Health Organization and its League of Nations predecessor agency. It is one of the most effective orally administered opioid analgesics and has a wide safety margin.
Recreationally, it is usually purchased over the counter within painkillers that mix it with other more toxic substances. These can be separated using a cold water extraction technique.
Codeine, or 3-methylmorphine, is an opioid of the morphinan class. Codeine and other molecules of this class contain a polycyclic core of three benzene rings fused in a zig-zag pattern called phenanthrene. A fourth nitrogen-containing ring is fused to the phenanthrene at R9 and R13 with the nitrogen member looking at R17 of the combined structure. This structure is called morphinan. Codeine (along with other morphinans) contains an ether bridge between two of its rings, connecting R4 and R5 through an oxygen group. It contains a hydroxy group (OH-) bound at R6 and a methyl group located on the nitrogen atom at R17.
On the same ring containing the hydroxy group, codeine contains a double bond which dihydrocodeine lacks. Codeine is closely related to morphine as both contain an oxygen group at R3, but this oxygen group in codeine is substituted by a methyl group (making a methoxy group). Codeine is analogous to the other morphinans including dihydrocodeine, heroin, ethylmorphine, hydrocodone, and oxycodone.
Codeine is not itself centrally active, and must first be converted via first-pass metabolism into morphine by the cytochrome P450 enzyme CYP2D6 (as such, it is a prodrug for morphine). Codeine is also metabolized into the inactive norcodeine via the CYP3A4 enzyme system. Both resultant forms are conjugated by UGT2B7 into their corresponding 3-glucuronide.
Some percentage of the population produces less CYP2D6 enzymes and so experience a significant reduction of effects from codeine in comparison to that of the average person. However, others produce CYP2D6 enzymes in higher quantities which can result in hypersensitivity to the drug. Some methods of potentiating opioids, such as using grapefruit juice throughout the day before consumption, inhibits the CYP3A4 enzyme. This results in less codeine being converted into norcodeine which leaves more to be metabolized into morphine. This also indicates a lacking capability in the metabolism of codeine into morphine when a user consumes antihistamines such as diphenhydramine prior to the ingestion of codeine. 
There is an upper limit to the amount of codeine which can be converted by enzymatic metabolism into morphine throughout an individual session. This limit is commonly referred to as the "ceiling dose", which is commonly believed to be around 400mg. Consuming higher doses will lead to greater side effects such as itchiness and nausea, but will not increase euphoria.
The active metabolites of codeine, notably morphine, exert their effects by binding to and activating opioid receptors, mainly 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, muscle relaxing 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.
Binding affinities (Ki)
- Mu opioid agonist - 589 nM
- Kappa opioid agonist - 18061 nM
- Delta opioid agonist - 11442 nM
Disclaimer: The effects listed below cite the Subjective Effect Index (SEI), a research literature based on anecdotal reports and the personal experiences of PsychonautWiki contributors. As a result, they should be regarded with a healthy degree of skepticism. It is worth noting that these effects will not necessarily occur in a predictable or reliable manner, although higher doses are more liable to induce the full spectrum of effects. Likewise, adverse effects become much more likely with higher doses and may include addiction, serious injury, or death.
The general head space of codeine is described by many as one of euphoria, relaxation, anxiety suppression, and pain relief.
- Pain relief
- Physical euphoria - This particular substance can be considered as less intense in its physical euphoria when compared with that of morphine or diacetylmorphine (heroin) due to the upper limit of how much can be converted into its active form through metabolism. The sensation itself can be described as extreme feelings of intense physical comfort, warmth and bliss which spreads throughout the body.
- Itchiness - This compound presents greater amounts of itchiness due to higher amounts of histamine release in comparison to other opioids.
- Respiratory depression - At low to moderate doses, this effect results in the sensation that the breath is slowed down mildly to moderately, but does not cause noticeable impairment. At high doses and overdoses, opioid-induced respiratory depression can result in a shortness of breath, abnormal breathing patterns, semi-consciousness, or unconsciousness. Severe overdoses can result in a coma or death without immediate medical attention.
