Endogenous Opioids

We are all naturally dependent on opioids for our emotional health. Both narcotics and internally generated endorphins exert their action on the body by interacting with specific membrane receptor-proteins on our nerve cells. The body produces three large pro-compounds: proenkephalin, prodynorphin, and pro-opiomelanocortin. Endorphins can further decompose to small fragments, oligomers, which are still active. Oligomers pass the blood-brain barrier more readily. Enzymatic degradation of small-chain endorphins is accomplished by dipeptidyl carboxypeptidase, enkephalinases, angiotensinases, and other enzymes. This limits their lifetime in the unbound state.

Opioid receptors presynaptically inhibit transmission of excitatory pathways. These pathways include acetylcholine, the catecholamines, serotonin, and substance P. Substance P is a neuropeptide active in neurons that mediate our sense of pain; antagonists of substance P are currently under investigation as clinical antidepressants. Endorphins are also involved in glucose regulation. Opioid receptors are functionally designated as mu, delta, kappa, etc. These categories can be further sub-classified by function or structure. Decoding the human genome has allowed the genetic switching-mechanisms that control the expression of each opioid receptor to be determined at the transcriptional and post-transcriptional level. All classes of opioid receptor share key similarities. Opioid-driven inhibition of neuronal excitability is mediated by the activation of a variety of potassium channels in the plasma membrane. The disparate subjective and behavioural effects evoked by activation of the different categories of opioid receptor are typically not the outcome of different cellular responses, but reflect the different anatomical distributions of each receptor. Unlike kappa opioid receptors, however, both mu and delta opioid receptors internalise on exposure to agonists. Activation of any type of opioid receptor inhibits adenylate cyclase, resulting in a fall in intracellular cAMP and diminished action potential firing. This causes a reduced flow of nociceptive information to the brain. Conversely, opioid addicts undergoing withdrawal suffer elevated cAMP levels and enhanced protein kinase A activity, resulting in increased neurotransmitter release. The opioid receptors all have a common general structure. They are characteristically G protein-linked receptors embedded in the plasma membrane of neurons. Once the receptors are bound, a portion of the G protein is activated, allowing it to diffuse within the plasma membrane. The G protein moves within the membrane until it reaches its target either an enzyme or an ion channel. These targets normally alter protein phosphorylation and/or gene transcription. Whereas protein phosphorylation alters short-term neuronal activity, gene transcription acts over a longer timescale. Two new classes of opioid neuropeptide have recently been identified. These are nociceptin and the endomorphins. Nociceptin (also known as orphanin) was first identified in 1995. It is the endogenous ligand of the opioid receptor-like 1 receptor. Depending dosage and site, nociceptin has subjectively extremely nasty hyperalgesic effects. Nociceptin receptor antagonists are candidate antidepressants and analgesics. Endomorphin1 and endomorphin2 are newly-discovered ligands with the highest affinity and selectivity for the mu opioid receptor of all the endogenous opioids. Critically, endomorphin1 increases dopamine efflux in the nucleus accumbens via mu-1 opioid receptors. In the absence of selective endogenous mu-opioid receptor agonists, our vulnerability to pain and suffering would be even worse. Several novel, peripherally administered endomorphin1 analogues are under investigation that are more resistant to enzymatic hydrolysis. They should offer new opportunities for euphoric well-being, enriched mental health and more effective pain-relief. Morphine itself is produced naturally by the human body and brain, albeit in much lower concentrations than in the opium poppy Papaver somniferum. Morphine is synthesised in human neuroblastoma cells via a biosynthetic route similar to that of the opium poppy. It is also present in healthy neurons, where it undergoes Ca2+-dependent release suggestive of a neurotransmitter or neuromodulator role. But the physiological role of endogenous morphine is still obscure. Opioidergic neurons are particularly concentrated in the ventral tegmental area. The VTA is an important nerve tract in the limbic system. The VTA passes messages to clusters of nerve cells in the nucleus accumbens and the frontal cortex. This forms the brain's primary reward pathway, the mesolimbic dopamine system. Its neurons are called dopaminergic because dopamine is manufactured, transported down the length of the neuron, and packaged for release into the synapses. GABA normally plays a braking role on the dopaminergic cells. Opioids and endogenous opioid neurotransmitters activate the presynaptic opioid receptors on GABA neurons. This inhibits the release of GABA in the ventral tegmental area. Inhibiting GABA allows the dopaminergic neurons to fire more vigorously. The release of extra dopamine in the nucleus accumbens is intensely pleasurable. Both delta opioid agonists and inhibitors of enkephalin catabolism have anxiolytic and antidepressant activity. Kappa opioid receptor antagonists have antidepressant activity; the first orally active selective kappa receptor antagonist is the investigational drug JDTic. Mu receptor activation is crucial to the rewarding, analgesic and addictive properties of opioids. Government researchers and pharmaceutical companies are searching for powerful analgesics that won't make the user feel happy ["high"] too. Mu-receptors are found mainly in the brainstem and the medial thalamus. There are two primary sub-types: mu-1 and mu-2. More than 100 polymorphisms have been identified in the human mu opioid peptide receptor gene. Stimulation of the mu-1 receptors is primarily responsible for the beautiful sense of euphoria, serenity and analgesia induced by a potent and selective mu opioid agonist. Receptor activation by mu opioid agonists increases cell firing in the ventral tegmental area. This triggers dopamine release in the nucleus accumbens by reducing GABA's tonic inhibitory control of the dopaminergic neurons. By contrast, at the height of the opioid withdrawal syndrome, typical firing rates and burst firings of VTAnucleus accumbens neurons are reduced to around 30% of normal. The withdrawal syndrome can be quickly remedied by the administration of a potent mu agonist such as morphine. Care is needed: stimulation of the mu-2 opioid receptors helps modulate respiratory depression. For obvious reasons, this is potentially dangerous. The endogenous ligands for the mu opioid receptors have recently been discovered. They are endomorphin-1 (Tyr-Pro-Trp-Phe-NH2, EM-1) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2, EM-2). Unfortunately, we still lack clinically available opioids specific to the mu-1 receptor. Their advent will (potentially) be a tremendous boon to mental and physical health. Heroin is named after the German word for powerful, heroic, heroisch. According to popular legend, its substitute, methadone, was initially christened Dolophine in honour of Adolf Hitler. In reality, the name comes from the Latin dolor, meaning "pain", and fin, meaning "end": hence "end of pain". The consumption of heroin is marked by a euphoric rush, a warm feeling of relaxation, a sense of security and protection, and a dissipation of pain, fear, hunger, tension and anxiety. When heroin is snorted or smoked, the rush is intense and orgasmic. Subjectively, time may slow down. Any sense of anger, frustration or aggression disappears. Users enjoy the feeling of "being wrapped in God's warmest blanket". Heroin is the most fast-acting of all the opiates. When injected, it reaches the brain in 15-30 seconds; smoked heroin reaches the brain in around 7 seconds. The peak experience via this route lasts at most a few minutes. The surge of pleasure seems to start in the abdomen; a delicious warmth then spreads throughout the body, or at least the somatosensory cortex. After the intense euphoria, a period of tranquillity ("on the nod") follows, lasting up to an hour. Experienced users will inject between 2-4 times per day. After taking heroin, some people feel cocooned and emotionally self-contained. Others feel stimulated and sociable. Either way, there is a profound sense of control and well-being. The euphoria gradually subsides into a dreamy and relaxed state of contentment. Higher doses of heroin normally make a person feel sleepy. At higher doses still, the user will nod off into a semi-conscious state. The effects usually wear off in 3-5 hours, depending on the dose. Heroin is not inherently toxic to the organ systems of the body. Whereas a 200-400mg dose of heroin could kill a novice, a chronic user may take 1800mg without ill-effects. But in prohibitionist society the mortality of street users is high. Diacetylmorphine, or heroin, was first synthesized from morphine in 1874. It is formed simply by adding two acetyl groups. Heroin is around three times more potent than morphine. Its increased lipid solubility allows heroin to cross the blood-brain barrier more quickly. The drug is reconverted back to morphine before it binds to brain-tissue receptors. Pure heroin is a white, odourless powder with a bitter taste. Most illicit heroin, however, varies in color from white, pink/beige to dark brown. This is because of impurities left from the manufacturing process or the presence of additives. In the late nineteenth century, it was fondly believed that if only one could filter out the "addictive" properties of opium, then one would capture its therapeutic essence. Heinrich Dreser, in charge of drug development at Bayer, tested the new semi-synthetic drug on animals, humans, and most notably himself. Dreser was impressed. He pronounced heroin an effective treatment for a variety of respiratory ailments, especially bronchitis, asthma and tuberculosis. Commercial production of heroin began in 1898. Heroin was advertised under its well-known trademark by German manufacturers Bayer as "the sedative for coughs". The new wonderdrug enjoyed widespread acceptance in the medical profession. This was because heroin induces a serene, un-manic euphoria with minimal interference with sensation, motor skills or intellect - though chronic opioid use typically diminishes the inclination to abstract thought. Bayer was soon enthusiastically selling heroin to dozens of countries. Free samples were handed out to physicians. The medical profession remained largely unaware of the potential risk of addiction for years. Eventually news filtered out. Doctors noticed that some of their patients were consuming inordinate quantities of heroin-based cough remedies. It transpired that heroin was not the miracle-cure for morphinism that some of its early boosters had supposed. In 1913, Bayer halted production. They wrote the drug out of their official company history, and focused instead on marketing their second blockbuster drug, aspirin.

