|Summary sheet: Codeine|
|Molecular structure of codeine|
|Routes of Administration|
Codeine (also known as 3-Methylmorphine) is a naturally-occurring opioid within the morphinan chemical class. It is widely used for its analgesic, antitussive, antidiarrheal, anxiolytic, antidepressant, sedative, depressant and hypnotic properties. It is also used to suppress premature labor contractions, myocardial infarction, and has many other potential and indicated uses.
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, hydrocodone, and oxycodone).
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.
- 1 Chemistry
- 2 Pharmacology
- 3 Subjective effects
- 4 Toxicity and harm potential
- 5 Common forms
- 6 Legal status
- 7 See also
- 8 External links
- 9 Literature
- 10 References
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 metabolised 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 produce 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 a hypersensitivity to the drug.
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 necessarily increase the euphoria experienced.
Some methods of potentiating opioids, such as using grape fruit juice throughout the day before consumption, rely on disrupting the cytochrome P450 enzymes' ability to metabolize the chemical. Since codeine is a prodrug and relies on enzymatic conversion for activation, these methods will actually inhibit its effectiveness.
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
The effects listed below are based upon the subjective effects index and personal experiences of PsychonautWiki contributors. The listed 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 and are more likely to induce a full range of effects. Likewise, adverse effects become much more likely on higher doses and may include 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 powerful and overwhelming feeling of emotional bliss, contentment, and happiness.
- Anxiety suppression
- Compulsive redosing
- 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:
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 safe on their own, they can become dangerous and even life-threatening when combined with other substances. The list below contains some common potentially dangerous combinations, but may not include all of them. Certain combinations may be safe in low doses of each but still increase the potential risk of death. Independent research should always be done to ensure that a combination of two or more substances is safe before consumption.
- Depressants (1,4-Butanediol, 2M2B, alcohol, benzodiazepines, barbiturates, GHB/GBL, methaqualone, opioids) - This combination potentiates the muscle relaxation, amnesia, sedation, and respiratory depression caused by one another. At higher doses, it can lead to a sudden, unexpected loss of consciousness along with a dangerous amount of depressed respiration. There is also an increased risk of vomiting while unconsciousness and dying from the resulting suffocation. If nausea or vomiting occurs before a loss of consciousness, users should attempt to fall asleep in the recovery position or have a friend move them into it.
- 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.
- Dissociatives - This combination can unpredictably potentiate the amnesia, sedation, motor control loss and delusions that can be caused by each other. It may also result in a sudden loss of consciousness accompanied by a dangerous degree of respiratory depression. If nausea or vomiting occurs before consciousness is lost, users should attempt to fall asleep in the recovery position or have a friend move them into it.
Codeine is available within pharmacies across the world in a variety of forms which combine it with other products which 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.
Many prescription-strength cough syrups contain codeine and promethazine - an antihistamine. When used recreationally they are commonly known as lean or purple drank.
- Australia: In Australia, codeine preparations are S4 (schedule 4, or Prescription Only) medications. Preparations containing pure codeine (e.g., codeine phosphate tablets or codeine phosphate linctus) are available on prescription and are considered S8 (schedule 8, or Controlled Drug (Possession without authority illegal)). Schedule 8 preparations are subject to the strictest regulation of all medications available to consumers.
- Austria: Codeine is legal for medical use and illegal when sold or possessed without a prescription under the AMG (Arzneimittelgesetz 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 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 mixture. The item is given over the counter, 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).
- 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. A 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.
- 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.
- 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.
- 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.
- 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 formula.
- 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.
- 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.
- Romania: Codeine is not allowed without a medical prescription.
- 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 offence. 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.
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- 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