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Providing straightforward information pertaining to drugs, drug use & drug policy. The Grey Pages promotes drug-related literacy and advocates a system of viable and tolerant drug policies. This is my personal collection of commentaries, essays, tid-bits, and other such writings on everything ranging from drug use, drug policy and drug-myths, to drug-science, addiction, human behavior, and the workings of the human brain. I started this blog with a particular focus on opioids, and over the past year have found my interest gravitate toward the intriguing, ever-changing world of designer intoxicants (i.e. "research chemicals" or "designer drugs").

Thursday, December 22, 2011

Amphetamines Vault

Amphetamine:

Basic:

The term amphetamine in a general sense, can be used to describe a family of exogenous, usually synthetic, pharmaceuticals classified as "sympathomimetic amines" - which are similar in structure and pharmacology to the endogenous catecholamines or monoamines - specifically dopamine, norepinephrine, and phenylalanine. Compounds of the amphetamine family are built off of a phenethylamine skeleton. Phenethylamines are alternatively described as phenylpropylamines. Amphetamine is the alpha-methyl analogue of phenethylamine.

Amphetamine itself is a widely used psychostimulant drug and is the prototype off of which a series of amphetamine analogues have been built. It is a schedule 2 controlled substance in the US and is therefore used medicinally & illicitly. It is one of the most widely prescribed drugs in psychiatry practice. Amphetamine itself was first synthesized in 1887 Germany.

Use:

In the United States (and elsewhere), Amphetamine is used clinically for the following indications:

30mg prescription amphetamine tablets
Treatment of attention deficit disorder (ADD) & attention deficit hyperactivity disorder (ADHD).

Treatment of resistant cases of major depression.

Treatment of chronic fatigue syndrome & narcolepsy.

Emergency treatment of cardiac arrest & other types of acute cardiac failure.

As a nasal decongestant much like ephedrine or pseudoephedrine.

As an appetite suppressant, typically in obese individuals.

Chemistry:

Amphetamine is an analogue of the phenethylamine class and occurs as a racemic mixture. It is similar in structure to ephedrine & pseudoephedrine. Many analogues of amphetamine have been synthesized. 

Pharmacology:

Amphetamine acts as a traditional stimulant, by producing sympathomimesis - i.e. arousing the fight or flight response of the sympathetic nervous system by promoting the release of catecholamine neurotransmitters such as adrenaline, noradrenaline, and dopamine. Amphetamine increases alertness, energy, and mood, as well as vital functions such as breathing & cardiac output. Blood vessels in these areas dilate while blood vessels in non vital areas constrict - sympathetic arousal entails parasympathetic inhibition. These two systems operate in contrast to each other, maintaining a balanced system whereby the body's resources are mobilized according to current needs.

Sympathomimetic agents act by either directly activating post synaptic receptor sites and mimicking neurotransmitters, or by enhancing the actions of the neurotransmitters themselves.

Amphetamine works by the latter mechanism, specifically targeting reuptake of norepinephrine, dopamine, and serotonin by the following means:

Dopamine & Serotonin: Multiple theories have been proposed as to its exact mechanism. It is generally believed that amphetamine targets DAT and SERT - the presynaptic reuptake pumps for dopamine & serotonin; triggering a series of cellular changes which causes the transporter to function in reverse - i.e. rather than collecting excess dopamine from the synapse like a vaccum, it spits more dopamine or serotonin out into the synapse, basically flooding the synaptic cleft with the neurotransmitter. 

The dopaminergic actions of amphetamine take place throughout the mesolimbic & mesocortical reward pathways of the brain - key areas of these pathways include the striatum, ventral striatum, ventral tegmentum, and the nucleus accumbens. The serotonergic actions of amphetamine seem to be limited to key areas of the brain - for instance, projections of serotonergic neurons which run from the VTA to the prefrontal cortex; in addition to other corticolimbic projections.

Norepinephrine: Amphetamine increases extrecellular concentrations of norepinephrine (i.e. noradrenaline). In this case it is believed to act as a norepinephrine reuptake inhibitor. NE activity is heavily associated with arousal of the sympathetic nervous system - i.e. the fight or flight response, and possibly to a lesser extent, reward.