Comprehensive control of opiates in the United States was first established in 1914 with the Harrison Narcotic Act. In 1924, federal law made any use of heroin illegal. Within a decade, the Bureau of Narcotics had arrested some 50,000 users and 25,000 physicians. Most of the problems suffered by contemporary users derive, directly or indirectly, from the criminalisation of heroin use and the draconian penalties inflicted on those who take it. Likewise, most of the needless pain suffered by the physically ill today derives, directly or indirectly, from the demonisation of opioid drugs and from the reluctance of physicians to prescribe stigmatised remedies for pain that really work. During World War One, newspaper editors, police forces, politicians and "patriots" whipped up a climate of hysteria against seditious "dope fiends" enslaved by "the German invention". Heroin use was associated with anarchy, violence, foreigners and Bolshevism. Prohibition led inexorably to control of the heroin business by organised crime. Jewish gangsters such as Meyer Lansky dominated distribution in the 1920s. In the 1930s, they were superseded by the Mafia: this was the era of "Lucky" Luciano, the celebrated Sicilian mobster. Drug law was widely flouted. In explaining the failure of decades of prohibitionist legislation, former chief of police of the USA, Joseph D McNamara, wrote in National Review... "It's the money, stupid. After 33 years as a police officer in three of the country's largest cities, that is my message to the righteous politicians who obstinately proclaim that a war on drugs will lead to a drug-free America. About $500 of heroin or cocaine in a source country will bring in as much as $100,000 on the streets of an American city. All the cops, armies, prisons and executions in the world cannot impede a market with that kind of tax-free profit-margin. It is the illegality that permits the obscene mark-up, enriching drug-traffickers, distributors, dealers, crooked cops, lawyers, judges, politicians, bankers, businessmen..." Choking off the supply of narcotics at source isn't a realistic prospect either. Myles Ambrose, one of President Nixon's closest advisers in the War on Drugs, was scathing in his judgement of some of his fellow drug-warriors... "...The basic fact that eluded these great geniuses was that it takes only ten square miles of poppy to feed the entire American heroin market, and they grow everywhere...." Traditionally, the purity of heroin in a bag has ranged from 1% to 10%; more recently, heroin purity has ranged from 1% to 98%, with a US national average of 35 percent. Pure heroin is rarely sold on the street. A bag may contain 100 mg of powder, only a portion of which is heroin; the remainder could be sugars, starch, powdered milk, or quinine. Until recently, heroin in the United States was almost exclusively injected, either intravenously, subcutaneously ("skin-popping"), or intramuscularly. Injection is the most practical and efficient way to administer low-purity heroin. The availability of higher-purity heroin, however, allows users to snort or smoke ("chasing the dragon"). Snorting is most widespread in those areas where high-purity heroin is easy to obtain. When injected, heroin provides an extremely powerful rush. After 4 to 8 hours, the effects start to wear off. Tolerance develops to the respiratory depressant, sedative, analgesic, emetic and euphorigenic effect. So users tend to increase their daily dose - sometimes as much as a hundredfold or more - if financial resources permit. Financial resources frequently don't: the term "junkie" derives from addicts who stole junk metal to support their habit. Injecting drugs can be a risky business in prohibitionist society. This is because hygiene is difficult, education is minimal, and fluctuations in quality can lead to accidental overdose. US opposition to needle-exchange programs at home and abroad has massively promoted the spread of HIV and hepatitis in users - and non-users - alike. Noxious tobaccosmoking aside, the Supreme Court of the United States has never been sympathetic to a drug-based lifestyle.... "To be a confirmed drug addict is to be one of the walking dead....The teeth have rotted out, the appetite is lost, and the stomach and intestines don't function properly. The gall bladder becomes inflamed; eyes and skin turn a bilious yellow; in some cases membranes of the nose turn a flaming red; the partition separating the nostrils is eaten away-breathing is difficult. Oxygen in the blood decreases; bronchitis and tuberculosis develop. Good traits of character disappear and bad ones emerge. Sex organs become affected. Veins collapse and livid purplish scars remain. Boils and abscesses plague the skin; gnawing pain racks the body. Nerves snap; vicious twitching develops. Imaginary and fantastic fears blight the mind and sometimes complete insanity results. Often times, too, death comes-much too early in life....Such is the torment of being a drug addict; such is the plague of being one of the walking dead..." (1962) Heroin is sometimes smoked with crack cocaine. This combination delivers an even more intensely rewarding experience than taking either drug alone. "Speedballs" are hugely addictive and ruinously expensive. Yet in a clinical setting and among the terminally ill, the simultaneous use of cocaine, methylphenidate or amphetamines with heroin or morphine can augment the opioid's analgesic and anxiolytic effect while allowing its dosage to be lowered. The risks of respiratory depression are thus diminished. Why do we like opium and its derivatives so much? Heroin mimics the action of natural chemicals, endorphins, produced by the body in response to pain. Endorphins are small-chain peptides that activate our endogenous opioid receptors. Opioid receptors are proteins embedded in the cell membrane; opioid agonists bind to the receptors to initiate their effects. The highest density of opioid receptors is found in the limbic system. Their activation produces feelings of happiness, relaxation, fearlessness and tolerance to pain. Endorphins are hundreds or even thousands of times more potent than morphine on a molar basis. Their potency means their concentrations in vivo are low. Endorphins are also involved in respiration, nausea, vomiting, pain modulation, hormonal regulation and itching. Opioid drugs also act in these limbic brain regions. Yet except at very high doses, the opioids don't block the pain messages themselves. Rather, they change the subjective experience of the pain. This is why people receiving morphine for pain-relief may say that they still feel the pain - but that it doesn't bother them any more. Many users self-medicate: opioids are powerful antidepressants and antianxiety agents. Response and remission rates are high; but so are tolerance, dependence and addiction.

Chemical Classes of Opioid Analgesics

Opium (Paregoric, Laudanum, etc.)

Opiates

Morphine

Codeine*

Hydrocodone (Vicodin, Codiclear) Opioid Analgesics Hydromorphone (Dilaudid) Derivates or Analogues of Morphine & Codeine

Oxycodone (Percodan)

Oxymorphone (Numorphan)

Diacetylmorphine (Heroin)

Dihyhdrocodeine (Synalgos)

Levorphanol (Levo-Dromoran)

Morphinian Derivates

Dextromethorphan

Butorphanol (Stadol)

Phenazocine Benzomorphan Derivatives Pentazocine (Talwin)

Meperidine/Pethidine

Diphenoxylate (Lomotil)

Loperamide (Immodium)

Fentanyl (Duragesic, Sublimaze etc.)

Piperidine Derivatives

Remifentanil (Ultiva)

Sufentanil (Sufenta)

Alfentanil (Alfenta)

Piminodine

Anileridine

Methadone Methadone Class Compounds Propoxyphene (Darvon)

Pain, Itself, Elicits Pain Relief, And Does So Through "Reward" Pathway

" Researchers have long known that the body can activate its own form of pain relief in response to painful stimuli. Now, UC San Francisco investigators have determined that, in rats, this long-lasting relief is produced by the brain's "reward" pathway - the neural circuitry activated by drugs of abuse. In their study, published in the August 15 issue of Journal of Neuroscience, the investigators determined that, at its maximum, the pain relief was as potent as a high dose of morphine. While various individual structures in the brain have been known to produce analgesia, or pain relief, when electrically stimulated or exposed to narcotic painkillers, the finding provides the first physiological evidence that pain itself elicits analgesia. It also provides a surprising twist on the perceived workings of the neural circuitry associated with gratification, said the lead author of the study, Robert W. Gear, PhD, assistant clinical professor of Oral and Maxillofacial Surgery in the NIH Pain Center at UCSF. "We're showing that something aversive - exposure to a painful stimulus - as well as exposure to drugs of abuse, stimulate the same reward circuit," said Gear, whose lab is directed by senior author Jon D. Levine, MD, PhD, a professor of Oral and Maxillofacial Surgery and Medicine and director of the NIH Pain Center. "Our result casts new light on how to look at the key structure in the reward pathway, the nucleus accumbens, and the role it plays in affirming certain behaviors and thus motivating individuals to act in particular ways," said Gear. The reward pathway is a neural network in the middle of the brain that prompts good feelings in response to certain behaviors, such as relieving hunger, quenching thirst or having sex, and it thereby reinforces these evolutionarily important drives. However, the circuit also responds to drugs of abuse, such as heroin, cocaine, amphetamine and nicotine, which seem to hijack the circuitry, altering the behavior of its neurons. The nucleus accumbens is the engine of the reward response. And, in their study, the UCSF researchers determined that the reward pathway activates pain relief through the release of both opioids, a morphine-like drug produced by the body, and dopamine, a chemical messenger whose effects can be mimicked by amphetamine and cocaine, in this structure. The finding overturns the long-held assumption that the release of dopamine in the nucleus accumbens is associated only with positive experiences. The evolutionary value of a rush of analgesia is clear, as it could allow, for example, a badly injured individual to escape an attacker. It probably could also explain why some individuals can be injured without persistent pain. But the phenomenon may also explain why heroin addicts, in withdrawal, can experience pain or increased sensitivity to painful stimuli. "It may be that one of the reasons people stay addicted is to avoid going through this unpleasant state of withdrawal," said Gear.