- Sedation - At higher dosages, this compound can result in feelings of sedation and is considerably more sedating than that of oxycodone and hydrocodone.
- Appetite suppression
- Cough suppression
- Decreased libido
- Difficulty urinating
- Nausea - This effect is more likely to occur during high dosages and/or when the user doesn't adequately pace themselves.
- Orgasm suppression
- Pupil constriction
- Cognitive euphoria - This particular substance can be considered as less intense in its cognitive euphoria when compared with that of morphine or diacetylmorphine (heroin) due to the upper limit of how much can be converted into its active form through metabolism. It is still, however, capable of extreme intensity and overwhelming bliss at heavier dosages with a low tolerance. The sensation itself can be described as a powerful and overwhelming feeling of emotional bliss, contentment, and happiness.
- Anxiety suppression
- Compulsive redosing - It is worth noting that redosing codeine will not amplify the intensity of its effects.
- Dream potentiation
- Double vision - At high doses, the eyes un-focus and re-focus uncontrollably. This creates a blurred effect and double vision that is present no matter where one focuses their eyes. This can be so intense it becomes impossible to read or drive.
There are currently no anecdotal reports which describe the effects of this compound within our experience index. Additional experience reports can be found here:
Codeine is available within pharmacies across the world in a variety of forms that combine it with other products that are dangerous or even fatal to consume at higher dosages. This is done to act as a deterrent to prevent their recreational use but can easily be circumvented with the use of a cold water extraction.
Nurofen plus contain 12.8mg of codeine alongside ibuprofen. It is available behind the counter in any British pharmacy. Due to the higher codeine content than co-codamol, they are better for cold water extraction.
Many prescription-strength cough syrups contain codeine and promethazine - an antihistamine. When used recreationally they are commonly known as lean or purple drank.
Toxicity and harm potential
Codeine 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. Some people may also have an allergic reaction to codeine, such as the swelling of skin and rashes. It is also potentially lethal when mixed with depressants like alcohol or benzodiazepines.
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 codeine 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 codeine 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). Codeine presents cross-tolerance with all other opioids, meaning that after the consumption of codeine all opioids will have a reduced effect.
Although many psychoactive substances are reasonably safe to use on their own, they can suddenly become dangerous or even life-threatening when combined with other substances. The following list includes some known dangerous combinations (although it is not guaranteed to include all of them). Independent research (e.g. Google, DuckDuckGo) should always be conducted to ensure that a combination of two or more substances is safe to consume. Some of the listed interactions have been sourced from TripSit.
- Alcohol - Both substances potentiate the ataxia and sedation caused by the other and can lead to unexpected loss of consciousness at high doses. Place affected patients in the recovery position to prevent vomit aspiration from excess. Memory blackouts are likely
- Amphetamines - Stimulants increase respiration rate which allows for a higher dose of opiates than would otherwise be used. If the stimulant wears off first then the opiate may overcome the user and cause respiratory arrest.
- Benzodiazepines - Central nervous system and/or respiratory-depressant effects may be additively or synergistically present. The two substances potentiate each other strongly and unpredictably, very rapidly leading to unconsciousness. While unconscious, vomit aspiration is a risk if not placed in the recovery position blackouts/memory loss likely.
- Cocaine - Stimulants increase respiration rate, which allows for a higher dose of opiates than would otherwise be used. If the stimulant wears off first then the opiate may overcome the patient and cause respiratory arrest.
- DXM - Generally considered to be toxic. CNS depression, difficulty breathing, heart issues, and liver toxicity have been observed. Additionally if one takes DXM, their tolerance of opiates goes down slightly, thus causing additional synergistic effects.
- GHB/GBL - The two substances potentiate each other strongly and unpredictably, very rapidly leading to unconsciousness. While unconscious, vomit aspiration is a risk if not placed in the recovery position
- Ketamine - Both substances bring a risk of vomiting and unconsciousness. If the user falls unconscious while under the influence there is a severe risk of vomit aspiration if they are not placed in the recovery position.