Effects:

Excitement, euphoria, increased energy, alertness, wakefullness, insomnia.

Amphetamine & amphetamine type drugs tend to produce paradoxial effects in those with behavioral disorders such as ADHD - rather than causing excitation, they produce calmness, concentration, and promote pragmatism over a racing thought process.

Amphetamine is a precursor to countless
other psychostimulants just as morphine
is to other narcotics 
 
Side effects include jitteriness, anxiety, agitation, fight or flight mode (adrenaline rush), hypertension, vasodilation, mydriasis (dilated pupils), bowel stimulation, diuresis. Overdose symptoms include irregular heartbeat, psychotic breaks, extreme confusion, slurred speech, aphasia (inability to speak), lazy eye or crossed-eyes, fear & panic, heart attack, stroke, cardiac arrest & death.

Methamphetamine:

Methamphetamine is the N-methyl analogue of amphetamine. It is one of the most potent psychostimulants in use.

Illicit methamphetamine as it commonly appears
Methamphetamine has a history of medicinal use and is available in the US under the trade name Desoxyn; which is used in the treatment of narcolepsy, chronic fatique, severe depression and obesity.

In the medical setting, the drug is given orally in tablet form. The effective therapeutic dosage for methamphetamine is much lower than dosages reported in the recreational setting, single doses beginning at 5 mg  and daily doses up to 20 mg. When used outside the medical setting, dosages vary depending on the route of administration and user experience. Naive users often attain pleasant and lasting effects with doses of 10-20 mg intranasally, while habitual users may easily exceed 100 mg in a single dose. Many report exceeding 1 gram of methamphetamine daily, while for non tolerant users these doses will surely be toxic. Keep in mind, these figures represent pure methamphetamine intake, they do not reflect variations in cut, bulk & purity.

When used casually or recreationally, methamphetamine is administered by various routes and in various forms. It can be snorted as a powder, injected as a solution, heated to vaporize and smoked in its crystallized form (known as ice or crystal meth), or taken orally. Both insufflation and inhalation are effective as alternatives to injection, they allow good absorbtion and a fairly rapid onset.


The N-methyl substitution of this compound is responsible for the potentiation of its effects, as compared to amphetamine, as it renders the compound more lipophilic, more brain penetrable, and more resistant to destruction by monoamine oxidase enzymes.

Methamphetamine, and its major metabolite amphetamine, bind with dopamine, NE, and serotonin (5HT) reuptake transporters and reverse their direction of flow, thus increasing the overall cellular flow of monoamine transmitters.


Methamphetamine has a plasma half life of around 4-6 hours and may be detected in urine for up to 2 days following a single use. Its effects can endure a few to several hours, depending on the dose and route of administration - 4 to 8 hours is common. Habitual or heavy users may stay awake for days at a time.

Side effects of this drug are the same as those of amphetamine. They include jitteriness, anxiety, agitation, hypertension, vasodilation, mydriasis (dilated pupils), bowel stimulation, diuresis. Overdose symptoms include irregular heartbeat, psychotic breaks, extreme confusion, slurred speech, aphasia (inability to speak), lazy eye or crossed-eyes, fear & panic, heart attack, stroke, cardiac arrest & death.

Long term habitual methamphetamine use is known to have toxic effects on dopaminergic neurons. This often leads to an extended state of depression, fatigue and anhedonia which can last for weeks to months while dopaminergic systems are restored to their original state.

Illicitly produced methamphetamine often contains a large amount of toxic impurities, due to the limited skills  and resources of those who produce the drug themselves. Methamphetamine produced using the new "one bottle" or "shake and bake" method has the potential to be particularly toxic and should be avoided.