Under other conditions, it's possible that a painful stimulus, by activating the nucleus accumbens, might itself be experienced as rewarding, as appears to occur in self-injurious behaviors. Interestingly, treatment for this class of disorders, characterized by pursuit of painful experiences often for apparent thrill-seeking value, includes administration of naloxone, a drug that blocks the effects of opioids in this reward circuit. The researchers conducted the bulk of their study in anesthetized rats, measuring the animals' response to pain signals in the paws. Because these animals were anesthetized, the measurements were taken using a technique known as the jaw-opening reflex, in which the degree to which the jaw opens reflexively in response to painful stimuli to the tooth indicates the level of pain experienced. The jaw-opening reflex decreased, a sign of analgesia, as the painful stimulus increased. The fact that the analgesic effect was demonstrated in the teeth, far from the hindpaw, indicated its general effect in the whole body. The analgesic effects did not require repeated application of the stimuli, and were shown to last at least an hour. "Our results were quite dramatic," said senior author Levine. "They've spawned several new studies in our lab aimed at revealing more about the role of the reward pathway, and the nucleus accumbens specifically, in human behaviors

Receptors
Preparations of the opium poppy papaver somniferum have been used for many hundreds of years to relieve pain. In 1803, Sertrner isolated a crystalline sample of the main constituent alkaloid, morphine, which was later shown to be almost entirely responsible for the analgesic activity of crude opium. The rigid structural and stereochemical requirements essential for the analgesic actions of morphine and related opioids led to the theory that they produce their effects by interacting with a specific receptor.1 The concept that there is more than one type of opioid receptor arose to explain the dual actions of the synthetic opioid nalorphine, which antagonises the analgesic effect of morphine in man but also acts as an analgesic in its own right. Martin (1967) concluded that the analgesic action of nalorphine is mediated by a receptor, later called the -opioid receptor, that is different from the morphine receptor.2 Evidence for multiple receptors, , and , came from the demonstration of different profiles of pharmacological activity in the chronic spinal dog with the prototype agonists morphine, ketazocine and N-allylnormetazocine (SKF 10047).3 The existence of the -receptor was subsequently proposed to explain the profile of activity in vitro of the enkephalins (the first endogenous opioid peptides), and on the basis of the relative potency of the non-selective opioid antagonist naloxone to reverse endogenous opioid peptide inhibition of the nerve-evoked contractions of the mouse vas deferens.4 Its existence was further confirmed by radioligand binding studies using rat brain homogenates. It is now clear from work carried out in many laboratories over the last 20 years that there are 3 well-defined or "classical" types of opioid receptor , and . Genes encoding for these receptors have been cloned.5, 6, 7, 8 More recently, cDNA encoding an "orphan" receptor was identified which has a high degree of homology to the "classical" opioid receptors; on structural grounds this receptor is an opioid receptor and has been named ORL1 (opioid receptor-like).9 As would be predicted from their known abilities to couple through pertussis toxin-sensitive G-proteins, all of the cloned opioid receptors possess the same general structure of an extracellular N-terminal region, seven transmembrane domains and intracellular C-terminal tail structure. There is pharmacological evidence for subtypes of each receptor and other types of novel, less well-characterised opioid receptors, , , , , have also been postulated. The -receptor, however, is no longer regarded as an opioid receptor. Receptor Subtypes -Receptor subtypes The MOR-1 gene, encoding for one form of the -receptor, shows approximately 50-70% homology to the genes encoding for the -(DOR-1), -(KOR-1) and orphan (ORL1) receptors. Two splice variants of the MOR-1 gene have been cloned, differing only in the presence or absence of 8 amino acids in the C-terminal tail. The splice variants exhibit differences in their rate of onset and recovery from agonist-induced internalization but their pharmacology does not appear to differ in ligand binding assays.10 Furthermore, in the MOR-1 knockout mouse, morphine does not induce antinociception demonstrating that at least in this species morphines analgesia is not mediated through - or -receptors.11 Similarly morphine did not exhibit positive reinforcing properties or an ability to induce physical dependence in the absence of the MOR-1 gene. 1 and 2: The 1/ 2 subdivision was proposed by Pasternak and colleagues to explain their observations, made in radioligand binding studies, that [3H]-labelled- , - and ligands displayed biphasic binding characteristics.12 Each radioligand appeared to bind to the same very high affinity site ( 1) as well as to the appropriate high affinity site ( , or ) depending on the radioligand used. Naloxazone and naloxonazine were reported to abolish the binding of each radioligand to the 1-site. Furthermore, in in vivo studies it was observed that naloxazone selectively blocked morphine-induced antinociception but did not block morphine-induced respiratory depression or the induction of morphine dependence.13, 14 Subsequent work in other laboratories has failed to confirm this classification. Is there another, novel form of the -opioid receptor? Several related observations suggest the existence of a novel form of -receptor at which analogues of morphine with substitutions at the 6 position (e.g. morphine-6 -glucuronide, heroin and 6-acetyl morphine) are agonists, but with which morphine itself does not interact.15 In antinociception tests on mice it has been reported that morphine does not exhibit cross tolerance with morphine-6 -glucuronide, heroin or 6-acetyl morphine. Furthermore, in mice of the CXBX strain morphine is a poor antinociceptive agent whereas morphine-6 glucuronide, heroin and 6-acetyl morphine are all potently antinociceptive. The 6-substituted morphine analogues do not appear to be acting through - or -receptors because the antinociception they induce is not blocked by selective - or receptor antagonists, whereas 3-methoxynaltrexone has been reported to antagonise morphine-6 -glucuronide- and heroin-induced antinociception without affecting that induced by morphine, [D-Pen2, D-Pen5]enkephalin (DPDPE , -selective) or U50488 ( -selective).16 Recently it has been reported that heroin and morphine-6-glucuronide, but not morphine, still produce antinociception in MOR-1 knockout mice in which the disruption in the MOR-1 gene was engineered in exon-1.17 The same authors observed that in other MOR-1 knockout mice in which exon-2, not exon-1, had been disrupted, all three agonists were ineffective as antinociceptive agents. They conclude that the antinociceptive actions of heroin and morphine-6-glucuronide in the exon-1 MOR-1 mutant mice are mediated through a receptor produced from an alternative transcript of the MOR-1 gene differing from the MOR-1 gene product, the -opioid receptor, in the exon-1 region. To substantiate this conclusion they report that in RT-PCR experiments using primers spanning exons 2 and 3, a MOR-1 gene product was still detected in MOR-1 knockout mice. -Receptor subtypes The DOR-1 gene is the only -receptor gene cloned to date. However, two, overlapping subdivisions of and in vitro pharmacological experiments.

-receptor have been proposed (

1/ 2 and

cx/

ncx) on the basis of in vivo

1 and 2: The subdivision of the -receptor into 1 and 2 subtypes was proposed primarily on the basis of in vivo pharmacological studies (Table 1). In rodents in vivo, the supraspinal antinociceptive activity of DPDPE can be selectively antagonised by 7-benzylidenenaltrexone (BNTX) or [D-Ala2, D-Leu5]enkephalyl-Cys (DALCE)18, 19 whereas the antinociceptive activity of [D-Ala2]-deltorphin II (deltorphin II) and [D-Ser2, Leu5]enkephalylThr (DSLET) can be reversed by naltriben or naltrindole 5 -isothiocyanate (5 -NTII).18, 19, 20 Furthermore, while mice develop tolerance to the antinociceptive effects of repeated injections of either DPDPE or deltorphin II, this tolerance appears to be homologous in that there is no cross tolerance between these ligands.21 In vivo, 1- and 2-receptor-induced antinociception can be differentially antagonised by blockers of different types of potassium channels.22 Table 1 . Putative ligands for -receptor subtypes

