Morphine

Morphine was first isolated in 1806 by German pharmacist's assistant, Friedrich Sertürner.^[3]

In Sertürner's, over 50 experiments he believed he had isolated the primary active ingredient in opium. This is generally believed to be the first isolation of an active ingredient from a plant.[8][9] The active ingredient, was found to be 10 times as potent as opium. Sertürner originally named the substance morphium after the Greek god of dreams, Morpheus, for its tendency to cause sleep.[10][11] Merck began marketing it commercially in 1827.[12] Morphine's clinical significance was not recognized by the greater medical community until 1831, when Sertürner was recognized for his contribution and granted the French equivalent of the Nobel Prize. Other alkaloids were later identified from the opium plant, one of these thirty such alkaloids later became codeine. Codeine from the ancient Greek, κώδεια, means cup shaped like a poppyhead.[13] Morphine use was spearheaded by Dr. Alexander Wood's invention the hypodermic syringe in 1853.[12][10] However, it wasn't until the American Civil War in 1861, the Prussian-Austrian War in 1866, and the Franco-Prussian War of 1870 that morphine saw widespread use as part of military medicine. It wasn't until after these military conflicts that morphine habituation gained a reputation as the "soldier's disease" or the  "army disease". With the addictive and habit forming properties of morphine now known the medical establishment was on the lookout for a less addictive alternative to morphine. This came in the form of diacetylmorphine or as it was later marketed, Heroin. Although it was later learned that heroin was not less addictive than codeine and in fact the contrary. The first chemical structure of morphine was proposed by Robinson and colleagues in 1923 then confirmed in 1927.[14][15][16] The total chemical synthesis of morphine occurred in 1952 by Gates and Tschudi.[17]

The primary source of morphine is isolated from the poppy straw of the opium poppy.^[18] In 2013 an estimated 523,000 kilograms of morphine were produced.^[19] About 45,000 kilograms were used directly for pain, an increase over the last twenty years of four times.^[19] Most use for this purpose was in the developed world.^[20] About 70% of morphine is used to make other opioids such as hydromorphone, oxycodone and heroin.^[21][22][23]

Morphine, a benzylisoquinoline alkaloid, is an opiate of the morphinan class. Morphine 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.

Morphine (along with other morphinans) contain an ether bridge between two of its rings, connecting R₄ and R₅ through an oxygen group. It contains two hydroxy groups (OH-), bound at R₆ and R₃, and a methyl group located on the nitrogen atom at R₁₇.

Morphine is a precursor for many morphinan drugs, it is used to synthesize codeine through methylation of its R₃ hydroxy group, and heroin through acetylation. Other closely related opioids include hydrocodone, oxycodone, and dihydrocodeine. The chemical structure of morphine is the basis of hundreds of opioid derivatives with a wide range of effects.

Morphine exerts its effects by binding to and activating three known opioid receptors including: the κ-opioid (KOP), μ-opioid (MOP), and δ-opioid (DOP) receptors as an agonist. This occurs due to the way in which opioids functionally mimic the body's natural endorphins. Endorphins are responsible for analgesia (pain reduction), sleepiness, and feelings of pleasure and enjoyment. They are believed to be released in response to pain, strenuous exercise, orgasm, or excitement. This mimicking of natural endorphins results in the drug's euphoric, analgesic (pain relief), and anxiolytic (anti-anxiety) effects.

Morphine is produced by the human body in small amounts and acts as an immunomodulator. Endogenous morphine binds preferentially to the μ₃ opioid receptor.^[24]

Morphine along with hydromorphone and oxymorphone experience minimal CYP450 metabolism and are instead metabolized primarily by the UDP-glucuronosyltransferases (UGTs), specifically the UG2B7 isozyme.^[25] About 90% of Morphine is converted into metabolites, primarily into the glucuronide conjugates morphine-3-glucuronide (M3G) (45-55%) and morphine-6-glucuronide (M6G) (10-15%).^[26] Of these two MG3 has a low affinity for the opioid receptors and no analgesic activity. MG6 binds to the same receptor sites as morphine, but has a greater affinity and greater potency.^[26]

Binding affinities of morphine (K_i)^[27]

A lower Ki, indicates a greater binding affinity for the receptor.

• Mu opioid agonist - 4.9 nM
• Kappa opioid agonist - 206 nM
• Delta opioid agonist - 273 nM

Disclaimer: The effects listed below cite the Subjective Effect Index (SEI), an open research literature based on anecdotal user reports and the personal analyses of PsychonautWiki contributors. As a result, they should be viewed with a healthy degree of skepticism.

It is also 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 increasingly likely with higher doses and may include addiction, severe injury, or death ☠.