Monday, December 12, 2011

Morphine Family Vault

Table Of Contents:

1) Morphine
2) Heroin & Morphine Esters
3) Desomorphine
4) Dihydromorphine
5) Azidomorphine
6) Chem-Comparison

Morphine


Basics:

Morphine is the prototype narcotic. A naturally occuring opiate and the gold standard against which all other opioids are measured. Morphine sets the medical standard for all narcotics in regards to potency, pharmacology, and subjective effects. Morphine has a history of use spanning over 200 years since its discovery in 1804. It was the first isolated alkaloid ever to be extracted from a natural source. It is the primary component of opium extracted from within the seed pod walls of the opium poppy, known by the botanical name Papaver Somniferum. Morphine may constitute anywhere from 10 to 20 percent the weight of opium, depending on climate, location, plant variety, and harvest time.

Use:

Morphine is a strong opioid analgesic and is the world's most commonly used narcotic for the relief of moderate to severe pain, acute or chronic. The drug is available in various forms to suit various therapeutic needs.

In the United States, morphine is available as its sulfate salt, i.e. morphine sulfate - in liquid, tablet, and capsule form for oral use, parenteral solutions for injection or infusion, and rectal suppositories for anal use. Also available are preservative free solutions for use by the intraspinal route. Injectable morphine solutions are available in single or multiple dose vials, with a morphine concentration ranging from 2.5mg/ml to 20mg/ml or more. The higher concentrations are often diluted with saline for single doses in opioid tolerant individuals, or in preparation of large volume parenterals (i.e. infusion via PCA, TIVA machine, regular drip, etc).

When treating pain in a hospital setting such as the emergency department, morphine is typically the first drug of choice for analgesia; most often given as a solution which is injected by intravenous, intramuscular, or subcutaneous routes. Intravenous morphine takes effect within seconds and provides full analgesia in minutes.

Morphine Sulfate Extended Release Tablets - 30mg
Morphine has become the analgesic of choice for epidural and intrathecal use in general anaesthesia and procedural analgesia. Recently, intraspinal morphine has caught on along with fentanyl and hydromrphone, in the use of spinal or subcutaneous implantable pumps. Implantable infusion pumps are often used in palliative or hospice care, or treatment of resistant pain in opioid tolerant individuals or those who experience significant side effects with oral opioids.

The tablet and capsule forms of morphine are commonly used for treatment of pain by prescription, and available in doses of 10 to 30 mg IR tablets, or doses of 15 to 200 mg as a sustained release product indicated for around-the-clock treatment of chronic pain. The long acting form is available in 12 or 24 hour tablet or capsules, the latter includes a newer product called "Embeda", which contains an opioid antagonist to deter sinful use and "abuse".

Pharmacology & Chemistry:

Morphine relieves pain by acting on the central nervous system; binding and activating opioid receptors in the brain and spinal cord - though morphine like other narcotics, activates receptor site throughout the peripheral nervous system as well, especially within the bowels & GI tract where it works to inhibit gastrointestinal motility thus reducing bowel movements. Morphine therefore is an effective treatment for diarrhea and other diseases of the bowel (i.e. poop pipes). Most of morphine's efficacy in a clinical context is mediated via the mu (micro) opioid receptors; in addition, the compound binds to delta and kappa opioid receptors. Relative to other opioids, morphine's pharmacological properties are non-selective in regards to its target receptor sites - therefore, along with the drug's intended clinical effects will be a wide range of side effects, mediated via delta or kappa activity, many of which are clinically irrellevant. These side effects may or may not be desireable to the user or patient.

Effects:

Despite remaining the standard first line opioid in treating chronic cancer & non cancer pain, morphine's non-selective pharmacology and relatively unrefined profile of effects are known to come off as 'rough' or 'dirty' to some users. Morphine's more significant side effects include dry skin, pruritis and itching which may be intense with certain individuals, constipation, nausea, respiratory depression, and sedation or somnolence. Subjects receiving morphine intravenously note an often overwhelming sensation of itching, described as 'pins and needles' which is caused by the large release of histamine experienced upon a rapid introduction of morphine to the bloodstream. It is not uncommon for some users to scratch themselves senseless causing bleeding and scabbing. This effect however may be avoided with the use of an over the counter antihistamine up to 30 minutes or an hour before dosing.