Receptor subtype

Antagonists

Competitive

Nonequilibrium

DPDPE / DADLE

BNTX

DALCE

Deltorphin II / DSLET

Naltriben

5 -NTII

N.B. DPDPE may not in fact be a selective

1 agonist but may also be a partial agonist at

2-sites.23

The best evidence from in vitro experiments to support the 1 and 2 subdivision of -receptors comes from inhibition of adenylyl cyclase activity in membranes from rat brain24, 25 and from the -receptor-mediated elevations of intracellular Ca2+ in the ND8-47 cell line26 where BNTX selectively antagonised DPDPE, and naltriben selectively antagonised deltorphin II. Surprisingly, little selectivity was seen in radioligand displacement studies.24 The converse has been observed in studies on neuronal cell lines. Two distinct -receptor binding sites were observed in radioligand binding experiments on SK-N-BE cells.27 Studies on NG108-15 cells28 or the human neuroblastoma cell line, SH-SY5Y,29, 30 have failed to find any functional evidence for -receptor subtypes. The pharmacological properties of the cloned DOR-1 receptor are somewhere between those predicted for either the 1 or 2 subtypes. DPDPE and deltorphin II are both potent displacers of [3H]-diprenorphine binding to mouse and human recombinant receptors, which is not consistent with either the 1 or 2 classifications.31 In contrast, [3H]-diprenorphine binding to the mouse recombinant receptor is more potently displaced by naltriben than BNTX, suggesting that the cloned receptor is of the 2 subtype. It will be of importance to determine in the DOR-1 knockout mouse if analgesia can still be induced by either 1- or 2-receptor selective agonists. cx and ncx: The cx and ncx subdivision of -receptors was based on the hypothesis that one type of -receptor ( cx) was complexed with -receptors (and perhaps also receptors) whereas the other type of -receptor ( ncx) was not associated with an opioid receptor complex.32 It was originally observed that sub-antinociceptive doses of agonists at the cx receptor (e.g. low doses of DPDPE), potentiated -receptor-mediated analgesia, an effect which could be antagonised by 5 -NTII. On the other hand, at higher doses, DPDPE then acted as an agonist at the ncx-receptor and itself induced analgesia which was reversed by DALCE. Data obtained from subsequent radioligand binding studies have been interpreted as demonstrating the existence of further subtypes of the ncx receptor i.e. ncx-1) and (ncx-2). More recently it has been suggested that the (ncx-1) receptor is in fact synonymous with the 1-receptor and the cx-receptor synonymous with the 2-receptor of the previous classification.33 -Receptor subtypes The situation regarding the proposals for subtypes of the -receptor is rather more complex than for the - and -receptors, perhaps because of the continuing use of non-selective ligands to define the putative sites. The evidence for the need for sub-division of the -receptor comes almost entirely from radioligand binding assays. The first characterisation of a -receptor binding site in brain came from work using [3H]-ethylketocyclazocine (EKC).34 Crucial to this success was the use of the guinea-pig brain where -sites are present in relative abundance, and of "suppression", or quenching of the binding of this non-selective ligand to - and -sites, by incubation with non-radioactive ligands that bound selectively at these other sites. Studies of [3H]-EKC binding in guinea-pig spinal cord pointed to the existence of a non-homogeneous population of high-affinity binding sites, and led to the first proposal for 1- and 2-sites distinguished by their sensitivity to DADLE.35 The DADLE-sensitive 2 site bound -endorphin with high affinity, and was later identified with the recognition site of the receptor in brain.36 Another study using [3H]-EKC identified a -site in bovine adrenal medulla, with a pharmacology similar to that of the 1-site in guinea-pig cord37 but labelling with [3H]-etorphine revealed two additional sites, one resembling 2 that bound [Met]enkephalyl-Arg-Gly-Leu with high affinity and another termed " 3" or "MRF" that bound [Met5]enkephalyl-Arg-Phe with high affinity. The 1/ 2 terminology has more recently been applied by other groups to the putative subtypes defined in other tissues in their hands, but it is not always clear how closely the common nomenclature reflects a common pharmacology. The introduction of the first selective -agonist U-50,488 and its congeners (U-69,593, PD 117302, CI 977, ICI 197067) led to a refinement of the definition of the putative subtypes, but pointed to the need for careful considerations of the effect of technical differences in assays and of species as a possible explanation for discrepancies. Thus a direct comparison of the binding of [3H]-EKC in guinea-pig and rat (with suppression of binding to - and -sites) pointed to the existence of a high affinity 1-site that predominated in guinea-pig brain and was selectively sensitive to U-69,593, and a low affinity, U-69,593-insensitive 2-site that predominated in rat brain.38 Others resorted to the binding of [3H]-bremazocine to reveal U-69,593-insensitive 2-binding sites; in contrast to the 2-site originally defined in guinea-pig spinal cord, the 2-site in brain after suppression of 1 was insensitive to DADLE.39 Subdivision of the 1-site in guinea-pig brain into 1a and 1b, was proposed to resolve the complex displacement of either [3H]-EKC or [3H]-U-69,593 with dynorphin B and -neoendorphin which both preferentially bound to the proposed 1b sub-subtype.40 The same study proposed the existence of a 3 subtype, insensitive to U-50,488, that was identified from the binding of [3H]-naloxone benzoylhydrazone. The pharmacology of this later " 3-site" is rather different from the 3/MRF site of bovine adrenal medulla, and has been proposed to be the receptor mediating the antinociceptive effect of nalorphine, Martins "N"-receptor.41 Nomenclature differences appear to have arisen in the context of subtyping of the 1-subtype. Using binding surface analyses to allow highly accurate estimation of binding parameters, the binding of [3H]-U-69,593 resolved two binding sites termed 1a and 1b. The ligand demonstrating the highest affinity, and around 30-fold preference, for the " 1a binding site" was -neo-endorphin.42 More recently putative 1a- and 1b-sites in mouse brain were identified from complex displacement curves against the binding of [3H]-U69,593, in an attempt to compare the pharmacology of the mouse 1-sites, with that at the cloned rat KOR stably expressed in a host neuroblastoma cell line.43 Based on the high affinity of bremazocine and -neo-endorphin, it was deemed "consistent to term the cloned KOR a 1b subtype". Rothman (1990) also reported subdivision of the 2-binding of [3H]-bremazocine into 2a- and 2b-sub-subtypes.42 The 2b-site had high affinity for -endorphin and DADLE, reminiscent of the original 2-binding site of guinea-pig spinal cord. The 2a- and 2b-sites in guinea-pig brain have undergone a further subdivision (sub-sub-subtypes?) on the basis of investigations using a combination of depletion (of - and -sites) and suppression, against the binding of 6 -[125I]-3,14-dihydroxy-17-cyclopropylmethyl-4,5 epoxymorphinan ([125I]OXY).44 So were defined the 2a-1 and 2a-2 sites, having relatively high and low affinities respectively for nor-BNI and enadoline (CI-977), and 2b-1 and 2b-2 sites with high and low affinities for DAMGO and -neo-endorphin. Definitive functional pharmacological evidence supporting the existence of this confusing number of putative subtypes of the -receptor is lacking, because of the absence of subtypespecific antagonists. It has been reported however, that pretreatment with the isothiocyanate analogue of U-50,488 called (-)-UPHIT, was able to produce a long-lasting block of the antinociceptive effect of U-69,593 in the mouse without affecting the action of bremazocine, while treatment with the non-selective antagonist WIN 44,441 (quadazocine) blocked selectively the antinociception with bremazocine.45,46 These findings provide obvious support for the 1- 2 subdivision; the pharmacological corollary is that (-)-UPHIT and WIN 44,441 are antagonists with selectivity for the 1-and 2-subtypes respectively, at least in the mouse. Correlating genes with -, - and -receptor subtypes Although there is as yet little evidence for different genes encoding the different subtypes of -, - and -receptor these subtypes may result from different post-translational modifications of the gene product (glycosylation, palmytoylation, phosphorylation, etc), from receptor dimerization to form homomeric47 and heteromeric complexes,48, 49, 50 or from interaction of the gene product with associated proteins such as RAMPs.51 The Orphan Receptor Extending the screening of genomic and cDNA libraries, perhaps in an effort to identify putative subtypes of the classical opioid receptors, resulted in the identification of a novel receptor that bore as high a degree of homology towards the classical opioid receptor types, as they shared among each other. The receptor was identified in three species: rat, mouse and man, with the degree of homology among the species variants more than 90%. Although the putative receptor has had as many names as the number of groups who reported its identification,52 there is some consensus for the use of the original designation for the human form, "ORL1". Workers in the field are, however, divided in their preferred terminology for the endogenous peptide agonist for ORL1 with both "nociceptin"53 or "orphanin FQ"54 being used with roughly equal frequency. Although the ORL1 receptor was accepted as a member of the "family" of opioid receptors on the basis of its structural homology towards the classical types, there is no corresponding pharmacological homology. Even non-selective ligands that exhibit uniformly high affinity towards -, - and -receptors, have very low affinity for the ORL1 receptor, and for this

reason as much as for the initial absence of an endogenous ligand, the receptor was called an "orphan opioid receptor". Close comparison of the deduced amino-acid sequences of the four receptors highlights structural differences that may explain the pharmacological anomaly. Thus there are sites near the top of each of the trans-membrane regions, that are conserved in the -, - and -receptors, but are altered in ORL1. Work with site-directed mutants of ORL1 (rat) has shown that it is possible to confer appreciable affinity on the nonselective benzomorphan bremazocine by changing Ala213 in TM5 to the conserved Lys of , and , or by changing the Val-Gln-Val276-278 sequence of TM6 to the conserved IleHis-Ile motif.55 A splice variant of the ORL1 receptor from rat has been reported ("XOR")56 with a long form (XOR1L) containing an additional 28 amino acids in the third extracellular loop. In the homologous receptor from mouse (also sometimes referred to as "KOR-3") five splice variants have been reported to date.57 ORL1-Receptor subtypes Selective high affinity ligands with which to attempt pharmacological definitions of the ORL1 receptor are few in number (Table 2). Besides the natural heptadecapeptide agonist nociceptin/orphanin FQ and some closely related peptides, the only other ligands offering high affinity and selectivity belong to a class of peptides obtained by a positional scanning approach to combinatorial libraries of hexapeptides.58 Being basic peptides highly susceptible to degradation, all of those agents are chancy tools in the hands of the unwary. So the paucity of safe and sure pharmacological tools may partly explain some of the confusion in the literature regarding the effect of nociceptin in tests of response latency to noxious stimulation; antinociception, pro-nociception/hyperalgesia, allodynia, or no overt effect, have all been reported. Table 2. Selective opioid ligands