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:

• Erowid Experience Vaults: Morphine

Like most opioids, unadulterated morphine does not cause many long-term complications other than dependence and constipation.^[28] Outside of the extremely powerful addiction and physical dependence, the harmful or toxic aspects of morphine usage are exclusively associated with not taking appropriate precautions in regards to its administration, overdosing and using impure products.

Heavy dosages of morphine can result in respiratory depression, leading onto fatal or dangerous levels of anoxia (oxygen deprivation). This occurs because the breathing reflex is suppressed by agonism of µ-opioid receptors proportional to the dosage consumed.

Morphine can also cause nausea and vomiting; a significant number of deaths attributed to opioid overdose are caused by aspiration of vomit by an unconscious victim. This is when an unconscious or semi-conscious user who is lying on their back vomits into their mouth and unknowingly suffocates. It can be prevented by ensuring that one is lying on their side with their head tilted downwards so that the airways cannot be blocked in the event of vomiting while unconscious (also known as the recovery position).

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

Dependence and abuse potential

As with other opiate-based painkillers, the chronic use of morphine can be considered extremely addictive and is capable of causing both physical and psychological dependence. When physical dependence has developed, withdrawal symptoms may occur if a person suddenly stops their usage.

Tolerance to many of the effects of morphine develops with prolonged use, including therapeutic effects. This results in users having to administer increasingly large doses to achieve the same effects. The rate at which this occurs develops at different rates for different effects with tolerance to the constipation-inducing effects developing particularly slowly. Morphine presents cross-tolerance with all other opioids, meaning that after the consumption of morphine all opioids will have a reduced effect.

The risk of fatal opioid overdoses rise sharply after a period of cessation and relapse, largely because of reduced tolerance.^[29] To account for this lack of tolerance, it is safer to only dose a fraction of one's usual dosage if relapsing. It has also been found that the environment one is in can play a role in opioid tolerance. In one scientific study, rats with the same history of heroin administration were significantly more likely to die after receiving their dose in an environment not associated with the drug in contrast to a familiar environment.^[30]

Dangerous interactions

Morphine is dangerous to use in combination with other depressants as many fatalities reported as overdoses are caused by interactions with other depressant drugs like alcohol or benzodiazepines, resulting in dangerously high levels of respiratory depression.^[31]

Warning: Many psychoactive substances that are reasonably safe to use on their own can suddenly become dangerous and even life-threatening when combined with certain other substances. The following list provides some known dangerous interactions (although it is not guaranteed to include all of them).

Always conduct independent research (e.g. Google, DuckDuckGo, PubMed) 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^[32]. 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^[32]. 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.

Internationally, morphine is a Schedule I drug under the Single Convention on Narcotic Drugs.^[33] It is on the WHO Model List of Essential Medicines, a list of the most important medications needed in a basic health system.^[34]

• Australia: Morphine is classified as a Schedule 8 drug under the variously titled State and Territory Poisons Acts.^{[citation needed]}
• Austria: Morphine 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]}
• Canada: Morphine is classified as a Schedule I drug under the Controlled Drugs and Substances Act.^[35]
• France: Morphine is in the strictest schedule of controlled substances, based upon the December 1970 French controlled substances law.^{[citation needed]}
• Germany: Morphine is a controlled substance under Anlage III of the BtMG. It can only be prescribed on a narcotic prescription form.^[36]
• Japan: Morphine is classified as a narcotic under the Narcotic and Psychotropic Drugs Control Act (麻薬及び向精神薬取締法).^[37]
• Netherlands: Morphine is classified as a List 1 drug under the Opium Law.^{[citation needed]}
• Russia: Morphine is a Schedule II controlled substance.^[38]
• Sweden: Morphine is legal for medical use and is a controlled substance.^[39]
• Switzerland: Morphine is a controlled substance specifically named under Verzeichnis A. Medicinal use is permitted.^[40]
• Turkey: Morphine is a 'red prescription' only substance^[41] and illegal when sold or possessed without a prescription.^{[citation needed]}
• United Kingdom: Morphine is listed as a Class A drug under the Misuse of Drugs Act 1971 and a Schedule 2 Controlled Drug under the Misuse of Drugs Regulations 2001.^[42][43]
• United States: Morphine is classified as a Schedule II controlled substance under the Controlled Substances Act with a main Administrative Controlled Substances Code Number (ACSCN) of ACSCN 9300. Morphine pharmaceuticals in the US are subject to annual manufacturing quotas; morphine production for use in extremely dilute formulations and its production as an intermediate, or chemical precursor, for conversion into other drugs is excluded from the US manufacturing quota.^[22]

• Responsible use
• Opioids
• Codeine
• Heroin
• Naloxone

• Morphine (Wikipedia)
• Morphine (Erowid Vault)
• Morphine (Isomer Design)

• 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
• 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.
• 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. Positive evolutionary pressure has apparently preserved the ability to synthesize chemically authentic morphine, albeit in homeopathic concentrations, throughout animal phyla.