Morphine produces dose-dependent respiratory depression, attributed to its inhibitory action on the area of the brainstem associated with involuntary breathing. Asphyxiation due to respiratory depression is the primary mechanism underlying fatal overdose. Because of its effect on involuntary or "reflexive" breathing, the major danger with morphine use is the aforementioned respiratory depression coupled with sedation or somnolence. When an overdose victim is not awake to force his own breathing, the breathing reflex may not be able to maintain unconscious breathing. The average lethal dose of morphine in opioid naive individuals is 120-250 mg by the oral route, which equates to about 40-83 mg by IV or IM injection. These thresholds are significantly lowered when morphine is taken in conjunction with other CNS depressants such as alcohol or benzodiazepines.

None the less, the full spectrum of narcotic effects offered by morphine is highly desired and sought out by users. The euphoric & dreamy subjective effects as well as the side effects of morphine long ago set the precedent for the overall "narcotic experience" - sure enough, the natural painkillers and antidepressants produced naturally within the human body aquired their name (endorphin, endomorphin, etc) from morphine itself.

For those who experience inadequate relief or intolerable side effects with morphine; the most common second choice analgesics are typically oxycodone, hydromorphone, or fentanyl - all of which are available in regular or long acting formulations.

Heroin

Basic:

Known by the trade name Diamorphine and the common name Heroin. Diamorphine was first discovered and produced in 1874 by an English chemist while studying the combination of morphine with various acids. In 1895, the drug was produced and marketed by a German Pharmaceutical company, which is presently Bayer, the pharmaceutical giant. Bayer marketed heroin as a substitute for morphine with a lesser potential for addiction and dependence.

It was later discovered that heroin in fact had no less addiction & dependency potential than its relative morphine, and that diamorphine in fact was converted to morphine once entering the brain. Research would come to show that heroin, essentially an acetylated ester of morphine, was a highly lipid (fat) soluble derivative of morphine - allowing more rapid and complete penetration of the blood-brain barrier. Heroin was essentially, a faster acting form of morphine, which simply produced a superior "rush" when injected.

Diamorphine sale and use was completely prohibited in 1914 within the United States; after which time a majority other nations followed suit, owing to US influence and the newly enacted international treaties (League of Nations, Single Convention on Narcotic Drugs).

Illicit opium for the heroin market is cultivated heavily throughout southwest asian countries of the middle east, including pakistan, and afghanistan. Most of the middle eastern supply is consumed by the european market, in both base form and salt form. Other major illicit opium sources (for the world heroin market) include southeast asia (primarily the golden triangle), colombia, turkey, and mexico.

Much of the world's diamorphine for pharmaceutical use is produced from Turkish, Tasmanian or Indian opium.

Use:

Diamorphine is the world's most widely used illicit opioid, and is available in most countries on the illicit market in the form of a base (#3 heroin), a soluble powder (#4 heroin), or a crude form ranging from gooey and sticky to solid known as black tar heroin.

Most of the available black market heroin in the US is either a water soluble heroin hydrochloride powder, or black tar heroin - the latter of which is more common in the southwest states, smuggled via the mexican border.

Heroin is available in pharmaceutical form, generally in liquid solution for injection under the name diamorphine, or in a water soluble powder for oral/intranasal compounds or parenteral preparation.

Chunky Powder Heroin 
Although pure heroin hydrochloride is a clean white powder, most street heroin varies in color. No. 4 Heroin of decent quality typically appears as a fine powder ranging in color from an off white beige to an off white pale grey. It is similar in consistency to a talc powder, and generally appears flaky when pressed tightly in a "stamp" bag, crumbling into a fine pile when removed from the package.

While diluting agents each have their own taste, relatively pure heroin has a very bitter, chemical taste which lingers in the mouth - it is similar to that of opiate based pharmaceuticals, but much stronger. If you like many others, suck the residue off the stamp bags, the strong taste may trigger nausea when combined with the emetic effect of the heroin you've administered. The taste is not unpleasant, just very strong.

Pure heroin has no significant odor, but most street heroin will have a distinct odor, often ranging from somewhat of a yeast-like scent, to a vinegar-type scent; this scent may vary depending on the type and quantity of dilutants used.

Good heroin will readily dissolve upon contact with water, and does not require "cooking". Stirring the mixture is advised, to ensure the product is fully dissolved.