Receptor type

-Receptor

-Receptor

-Receptor

ORL1

Selective agonists

endomorphin-1 endomorphin-2 DAMGO

[D-Ala2]-deltorphin I [D-Ala2]-deltorphin II DPDPE SNC 80

enadoline U-50488 U-69593

nociceptin / OFQ Ac-RYYRWK-NH2*

Selective antagonists

CTAP

naltrindole TIPPICI 174864

nor-binaltorphimine

None as yet**

Radioligands

[3H]-DAMGO

[3H]-naltrindole [3H]-pCI-DPDPE [3H]-SNC 121

[3H]-enadoline [3H]-U69593

[3H]-nociceptin

*Related combinatorial library hits are also selective agonists.58 **Ac-RYYRIK-NH2 has been proposed to be an ORL1 antagonist61 whereas the putative antagonist [Phe1 (CH2NH)Gly2]nociceptin(1-13)NH259 appears to be a partial agonist. Although the results of some studies have been interpreted as pointing to the existence of subtypes of ORL1, this conclusion is so far premature in most cases. The most reliable pharmacological definition of receptors is based on differences in antagonist affinity, and in this context the absence of useful antagonists for ORL1 is particularly galling to pharmacologists. Although the synthetic analogue of the N-terminal tridecapeptide of nociceptin, [Phe1 (CH2-NH)Gly2]nociceptin(1-13)NH2 was first reported to be a selective antagonist,59 increased use of this peptide points to it having agonist actions. There are no grounds for saying that this peptide is an antagonist at ORL1 receptors in the periphery, but an agonist in the brain (not least because agonist actions in the periphery, and antagonist actions in the brain have been reported) and that these differences in efficacy point to differences in the receptors. Although differences in the affinity for [Phe1 (CH2-NH)Gly2]nociceptin(1-13)NH2 may be found between central and peripheral sites,60 and there may indeed be different "subtypes" of ORL1 in the brain and periphery, the safest conclusion for the moment is just that [Phe1 (CH2-NH)Gly2]nociceptin(1-13)NH2 is a partial agonist, and that the observed differences in efficacy are consistent with differences in receptor reserve. Very recently a peptide related to the combinatorial hexapeptide library hit acetyl-Arg-Tyr-Tyr-Arg-Trp-Lys-NH2 (Ac-RYYRWK-NH2; Table 2), but with isoleucine substituting for tryptophan, was reported to block the effects of nociceptin/orphanin FQ in rat cortex (stimulation of GTP 35S binding) or heart (positive chronotropic effect in isolated myocytes). Although this peptide, like all of its structural homologues, was originally reported to be a potent agonist, but with somewhat less than full efficacy,58 it will be important to see if the antagonist activity of Ac-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2 (Ac-RYYRIK-NH2 ) at the ORL1 receptor61 is confirmed. Less Well-Characterised Opioid Receptors In addition to the -, -, - and ORL1-receptors, several other types of opioid receptor have been postulated. Since the contractions of the isolated vas deferens of the rat are much more sensitive to inhibition by -endorphin than by other opioid peptides, it was suggested that this tissue contains a novel type of opioid receptor, the -receptor, that is specific for -endorphin.62 The rabbit ileum has been proposed to possess -receptors, for which the enkephalins have high affinity but which are distinct from -receptors.63 A very labile binding site with high affinity for 4,5 epoxymorphinans has been found in freshly-prepared rat membrane fragments64 and there is evidence that opioids inhibit growth in S20Y murine blastoma cells by an action at yet another receptor type called the -receptor.65 The -, -, -and -receptors are poorly characterised and wider acceptance of their existence awaits further experimental evidence, in particular isolation of their cDNAs. Although originally classified as such, the -receptor appears not to be an opioid receptor but rather the target for another class of abused drugs, phencyclidine (PCP) and its analogues.66 Phencyclidine is an effective blocker of the ion channel associated with the N-methyl-D-aspartate (NMDA) receptor where it binds to the same site as MK 801.67 Endogenous Ligands In mammals the endogenous opioid peptides are mainly derived from four precursors: pro-opiomelanocortin, pro-enkephalin, pro-dynorphin and pro-nociceptin/orphanin FQ.68, 69, 70, 53 Nociceptin/orphanin FQ is processed from pro-nociceptin/orphanin FQ and is the endogenous ligand for the ORL1-receptor; it has little affinity for the -, - and -receptors.53, 54 The amino acid sequence of nociceptin/orphanin FQ has homology with other opioid peptides especially the prodynorphin fragment dynorphin A (Table 3), suggesting a close evolutionary relationship between the precursors. Nociceptin/orphanin FQ, however, has a C-terminal phenylalanine (F) whereas peptides derived from the other precursors all have the pentapeptide sequence TyrGlyGlyPheMet/Leu (YGGFM/L) at their N-termini. These peptides vary in their affinity for , - and -receptors, and have negligible affinity for ORL1receptors, but none binds exclusively to one opioid receptor type.71, 53 -endorphin is equiactive at -and -receptors with much lower affinity for -receptors; the post-translational product, N-acetyl- -endorphin, has very low affinity for any of the opioid receptors.72, 73 [Met]- and [Leu]enkephalin have high affinities for -receptors, ten-fold lower affinities for -receptors and negligible affinity for -receptors.71 Other products of processing of pro-enkephalin, which are N-terminal extensions of [Met]enkephalin, have a decreased preference for the -receptor with some products, e.g. metorphamide displaying highest affinity for the -receptor.71 The opioid fragments of pro-dynorphin, particularly dynorphin A and dynorphin B, have high affinity for -receptors but also have significant affinity for - and -receptors.71 Endomorphin-1 and endomorphin-2 are putative products of an as yet unidentified precursor, that have been proposed to be the endogenous ligands for the -receptor where they are highly selective.74 The endomorphins are amidated tetrapeptides and are structurally unrelated to the other endogenous opioid peptides (Table 3). Although the study of the cellular localisation of these peptides is at an early stage, endomorphin-2 is found in discrete regions of rat brain, some of which are known to contain high concentrations of -receptors.75 Endomorphin2 is also present in primary sensory neurones and the dorsal horn of the spinal cord where it could function to modulate nociceptive input.76 In comparison to the mainly non-selective mammalian opioid peptides (the exceptions being the endomorphins), amphibian skin contains two families of D-amino acid-containing peptides that are selective for - or -receptors. Dermorphin is a -selective heptapeptide Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2 without significant affinity at - and -receptors.77 In

contrast, the deltorphins - deltorphin (dermenkephalin; Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2), [D-Ala2]-deltorphin I and [D-Ala2]-deltorphin II (Tyr-D-Ala-Phe-Xaa-Val-Val-Gly-NH2, where Xaa is Asp or Glu respectively) - are highly selective for -opioid receptors.78 Table 3. Mammalian endogenous opioid ligands