- MAOIs - Coadministration of monoamine oxidase inhibitors (MAOIs) with certain opioids has been associated with rare reports of severe adverse reactions. There appear to be two types of interaction, an excitatory and a depressive one. Symptoms of the excitatory reaction may include agitation, headache, diaphoresis, hyperpyrexia, flushing, shivering, myoclonus, rigidity, tremor, diarrhea, hypertension, tachycardia, seizures, and coma. Death has occurred in some cases.
- MXE - MXE can potentiate the effects of opioids but also increases the risk of respiratory depression and organ toxicity.
- Nitrous - Both substances potentiate the ataxia and sedation caused by the other and can lead to unexpected loss of consciousness at high doses. While unconscious, vomit aspiration is a risk if not placed in the recovery position. Memory blackouts are common.
- PCP - PCP may reduce opioid tolerance, increasing the risk of overdose.
- Tramadol - Increased risk of seizures. Tramadol itself is known to induce seizures and it may have additive effects on seizure threshold with other opioids. Central nervous system- and/or respiratory-depressant effects may be additively or synergistically present.
- Grapefruit - While grapefruit is not psychoactive, it may affect the metabolism of certain opioids. Tramadol, oxycodone, and fentanyl are all primarily metabolized by the enzyme CYP3A4, which is potently inhibited by grapefruit juice. This may cause the drug to take longer to clear from the body. it may increase toxicity with repeated doses. Methadone may also be affected. Codeine and hydrocodone are metabolized by CYP2D6. People who are on medicines that inhibit CYP2D6, or that lack the enzyme due to a genetic mutation will not respond to codeine as it can not be metabolized into its active product: morphine.
- Australia: In Australia, codeine preparations are Schedule 4 (Prescription Only) medications when combined with other substances. Preparations containing pure codeine (e.g., codeine phosphate tablets or codeine phosphate linctus) are available on prescription and are considered Schedule 8 (Controlled Drug (Possession without authority illegal)). Schedule 8 drugs are drugs that are available to be prescribed but are heavily restricted to prevent abuse and dependence. Possessing Schedule 8 drugs without authority is a criminal offense and can have varying punishments depending on the state of prosecution.
- Austria: Codeine is legal for medical use under the AMG (Arzneimittelgesetz Österreich) and illegal when sold or possessed without a prescription under the SMG (Suchtmittelgesetz Österreich).
- Canada: In Canada, codeine is available over the counter in combination tablets with the following restrictions: no more than 8 mg per dosage unit and it must be combined with at least two other active ingredients. It is kept behind the counter, to be sold on request-- generally to those 18 and over-- after a brief consultation and at the pharmacist's discretion. The other active ingredients most commonly consist of another non-opioid analgesic (300 mg acetaminophen, as in Tylenol No. 1; or 325 mg aspirin, as in 222s) and 15 mg caffeine. OTC tablets containing ibuprofen are generally unavailable. Preparations with a codeine content higher than 8 mg per dosage unit, or fewer than two other active ingredients, are available on prescription.
- Denmark: In Denmark, codeine is sold over the counter with max 9.6 mg in the mixture. The item is given over the counter, with no prescriptions. The strongest available over the counter preparation containing codeine has 9.6 mg (with aspirin, brand name Kodimagnyl); anything stronger requires a prescription for legal possession.
- Finland: In Finland, codeine cough syrups with a maximum strength of 1mg/ml is sold in pharmacies over the counter. Codeine isn't available in pill form without a prescription. Any stronger cough syrup and combination painkillers (codeine with paracetamol or ibuprofen such as Panacod, Co-codamol, and Ardinex) require a prescription.
- France: In France, most preparations containing codeine do not require a doctor's prescription. Example products containing codeine include Néocodion (cough pills, and syrup), Codoliprane (codeine with paracetamol), Prontalgine and Migralgine (codeine, paracetamol, and caffeine). Codeine is regulated/controlled substance (schedule 2) since 2017 after a decision of the "Minister of Health" Agnès Buzyn, it is therefore now under prescription only and raw pure codeine is not being available altogether anymore. The most common prescribed codeine brands are Klipal and Codoliprane, both mixed with paracetamol heavily. Klipal being the strongest ratio, 50mg codeine for 600mg paracetamol.