Aside from the diluting & cutting agents, the vast majority of even raw, uncut heroin will have a portion of impurities from the manufacturing process. Impurities found in illicit heroin are generally limited to 6-acetylmorphine, 6-acetylcodeine, and often some traces of morphine and codeine. Morphine or 6-acetylmorphine occur due to incomplete or partial acetylation of the morphine base during the process, while 6-acetylcodeine occurs as a result of acetylation of any codeine which was extracted with the initial morphine base. Black tar heroin is known for its sloppy production process, which yields a product that is not the same as "heroin" strictly speaking, but rather an unrefined composition containing some heroin along with relatively high levels of 6-acetylmorphine and morphine itself, which some experienced users tend to prefer (Granted, most powder heroin products contain these impurities, however not to the extent that they could be considered a mixture or composition product, as black tar is).

Black Tar Heroin
Powder heroin is most commonly dissolved in water and injected intravenously or intramuscularly; IV injection offers complete bioavailability and takes effect in 8 to 10 seconds, while IM injection takes effect anywhere between 1 and 5 minutes. Powder heroin may also be smoked using indirect heat offering an immediate effect similar to IV use, or snorted intranasally, absorbing into the blood vessels of the mucous membranes and taking effect in 5 to 10 minutes at the most. Heroin in any form is very rarely taken orally, due to its negligible oral bioavailability - i.e. a vast majority of a dose is lost before reaching the blood-brain barrier, courtesy of its trip through the liver, allowing only 20 to 25% of a given dose to actually reach the central nervous system.

Due to its illegal status in most countries including the US, heroin use comes with health and lifestyle owing to the absence of regulation and quality control. Origin and purity are unknown, and product is diluted with various fillers to increase volume and multiply profit. Intravenous use of black market heroin comes with serious health risks due to the presence of insoluble fillers - many of which may be chemicals not intended for human consumption - which may cause vascular infection, hepatitis, and obstruction of tiny blood vessels in vital organs such as the heart, lungs, or brain. On the other end of the spectrum, unwitting use of an irregularly pure batch of product may lead to overdose and death - Not knowing the purity or quality of each dose makes the risk of use exponentially greater than that of a regulated, pharmaceutical-quality product.

Due the scarcity of injecting equipment in many areas, users often re-use and share dirty needles, increasing the prevalence of Hepatitis, HIV and other blood-bourne illness/infection. Proper hygeine, proper injecting technique, not to mention a basic level of pharmacological knowledge - these are essential, however largely lacking among both urban and rural drug users, unfortunately contributing further to the stereotypes and misconceptions of opioid use - primarily heroin.

Most risks and ills associated with the illicit use of heroin come not from the drug itself, but from the lifestyle of the user as well as the unregulated nature of the drug caused by prohibition itself.

Diamorphine Injectable Ampules (Top)
Pethidine (Bottom)
Heroin is used in a number of countries under its proper trade name Diamorphine. The drug is clinically interchangeable with morphine as an analgesic and anaesthetic, and provides remarkable relief from moderate to severe pain in the injured or terminally ill. Its relatively potent and rapid acting properties provide it advantages over morphine in certain settings. Diamorphine is used in the treatment of severe pain in a trauma or ER setting, postoperative units, intensive care units, and commonly in hospice medicine to relieve pain in cancer or other terminally ill patients, allowing a transcendent peace and pain free existence throughout one's final days, weeks, etc. Diamorphine in medicine is administered by parenteral, spinal, oral, rectal and intranasal routes.

Diamorphine in some Nations may be prescribed by physicians for the clinical maintenance of narcotic dependence to chronic addicts who have found limited success with other methods of opioid replacement such as methadone, morphine, hydromorphone, or buprenorphine. A similar approach is the establishment of supervised injecting centers - these centers serve as a safe area for the use of the drug, and often provide clean needles and injecting supplies. Some of these centers distribute pharmaceutical heroin and are staffed by a physician and medical staff. Clinical observations have shown heroin maintenance programs to be effective in maintaining the health of the addict, as well as encouraging compliance both with clinical guidelines and the law. Diamorphine as an addiction maintenance tool is prescribed either by itself or alongside a longer acting agent such as methadone. Heroin maintenance treatment and supervised heroin centers are becoming commonplace throughout Europe and Canada, and are becoming implemented or approved by multiple governments - highlighting the success of such systems.