Precursor

Endogenous peptide

Amino acid sequence

Pro-opiomelanocortin

-Endorphin

YGGFMTSEKSQTPLVTLFKNAIIKNAYKKGE

Pro-enkephalin

[Met]enkephalin [Leu]enkephalin

Metorphamide

YGGFM YGGFL YGGFMRF YGGFMRGL YGGFMRRV-NH2

Pro-dynorphin

Dynorphin A Dynorphin A(1-8) Dynorphin B -neoendorphin -neoendorphin

YGGFLRRIRPKLKWDNQ YGGFLRRI YGGFLRRQFKVVT YGGFLRKYPK YGGFLRKYP

Pro-nociceptin / OFQ

Nociceptin

FGGFTGARKSARKLANQ

Pro-endomorphin*

Endomorphin-1 Endomorphin-2

YPWF-NH2 YPFF-NH2

*Presumed to exist, awaiting discovery Effector Mechanisms The opioid receptor family, in common with the somatostatin receptor family, is somewhat unusual in that all of the cloned opioid receptor types belong to the Gi/Go-coupled superfamily of receptors. Opioid receptors do not couple directly with Gs or Gq and none of the cloned receptors forms a ligand-gated ion channel. It was originally thought that - and -receptors coupled through Gi/Go proteins to activate an inwardly rectifying potassium conductance and to inhibit voltage-operated calcium conductances whereas -receptors only inhibit voltage-operated calcium conductances. However it is now known that the -receptor is, in some cell types, also coupled to activation of an inwardly rectifying potassium conductance.79 It seems highly likely, therefore, that all of the opioid receptors will share common effector mechanisms. Indeed, many papers have recently appeared demonstrating that the ORL1-receptor couples to the same effector systems as the other more extensively studied opioid receptors. It should be borne in mind that, given the heterogeneity of i, o, and subunits which may combine to form a trimeric G protein, there may well be some subtle differences in the downstream effector mechanisms to which opioid receptors are coupled if one type of opioid receptor is unable to interact with a certain form of Gi/Go heterotrimer. However, different responses evoked in different cell types in response to activation of different opioid receptors or even in response to activation of the same receptor are likely to reflect changes in the expression of G proteins and effector systems between cell types rather than any inherent differences in the properties of the receptors themselves. Opioid receptor activation produces a wide array of cellular responses (Table 4). Although the pertussis toxin sensitivity has not been assessed in all instances it is highly likely that in each the first step is activation of Gi or Go . The functional significance of many of these opioid receptor-mediated effects is still unclear, but two recent observations on changes in neurotransmitter release following acute and chronic exposure to opioids are worthy of special mention because they provide potential solutions to long-asked questions. Table 4. Opioid receptor-evoked cellular responses

Direct G-protein bg or a subunit-mediated effects activation of an inwardly rectifying potassium channel inhibition of voltage operated calcium channels (N, P, Q and R type) inhibition of adenylyl cyclase

Responses of unknown intermediate mechanism activation of PLA2 activation of PLC b (possibly direct G protein bg subunit activation) activation of MAPKinase activation of large conductance calcium-activated potassium channels activation of L type voltage operated calcium channels inhibition of T type voltage operated calcium channels direct inhibition of transmitter exocytosis

Responses which are a consequence of opioid-evoked changes in other effector pathways activation of voltage-sensitive potassium channels (activation of PLA2) inhibition of M channels (activation of PLA2) inhibition of the hyperpolarisation-activated cation channel (Ih) (reduction in cAMP levels following inhibition of adenylyl cyclase) elevation of intracellular free calcium levels (activation of PLCb, activation of L type voltage operated calcium conductance) potentiation of NMDA currents (activation of protein kinase C) inhibition of transmitter release (inhibition of adenylyl cyclase, activation of potassium channels and inhibition of voltage operated calcium channels) decreases in neuronal excitability (activation of potassium channels) increases in neuronal firing rate (inhibition of inhibitory transmitter release - disinhibition) changes in gene expression (long-term changes in adenylyl cyclase activity, elevation of intracellular calcium levels, activation of cAMP response element binding protein (CREB))

The periaqueductal grey region (PAG) is a major anatomical locus for opioid activation of descending inhibitory pathways to the spinal cord and is thus an important site for -receptorinduced analgesia. Opioids do not excite descending fibres directly but disinhibit them by inhibiting spontaneous GABA release from local GABAergic interneurones.80 This inhibition of transmitter release results from activation of a dendrotoxin-sensitive, voltage-sensitive potassium conductance. The mechanism by which the voltage-sensitive potassium conductance is activated appears to be through activation of phospholipase A2 (PLA2) with subsequent metabolism of arachidonic acid along the 12 -lipoxygenase pathway because the inhibition of GABA release can be inhibited by quinacrine and 4-bromo-phenacylbromide, inhibitors of PLA2, and by baicalein, an inhibitor of 12 -lipoxygenase. This proposed mechanism of opioid

action also explains the synergy between opioids and non-steroidal analgesic drugs (NSAIDs) in producing analgesia because in the presence of a NSAID, with the cyclo-oxygenase enzymes inhibited, more of the arachidonic acid produced by opioid activation of PLA2 can be diverted down the 12 -lipoxygenase pathway. The cellular locus of opiate withdrawal has long been the Holy Grail of opioid biologists. Over 20 years ago, it was shown that following chronic exposure of NG108-15 neuroblastoma x glioma hybrid cells to opiates, withdrawal resulted in a rebound increase in adenylyl cyclase;81 the functional significance of this observation for opiate withdrawal in brain neurones has remained obscure. Recently, Williams and colleagues82 have observed an increase in the release of the inhibitory neurotransmitter GABA, in the nucleus accumbens during opiate withdrawal. This effect could be mimicked by the adenylyl cyclase activator, forskolin, and inhibited by protein kinase A inhibitors. Therefore, as proposed over 25 years ago by the late Harry Collier, rebound adenylyl cyclase activity in withdrawal may be the fundamental step in eliciting the withdrawal behaviour.83 Development and Clinical Applications of Opioid Ligands Among the receptors for the many neuropeptides that exist in the nervous system, the opioid receptors are unique in that there existed before the discovery of the natural agonists, an abundance of non-peptide ligands with which the pharmacology of the receptors was already defined. In current terms relating to the drug-discovery process, we would consider the 4,5-epoxy-methylmorphinan opioid alkaloids morphine, codeine and thebaine as "natural-product hits" on which were based chemical programmes to design analogues with improved pharmacology (Figure 1). The effects of morphine to reduce sensitivity to pain or to inhibit intestinal motility and secretion, have continued to be exploited clinically, however the presence of other undesirable effects (e.g. depression of respiration, tolerance/dependence, effects on mood) provided the stimulus to seek analogues that were selective in producing analgesia. Thus a semi-synthetic di-acetylated analogue of morphine was introduced in the 19th century in the mistaken belief that this compound (heroin) had those desired properties. More radical changes to the morphinan nucleus were subsequently explored in various synthetic programmes, in many early cases resulting in the development of low efficacy partial agonists. With the benefit of hindsight, it is possible to conceive an evolution of those opioid analogues, with a progressive simplification of chemical structure from the epoxymorphinans (nalorphine, nalbuphine) through the morphinans such as levorphanol, and the benzomorphans such as pentazocine, to the phenyl-piperidines including pethidine and the 4-anilinopiperidines as exemplified by fentanyl (Figure 1). The ultimate simplification of the morphine structure was in the methadone class, with methadone itself and d-propoxyphene (Darvon). Although thebaine is virtually inactive, the compound itself was an important chemical precursor in the synthesis of 14-hydroxy derivatives of morphine, most particularly the antagonists naloxone and naltrexone. Also derived from thebaine were the oripavine derivatives, and here the trend of chemical "simplification" was reversed with the introduction of an additional six-membered ring that appeared to enhance biological potency. For example, etorphine is about one thousand times more potent than morphine as an analgesic, but its use is limited to veterinary medicine as a sedative for large animals. For the most part, such compounds have highest affinity for the -receptor, and to a greater or lesser extent produce the full panoply of effects, good and bad, obtained with morphine. Depending on the level of affinity and efficacy, such compounds have been used acutely or chronically, to provide analgesia in cases of mild, through moderate to severe pain, alone or with adjuncts. The piperidines related to fentanyl include the most potent non-peptide -agonists known, and are generally used peri-operatively, often for the induction and maintenance of anaesthesia. The use of many of the benzomorphans (as had been found with the first of the "duallists" nalorphine) has been associated with dysphoric and psychotomimetic effects in man, a property originally thought to be attributable to affinity at the non-opioid -site. The attractiveness of the prospect for development of selective -agonists as analgesics was based on the preclinical pharmacology in animals of the 6,7-benzomorphans such as ketazocine and its derivatives (Figure 1). Although those agents are not selective in terms of affinity, their utility as pharmacological tools is based on their functional selectivity for the -receptor, where their efficacy is high. Such agents produced a powerful antinociceptive effect, but did not substitute for morphine in dependent animals. A full biochemical and pharmacological characterisation of the -receptor was not possible until the discovery of highly selective agonists in the aryl-acetamides that appear unrelated structurally to any of the morphine derivatives. The first compound of this class was U-50,488, but its importance was also as a chemical lead for the attempted design of related compounds of greater selectivity and potency. At least two such compounds have entered clinical trials as centrally acting analgesics, Spiradoline (U-62,066) and enadoline (CI-977). Although CNS-mediated, mechanism-related side effects of sedation and dysphoria may limit the potential for development of such compounds, the prospects for analogues with limited brain penetration to produce a peripherally mediated analgesic effect in inflammatory conditions is under exploration, with at least one compound (asimadoline, EMD-61753) in clinical trials for osteoarthritis. The observation of neuroprotective properties of -agonists in pre-clinical models of cerebral ischaemia has lead to consideration of the possible clinical development of selective -agonists for stroke or traumatic head injury. In this context the sedative properties of -agonists, and even perhaps their characteristic diuretic action, may be advantageous. The discovery of the enkephalins and of the -receptor, led to the idea that the peptides themselves might be taken as "leads" for the synthesis of a new class of opioid agonist that lacked the addictive properties of morphine. Although such synthetic activities produced many useful experimental tools, no direct benefit in the form of a drug appeared, in spite of the attempted development of several enkephalin analogues. It did become clear from the work of a number of laboratories that activation of the -receptor is associated with antinociception in animals, and the development of a selective non-peptide agonist is under consideration by a number of commercial drug houses. In some cases the synthetic strategy is based directly on structural considerations of the first non-peptide with significant selectivity, the 6,7-indole analogue of naltrexone, naltrindole.84 Applying the "message-address" concept that produced the antagonist naltrindole to a novel series of octahydroisoquinoline derivatives has been successful in producing non-peptide -selective agonists TAN-6785 or SB 213698.86 Similar considerations do not serve to explain the existence of another series of novel piperazine derivatives -agonists, BW 373U8687 or SNC 80.88 Preclinical studies suggest that -agonists may have a superior profile as analgesics, but this will only be established when such an agent is successfully introduced into clinical investigation; other possible applications of selective ligands for this receptor may emerge from clinical experience. The prospects for clinical utilities of agonists or antagonists for the ORL1 receptor can only be the subject of speculation. Elucidation of the role of the nociceptin/ORL-receptor system in pain control (and in other areas, for the peptide and its receptor have a dense and wide investment in the nervous system) must await the initial results of the drug-discovery process. Only with the availability of non-peptide selective agonists, and perhaps more particularly antagonists, will it be possible to undertake the definitive pre-clinical studies that will serve for the identification of possible clinical targets. There is some agreement that activation of the ORL1 receptor in the brain leads to a motor impairment, so it may be that the development of ORL1 agonists would be difficult.