- Germany: Codeine is a controlled substance under Anlage III of the BtMG. It can only be prescribed on a narcotic prescription form. There is an exception for preparations, containing up to 2,5% or 100mg codeine per unit, which can be prescribed on a regular prescription if not prescripted to an alcohol or drug dependent person.
- Greece: Codeine is classed as an illegal drug in Greece, and individuals possessing it could conceivably be arrested, even if they were legitimately prescribed it in another country. It is sold only with a doctor's prescription.
- Hong Kong: In Hong Kong, codeine is regulated under Laws of Hong Kong, Dangerous Drugs Ordinance, Chapter 134, Schedule 1. It can be used legally only by health professionals and for university research purposes. The substance can be given by pharmacists under a prescription. However, codeine is available without prescription from licensed pharmacists in doses up to 0.1%
- Iceland: Preparations of paracetamol and codeine require a prescription in Iceland.
- India: Codeine preparations require a prescription in India. Preparation of paracetamol and codeine is available in India. Codeine is also present in various cough syrups as codeine phosphate.
- Iran: Preparations of codeine in Iran normally comes with paracetamol, but can be purchased over-the-counter. Iran's deputy health minister reported that codeine is Iran's best selling OTC medication. The recreational use of codeine has also become widespread throughout Iran but authorities continue to let codeine be purchased without permission from a doctor, although the pharmacist may ask for the identification of the purchaser to verify they are 18 years or older to buy.
- Ireland: Codeine remains a semi non-prescriptive, over-the-counter drug up to a limit of 12.8 mg per pill, but codeine products must be out of the view of the public. Products containing more than 12.8 mg codeine are available on prescription only.
- Italy: Codeine tablets or preparations require a prescription in Italy. Preparations of paracetamol and codeine are available in Italy as Co-Efferalgan and Tachidol.
- Japan: Codeine and similar mid-level centrally acting agents in combination with non-opioid analgesics, antihistamines, vitamins, inert GI agents like kaolin & pectin, mild laxatives, antacids, and herbal preparations, can be purchased over the counter, with 10 mg being the ceiling for OTC dispensing.
- Maldives: The Maldives takes an infamously strict line on medicines, with many common drugs, anything containing codeine is banned unless you have a notarized and authenticated doctor's prescription. Visitors breaking the rules, even inadvertently, have been deported or imprisoned.
- Poland: Codeine is listed in "Wykaz środków odurzających i substancji psychotropowych" group " II-N" which means it's legal to use in scientific and medical pruposes, and is available over the counter in doses of 15mg in combination with 500mg paracetamol (Antidol) or 300mg sulfogaiacol (Thiocodin). However a pharmacy worker can refuse to sell it if they believe the client is a minor or wants to use it for drug abuse purposes. 
- Romania: Codeine is sold OTC (when combined with another active ingredient), the limit being 12.8mg of codeine per pill, which is seen in Nurofen Plus. Any amount above 12.8mg/unit requires a prescription, whether it has another ingredient or not.
- Russia: According to ITAR-Tass and Austria Presse-Agentur, OTC availability of codeine products was rescinded nationwide in 2012 because of the discovery of the Krokodil method of underground desomorphine synthesis.
- Spain: Codeine tablets or preparations require a prescription in Spain, although this is often not enforced and many pharmacies will sell codeine products without the requirement of a prescription.
- Sri Lanka: Codeine preparations are available as over the counter pharmacy medicines in Sri Lanka. The most common preparation is Panadeine, which contains 500 mg of Paracetamol and 8 mg of Codeine.
- Sweden: Codeine is Schedule III under Swedish law, which means it is heavily regulated and sold only to those who have a prescription.
- Switzerland: Codeine is a controlled substance specifically named under Verzeichnis A. Medicinal use is permitted. Some preparations containing codeine are included in Verzechnis C, while certain ones are excluded.