Properties:

Heroin itself produces little effect. Diamorphine serves as a prodrug for the distribution of several metabolites; morphine, 6-acetylmorphine, and morphine-6-glucuronide. The acetyl groups of diamorphine serve the purpose of increasing the lipid solubility of the drug, allowing rapid entrance to the brain upon injection. Heroin itself contributes to only the first few seconds to minutes of effect; it is rapidly deacetylated in the bloodstream via plasma enzymes within to form 6-acetylmorphine, and eventually morphine itself further down the line. Morphine is further conjugated to form morphine-6-glucuronide, a potent mu agonist. These metabolites more easily bind to mu receptors than does heroin itself, as they all have a free 3-hydroxyl group (large factor in opioid recognition). All produce typical opioid effects via binding primarily at mu-opioid receptors centrally throughout the brain and spinal cord & peripherally within the GI tract (i.e. the gut). As with all mu agonists, they indirectly elevate mesolimbic dopamine release via binding at sites in the ventral tegmental area (VTA).

6-acetylmorphine as well as morphine-6-glucuronide, have shown affinity at the third subset of mu-receptor (mu3) which morphine itself does not activate. Affinity for this novel mu receptor is speculated to contribute to reports of heroin's distinguished subjective effects. Diamorphine when injected intravenously is approximately twice as potent as morphine by the same route as an analgesic.

Heroin may be administered orally and is done so medically in the UK. Its bioavailability by this route is highly variable, being dependent on tolerance-level of the user and highly dose dependent. In opioid naiive users taking heroin acutely, its eventual systemic morphine bioavailability is roughly 25%. In opioid dependent or regular narcotic users however, oral bioavailability of these larger doses may increase to 60-70%. In the former (opioid naiive) population, oral heroin is roughly equipotent to oxycodone via the same route. In the latter (tolerant) population, its oral potency is closer to that of PO hydromorphone.

Effects:

The effects of heroin are segmental (i.e. come in phases). Upon initial IV administration comes an immediate rush of warmth & euphoria - with pure heroin this is due to diamorphine itself, and with illicit heroin may be partially due to minor amounts of unreacted morphine or 6-acetylmorphine present as impurities in the product.

Within a minute or so of the initial rush, an intensely pleasant state of relaxation becomes present, accompanied by positive mood and euphoria. This takes place during the and after the rapid breakdown to 6-acetylmorphine, which is responsible for the majority of heroin's acute effects. Peak levels of 6-AM are typically reached within 2 minutes. This acute period is generally known as the "flash".

This is followed by further breakdown to morphine, and morphine's further breakdown into morphine-6-glucuronide. The life of each metabolite may be considered a phase of its own, however following the rush, subjective effects are nearly impossible to differentiate. The metabolic process takes place generally during the first half hour following administration. The entire course of the experience following the initial rush and conversion to 6-AM, is known as the "bang" phase, These terms being an analogy to a thunderstorm - the initial lightning flash, and the following bang of thunder.

The effects of diamorphine are similar to morphine, but with an especially pleasant initial "rush" upon injection felt throughout the body. Physiological effects may include pruritis and itching, a general flushing or warmth, pinpoint pupils (miosis), myoclonus, constipation, emesis, respiratory depression and peripheral vasodilation.

Subjective effects include analgesia physical relaxation and release of all tension, a highly euphoric sense of peaceful well being, positive mood, empathy towards others and increased sociability or "chattiness", relief of anxiety and/or stress, temporary relief from depression, increased energy with a sense of motivation or productivity - if currently active, sedation and/or somnolence with intermittent periods of nodding the head as if falling asleep, a twilight state of shallow half-sleep - often with vivid dreams ("waking dreams") best described as a dreamlike state; this is common with all opioid users and is a highly regarded & greatly renowned state, known as "vivid dreaming", "nodding out", "opiate sleep", or "morphine dreams".