THE BIRTH OF A NEW GENERATION

A significant minority of the population only feel truly well on opioids. In effect, they self-medicate, taking responsibility for their own mental health in defiance of medical orthodoxy. It would indeed be extraordinary if - alone among the neurotransmitter systems of the brain - the endogenous opioid families were immune from dysfunction. Enkephalins are critical to "basal hedonic tone" i.e. whether we naturally feel happy or sad. Yet the therapeutic implications of a recognition that dysfunctional endogenous opioid systems underlie a spectrum of anxiety-disorders and depression are too radical - at present - for the medical establishment to contemplate. In consequence, the use of opioid-based pharmacotherapies for "psychological" pain is officially taboo. The unique efficacy of opioids in banishing mental distress is neglected. Their unrivalled efficacy in treating "physical" nociceptive pain is grudgingly accepted. Later this century and beyond, however, the development of highly selective, site-specific designer drugs and innovative gene-therapies may enhance our native opioid function and revolutionise mental health. Therapeutic intervention targeted on the opioid pathways will potentially enrich the quality of life of even the nominally "well", not least because - by the more enlightened health standards of posterity - we may all be reckoned mentally ill. Today, by contrast, immense energy is devoted by the authorities into persecuting "illicit" narcotic users. Many drug-"abusers" feel well thanks only to the "non-therapeutic" use of opioids. They are stigmatised, pilloried and criminalised in a futile War Against Drugs. In the "Inquisition against pleasure", victims of medically-sanctioned human-rights abuses - e.g. the hundreds of thousands of drug "offenders" incarcerated in the Amerikan gulag - are officially supposed to believe their malaise-ridden drug-nave states were "normal", "natural" and mentally healthy. In the course of our ill-conceived Drug War, vast resources are dissipated by the state-apparatus in an effort to choke off narcotic production and supply. When these efforts are temporarily successful, drug-deprivation makes the habitual opioid user feel ill; [s]he "cold-turkeys" with characteristic irritability, anhedonia, depression, sickness behaviour and sometimes raw physical pain. The ill-effects felt from involuntary deprivation of opioids are taken to demonstrate the likely ill-effects of legalised access, a paradox that might be thought laboured were its human costs not so tragic.

When caught up in the criminal justice system, users may be pressured into taking opioid antagonists like naltrexone (Trexan). Such drugs can induce dysphoria and suicidal despair. At best, their use subtly diminishes the victim's capacity ever to feel well. Meanwhile Chinese military surgeons have developed (2003) a new treatment weapon against narcotic users: surgical destruction of the pleasure centres. Western doctors are said to be following these procedures with interest, but are more likely to achieve their functional equivalent by non-surgical means. Even where it is acknowledged that many opioid users have a pre-existing anxiety or depressive disorder in urgent need of relief, those so afflicted are fobbed off with often thirdrate psychotropics instead. For a start, the monoamine hypothesis of depression - and the new classes of drug it has spawned (SSRIs, NARIs, SNRIs, NaSSAs, RIMAs etc to complement the dirty old tricyclics and irreversible unselective MAOIs) - is radically incomplete. A minority of people, admittedly, find such drugs effective. Often taking a licensed antidepressant is better than nothing at all - perhaps in part because of their positive effects on endogenous opioid peptide release. Yet even in the context of controlled clinical trials with relatively high dosageregimens and artificially good rates of patient-compliance, it's rare for response-rates to reach more than 70%. Rates of full remission of depressive symptoms are far lower, perhaps 25-30%. Out "in the field", the picture is worse still. Adverse side-effects are common. Response may take weeks. Withdrawal reactions can be unpleasant. A recognition of the crucial role of dopamine, and selective dopamine reuptake blockers, in sub-types of depressive mood-disorders might push response and remission rates higher. The mesolimbic dopamine system is critical to vitality, motivation, libido and a capacity to anticipate reward. Dopaminergics can also act as analgesics. They can also reverse the apathetic sedation induced by some antidepressants and opioid agonists. Yet the FDA stymies the licensing of effective dopamine reuptake-blocking mood-brighteners at home; and applies pressure to deny access to them abroad. This is because of worries about their (sometimes) faster efficacy - and mild psychostimulant effect - raise the spectre of "abuse-potential"; and proscription, persecution and indiction are favoured over consumer education. For Big Brother knows best. More controversially, adding customised opioids, enkephalinase-inhibitors and kappa-antagonists to our therapeutic armamentarium may prove critical to boosting response- and remissionrates towards 100% in the decades ahead. Crudely, whereas dopamine mediates "wanting", mu opioid agonists mediate "liking". Both systems can be fruitfully enhanced. Depressive and dysthymic people often suffer from a dysfunctional opioid system and anhedonia - an incapacity to experience pleasure. Sometimes orthodox "antidepressants" may even make them feel worse. Yet controlled clinical trials of designer narcotics for refractory and/or melancholic depression, let alone their use by "normal" people with "ordinary" mood-disorders, are not imminent. So what is to be done? Even in the context of today's crude agents, would some of us be better off as legalised junkies? No, usually not, at least in contemporary society. Self-medicating users with enough resources to maintain a regular supply may indeed find they can function as well as, or better than, their drug-nave state. Popular mythology aside, users don't seek to escalate dosage indefinitely: both humans and laboratory monkeys with unlimited access tend slowly to increase injection-frequency until eventually they self-administer a stable and subjectively optimal amount of the drug. Most users take heroin, not primarily to stave off the abstinence syndrome, but because they find life on heroin better than their pain-ridden life without it. Yet the existence of a typical heroin addict in prohibitionist society can still be exceedingly unpleasant at times. Contemporary opioid drugs, natural and synthetic alike, are flawed. The problem is not the euphoric well-being they can induce - an ill-named "adverse side-effect" but their tendency to induce a financially ruinous tolerance; perhaps insidiously to dull the intellect; trigger nausea; slow digestive processes; and sometimes induce a parodoxical hyperalgesia. Most seriously, when taken in acute excess, today's opioids can cause respiratory depression. This is a consequence of their stimulation of the mu-2 receptors in the medullary respiratory centres of the brain. These problems are exacerbated a thousandfold, however, by the illegal status of narcotics in contemporary society. Dosage, purity and regularity of supply cannot be guaranteed; prices are inflated; quality-control is negligible; good hygiene is difficult. Pharmacological education is non-existent, whereas it ought to be part of the core curriculum. Opioid users are frequently forced into crime to pay for pharmacotherapies that should be cheaply and safely available; and damned for seeking a state of mind which will one day be their birthright: invincible happiness. To promote emotional superhealth both durably and effectively, designer-opioids must be synthesised that are also subjectively nicer, richer and cleaner than today's product-line. For one of our three major endogenous opioid families is implicated in profoundly dysphoric psychological effects: a cruel negative-feedback system exists between the mu and kappa systems that "corrects" any "excess" tendency to well-being. Thus dynorphin activity at the kappa receptors tonically inhibits the release of dopamine from the mesolimbic terminals. By contrast, the mu-opioid receptor selective endomorphins, especially endomorphin 1, are potent antidepressants: they enhance mu opioid receptor-mediated dopamine release in the nucleus accumbens. If our well-being is to be sustainably enhanced, the balance between the two opposing opioid systems must be shifted. The role of the mu receptors appears to be crucial in another respect. Today, people vary hugely in their sensitivity to pain. This sensitivity is genetically regulated. Pain perception and, conversely, emotional well-being - is closely linked to the number of neuronal mu receptors. This number is controlled by a single gene, the mu opioid receptor gene. Pain-sensitivity is diminished when the receptors are present in relative abundance. When the receptors are reduced in number or missing altogether, relatively minor noxious stimuli may be perceived as painful. In the short-to-medium term, then, we need better-targeted opioids, safer and more site-specific than the present crop. Smarter opioids can potentially be combined with cholecystokinin antagonists (e.g. proglumide); nitric oxide (NO) synthase inhibitors; peroxynitrite-blockers; and also, perhaps, better-designed NMDA receptor antagonists - co-analgesics with potential antidepressant efficacy that inhibit the onset of tolerance. Although mu receptor agonists are the best analgesics and euphoriants, selective delta receptor agonists and enkephalinase inhibitors may prove clinically valuable antidepressants. The development of centrally active and more selective kappa antagonists - which block the endogenous excess production and reuptake of dynorphin underlying many depressive and anxiety disorders - is also a priority. Orally active JDTic, a potent, exceedingly long-acting selective kappa antagonist, is currently undergoing preclinical testing. In the meantime, Buprenorphine (Buprenex, Temgesic, Subutex), for instance, is certainly no panacea; but it would probably benefit a far wider section of the population than its current restriction to use in "detoxifying" heroin-addicts. Its role as a mixed mu agonist reduces buprenorphine's addictive potential as a euphoriant while increasing its safety in overdose. Buprenorphine's kappa receptor antagonism may contribute to its superior efficacy as an antidepressant. Even the humble codeine analogue tramadol (Ultram), a selective partial mu agonist analgesic with noradrenaline and serotonin reuptake inhibiting properties, can serve as a useful mood-brightening stopgap. But contemporary medico-legal opiophobia ensures such usage remains strictly off-label.