- Turkey: Codeine is a 'red prescription' only substance and illegal when sold or possessed without a prescription.
- United Arabian Emirates: The UAE takes an exceptionally strict line on medicines, with many common drugs, notably anything with containing codeine being banned unless you have a notarized and authenticated doctor's prescription. Visitors breaking the rules, even inadvertently, have been deported or imprisoned. The US Embassy to the UAE maintains an unofficial list of what may not be imported.
- United Kingdom: Under the Misuse of Drugs Act 1971 codeine is a Class B controlled substance or a Class A drug when prepared for injection. The possession of controlled substances without a prescription is a criminal offense. However, certain preparations of codeine are exempt from this restriction under Schedule 5 of the Misuse of Drugs Regulations 2001. It is thus legal to possess codeine without a prescription, provided that it is compounded with at least one other active or inactive ingredient and that the dosage of each tablet, capsule, etc does not exceed 100 mg or 2.5% concentration in the case of liquid preparations.
- United States: In the United States, codeine is regulated by the Controlled Substances Act. Federal law dictates that codeine be a Schedule II controlled substance when used in products for pain-relief that contain codeine alone or more than 90 mg per dosage unit. Tablets of codeine in combination with aspirin or acetaminophen (paracetamol/Tylenol) made for pain relief are listed as Schedule III; and cough syrups are Schedule III or V, depending on the formula.
- Friswell J, Phillips C, Holding J, Morgan CJ, Brandner B, Curran HV. (2008). Acute effects of opioids on memory functions of healthy men and women. Psychopharmacology (Berl.). 198 (2): 243–50. https://doi.org/10.1007/s00213-008-1123-x.
- Schmidt, H., Vormfelde, S. V., Klinder, K., Gundert-Remy, U., Gleiter, C. H., Skopp, G., Aderjan, R. and Fuhr, U. (2002), Affinities of Dihydrocodeine and its Metabolites to Opioid Receptors. Pharmacology & Toxicology, 91: 57–63. https://doi.org/10.1034/j.1600-0773.2002.910203.x
- Koch T, Höllt V. (2008). Role of receptor internalization in opioid tolerance and dependence. Pharmacol. Ther. 117 (2): 199–206. https://doi.org/10.1016/j.pharmthera.2007.10.003
- Pert, C. B., Pasternak, G., & Snyder, S. H. (1973). Opiate Agonists and Antagonists Discriminated by Receptor Binding in Brain. Science, 182 (4119), 1359-1361. https://doi.org/10.1126/science.182.4119.1359
- Stefano GB, Ptáček R, Kuželová H, Kream RM. (2012). Endogenous morphine: up-to-date review (2011). Folia Biol. (Praha). 58 (2): 49–56. PMID 22578954.
- Dicpinigaitis, P. V., Morice, A. H., Birring, S. S., McGarvey, L., Smith, J. A., Canning, B. J., & Page, C. P. (2014). Antitussive drugs—past, present, and future. Pharmacological Reviews, 66(2), 468-512.
- Affinities of Dihydrocodeine and its Metabolites to Opioid Receptors - Helmut Schmidt et al. (August 2002) | http://onlinelibrary.wiley.com/doi/10.1034/j.1600-0773.2002.910203.x/full
- Laws of Hong Kong, Dangerous Drugs Ordinance, Chapter 134
- "Verordnung des EDI über die Verzeichnisse der Betäubungsmittel, psychotropen Stoffe, Vorläuferstoffe und Hilfschemikalien" (in German). Bundeskanzlei [Federal Chancellery of Switzerland]. Retrieved January 1, 2020.
- KIRMIZI REÇETEYE TABİ İLAÇLAR | https://www.titck.gov.tr/storage/Archive/2019/contentFile/K%C4%B1rm%C4%B1z%C4%B1%20Re%C3%A7eteye%20Tabi%20%C4%B0la%C3%A7lar%2005072019_ebcc7e92-6661-4983-870a-fe8983a9c2b7.pdf