Main page for 3,6 morphine esters: here

Desomorphine

Unique narcotic related to morphine - distinct from morphine & other derivatives in that it lacks a furan ring & 6-alcohol substituent.

Developed in the 1930's as an alternative to morphine & diamorphine but never widely marketed due to its short duration.

Chemical name is desoxydihydromorphine - It is therefore an immediate derivative of dihydromorphine and a simple analogue of morphine. Desomorphine is 10x as potent as morphine, about equal to oxymorphone.

Rapid onset & short duration. For clinical purposes, its potency is believed to be offset by its very short duration; however, it may be particularly useful for traumatic pain due to injury, breakthrough pain, and of course as a substitute for heroin in recreational use.

Tolerance develops quickly unless administered at its minimally effective dose, at a time interval appropriate to its duration of effect.

Produces a rush similar to heroin when injected intravenously.

Effects last 3 hours at most and are similar to morphine & heroin - euphoria, analgesia, anxiolysis, sedation, excitation, respiratory depression, itching, constipation, nausea & vomiting.

Withdrawal appears more rapidly than with morphine and is at least as severe, but may be shorter in duration.

Desomorphine has unfortunately become associated in Russia with the street drug Krokodil - in which case it is synthesized (or rather "cooked up") by addicts, using over the counter codeine tablets as a starting material. Krokodil is a shame to the reputation of desomorphine and all opioids; as it is a low quality mixture of product containing toxic impurities, produced by lay-addicts using household chemicals & kitchen supplies. The name krokodil is a reference to "Crocodile". In reference to the scaly, rotten, boil-ridden, reptilian skin of the users who inject the crude homemade product. Use of the product by injection often leads to amputation of one or more limbs, and eventually death not by overdose, but due to the toxic & corrosive nature of the product they are injecting. This entire phenomena is a product of Russias' draconian narcotic laws - methadone maintenance is illegal in Russia. Criminal sentencing is harsh. Pain prescriptions are difficult to obtain. Those without access to heroin have turned to krokodil as a half-ass, toxic substitute.

Dihydromorphine

A strong opioid analgesic. Dihydromorphine is a derivative of morphine that has been hydrogenated at the 7,8 bond. Also known as Paramorphan.

First synthesized in Germany in 1900. It is a schedule 1 controlled substance in the US and therefore its medical use is illegal. Has been used elsewhere as an analgesic for moderate to severe pain.

Acts as an agonist predominantly at the mu receptor, with a low affinity for delta & kappa receptors. Frequently used in opioid receptor binding studies. Also used as a precursor or intermediate in the synthesis of other narcotics.

Saturation of the double bond makes DHM slightly more potent than morphine and longer acting. Its oral bioavailability may be greater than morphine.

Effects last 4-6 hours as opposed to 3-4 hours with morphine and include analgesia, euphoria, sedation, itching, constipation, nausea, peripheral vasodilation, miosis and respiratorty depression.

Can be taken orally, rectally, intravenously, intramuscularly or subcutaneously - just as morphine.

Azidomorphine


Azidomorphine is a potent analogue of morphine and is 50x more potent. In human studies it produced prototypic opioid effects including analgesia, respiratory depression, miosis, and supression of abstinence. Subjective effects were similar to morphine - including euphoria, anxiolysis and reward.


Chem-Comparison

Molecules of the morphine family

Thursday, December 1, 2011

Review of the 3 and 6 Esters of Morphine

Chemically speaking, the less polar a compound is, the more lipophilic it will be. Morphine has three polar groups; a 3 and a 6 hydroxyl, and an N-methyl. Effect on potency aside - masking a polar group with a subtituent results in an improved ability to cross the blood-brain barrier.

Take 6-acetylmorphine (6-AM) for instance, where the 6-hydroxyl has been masked by an acetyl ester. 6-AM therefore contains only 2 polar groups, rendering it lipophilic. The molecule reaches the brain more quickly and in higher volume than does morphine alone, and is therefore more potent. Further adding to its potency however is the fact that the 6-acetyl substituent increases its activity at the mu receptor, and is believed to reach a third binding site of the mu receptor. 6-AM is at least 4x as potent as morphine as a narcotic and has a higher affinity for the mu receptor.

As a side note: Not only are lipophilic opioids stronger and faster acting, but they reach the brain tissues and spinal cord in greater relative portions, and act more selectively on the central nervous system, therefore producing less constipation & itching, with more analgesia, sedation and euphoria. In short, lipophilic compounds are drawn to the brain like a magnet, while hydrophilic compounds linger outside of the brain, in the bloodstream and peripheral organs. Lipophilic opioids generally have a "cleaner" feel, while polar opioids like morphine feel less so, producing itching, flushing and 'body-load' - for instance, the heavy feeling in the gut and the deep "leg-burn" of a morphine buzz; as opposed to the serene, cerebral high of heroin, dilaudid or fentanyl.

Now let's consider diacetylmorphine, i.e. heroin. Heroin has both the 3 and 6 hydroxyl groups masked with acetyl groups. It is less polar than both morphine & 6-acetylmorphine and therefore reaches the brain very rapidly and in high volume, making it more potent than morphine. Unlike 6-acetylmorphine however, diacetylmorphine binds poorly to receptors because the essential 3-hydroxyl is masked. So although it is less polar and faster acting, it is less potent than 6-acetylmorphine as an opioid The 3-acetyl group is removed for maximum activity. Heroin is about twice as potent as morphine by weight and half as potent as 6-acetylmorphine, while it is faster acting than both.

Both heroin and 6-acetylmorphine are metabolized to morphine by enzymes in the blood and brain - heroin obviously requires 2-steps, while 6-acetylmorphine becomes morphine in one step. This process occurs over the first several minutes following venous injection or otherwise systemic absorbtion.

There are many other esters of morphine which have been synthesized at some point, and all of these share similar properties. They are all lipophilic drugs which are faster acting and stronger than morphine. Nicomorphine is the 3,6 nicotinate ester of morphine and is used medicinally as a potent painkiller mainly in Europe.

Dipropanoylmorphine: An Obscure Morphine Ester:

Semi synthetic opioid of the morphine type. Dipropanoylmorphine is a heroin analogue - specifically a 3,6 propionyl ester of morphine.

Discovered more recently than other morphine esters (in 1974) therefore its history & use dates back no longer than fentanyl.

Rarely used medicinally, if at all. 3-4x as potent as morphine due to its high lipophilicity. Longer lasting than morphine and heroin due to the presence of two propionyl groups which are broken down more slowly than the acetyl groups of heroin.

Effects are similar to heroin, and include analgesia, euphoria, sedation, itching, nausea, constipation peripheral vasodilation and respiratory depression. Its effects last 3-6 hours.

There exists a number of heroin-analogues which have never been marketed for medical use, and had not ever been used in humans until appearing on the illicit opiate market, The following are 3,6 morphine diesters as well:

Dihydroheroin:

 A semi-synthetic opioid of the morphine class. It is an analogue of heroin, where the 7,8 double bond has been saturated. It is about as potent as heroin with a longer duration of action. Dihydroheroin is immediately metabolized by plasma esterase enzymes to the much more active 6-acetyldihydromorphine and further dihydromorphine; both of which are potent opioid agonists. Effects are similar to heroin, but with a longer duration than either morphine or heroin and a possibly slower onset.

Dibenzoylmorphine:

Developed during the early 20th century in the years following the US Harrison Act and similar criminal laws passed in a handful of nations - which were the first steps in criminalizing the non-medical use of heroin and other narcotics. First synthesized in the United Kingdom. Dibenzoylmorphine was the most common morphine ester used as a heroin substitute. It serves as a fast acting prodrug for its monoester 6-benzoylmorphine and morphine, and is expected to have virtually identical effects to heroin - including an intense onset or "rush" when injected intravenously.

Acetylpropionylmorphine:

Acetylpropionylmorphine is the 3-acetyl, 6-propionyl ester of morphine. It was synthesized in Great Britain and appeared as a heroin substitute around the same time as dibenzoylmorphine. It serves as a fast acting prodrug for 6-propionylmorphine and its effects too are virtually identical to heroin - including the initial IV "rush".