THE QUEST FOR A DRUG-FREE SOCIETY

In the longer-run, however, irrespective of how clever our pharmacological interventions may one day be, we'd arguably be better off taking no drugs at all. For if there were nothing fundamentally wrong with our default-state of consciousness, then we wouldn't now try so hard to change it. Thus our sophisticated descendants may opt instead to rewrite the vertebrate genome and allow themselves life-long genetically pre-programmed bliss. They may "naturally" be animated by gradients of well-being beyond the bounds of normal human experience as an everyday part of mental health. Wouldn't lifelong happiness make us stagnate? No. In our genetically-enhanced post-human successors, the functional analogues of aversive experience can potentially perform an analogous functional role to mental and physical pain in our Darwinian past, but without its textures of phenomenal nastiness. Our descendants' enriched dopamine function will enhance their drive, energy and will-power, not just hedonic capacity. Thus outright abolitionism is not technically infeasible - just ideologically problematic. Tomorrow's bioscientists face another challenge. Taken in excess, opioid-based drugs of today tend to dull consciousness, inducing a dreamy warm contentment. The name "narcotic" derives from the Greek word for stupor. Indeed smacked-out bliss is typically used as the archetype of what any drug-or-gene-underwritten chemical utopia would be like. Most notably, soma in Aldous Huxley's Brave New World is depicted as a cross between a non-addictive opioid and a hangover-less tranquilliser. Thus Huxley's utopians enjoy only an empty imbecilic happiness, not life-enriching peak experiences. Unlike dopaminergics, soma doesn't increase incentive-motivation, nor does it heighten the felt intensity of experience. You can use soma to drift off to sleep. Yet this negative stereotype of synthetic bliss is profoundly misleading. Addictive tranquillity is only one option among many. It reflects a poverty in our conception of the range of options for paradise-engineering that biotechnology puts on offer. In reality, the quality of our consciousness can be intensified, sharpened and radically diversified by creative psychopharmacology. Intellect and empathy, and not just mood, can be prodigiously enhanced when the ideology of Better Living Through Chemistry finally enters mainstream culture.

Better still, when a wholesale genomic rewrite - and not just piecemeal genetic tinkering - unfolds in the millennium ahead, then any chemical manipulation of our descendants' emotionally- and intellectually-enriched superminds may be redundant. At most, lifestyle drugs will offer an optional fine-tuning for the parameters of their well-being - set against a backdrop of native-born bliss. In the wake of any such Post-Darwinian Transition, a wide variety of social interactions will "naturally" trigger a far richer endogenous opioid release than occurs today; and do so from a much higher baseline of emotional well-being. However, our present restrictive definitions of mental illness, and the technical challenges posed by large-scale genetic-rewrites, make germline gene-therapy seem a pipe-dream for now. In the present era, lifetime pure dysthymia afflicts far too many people; and periods of "mild" anxiety, malaise and depressive episodes blight the lives of hundreds of millions more. Meanwhile countless victims of chronic pain-disorders are condemned to a life of needless suffering by institutionalized opiophobia. Victims of the most unspeakable, spiritcrushing neuropathic or central pain are liable to be fobbed off with pain-management courses - "helping you to manage your pain" - rather than given the potent pain-relief they deserve. For with a bit of creative psychopharmacology, both the tolerance and adverse side-effects of chronic opioid use are manageable even with today's crude agents. Thanks to tomorrow's biotechnology, the real obstacles to curing the nasty side of life are set to become doctrinal, not technical. Suffering of any kind is due to become optional. It remains to be seen how quickly the ideological baggage of the past can be overcome.

IDK
Opium is an extract of the exudate derived from seedpods of the opium poppy, Papaver somniferum. The poppy plant was cultivated in the ancient civilisations of Persia, Egypt and Mesopotamia. Archaeological evidence and fossilised poppy seeds suggest that Neanderthals may have used the opium poppy over thirty thousand years ago. Less controversially, the first known written reference to the poppy appears in a Sumerian text dated around 4,000 BC. The flower was known as hul gil, plant of joy. The Egyptian Eber papyrus of some 3500 years ago advises use of condensed juice of the unripe seed pod "to prevent the excessive crying of children". Papaver somniferum is the only species of Papaver used to produce opium. It is believed to have evolved through centuries of breeding and cultivation from a Mediterranean-growing wild strain, Papaver setigerum.

Homer conveys its effects in The Odyssey. In one episode, Telemachus is depressed after failing to find his father Odysseus. But then Helen...

"...had a happy thought. Into the bowl in which their wine was mixed, she slipped a drug that had the power of robbing grief and anger of their sting and banishing all painful memories. No one who swallowed this dissolved in their wine could shed a single tear that day, even for the death of his mother or father, or if they put his brother or his own son to the sword and he were there to see it done..." In some parts of the contemporary Middle East, chilled glasses of poppy tea are served to mourners at funerals to ease their grief.

Papaver somniferum has long been popular in Europe. Fossil remains of poppy-seed cake and poppy-pods have been found in Neolithic Swiss lake-dwellings dating from over 4,000 years ago. Poppy images appear in Egyptian pictography and Roman sculpture. Representations of the Greek and Roman gods of sleep, Hypnos and Somnos, show them wearing or carrying poppies. Throughout Egyptian civilisation, priest-physicians promoted the household use of opium preparations. Such remedies were called "thebacium" after the highly potent poppies grown near the capital city of Thebes. Egyptian pharaohs were entombed with opium artefacts by their side. Opium could also readily be bought on the street-markets of Rome. Emperor Marcus Aurelius (161-180), author of the philosophical classic Meditations, regularly enjoyed opium; it may have contributed to his celebrated stoicism. By the eighth century AD, opium use had spread to Arabia, India and China. The Arabs both used opium and organised its trade. For the Prophet had prohibited the use of alcohol, not hashish or opiates.

Classical Greek physicians either ground the whole plant or used opium extract. Galen lists its medical indications, noting how opium...

"...resists poison and venomous bites, cures chronic headache, vertigo, deafness, epilepsy, apoplexy, dimness of sight, loss of voice, asthma, coughs of all kinds, spitting of blood, tightness of breath, colic, the lilac poison, jaundice, hardness of the spleen stone, urinary complaints, fever, dropsies, leprosies, the trouble to which women are subject, melancholy and all pestilences." Later authorities were scarcely less enthusiastic. Physicians commonly believed that the poppy plant was of divine origin; opium was variously called the Sacred Anchor Of Life, Milk Of Paradise, the Hand Of God, and Destroyer Of Grief. Medical pioneer Thomas Sydenham (1624-1689), sometimes known as 'the English Hippocrates' and 'the Shakespeare of medicine', writes.... "Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium." This may be overstating God's benevolence; but by relieving emotional as well as physical pain, opiates have been understandably popular. Robert Burton (1577-1640), scholar, priest and author of Anatomy of Melancholy, commended laudanum - essentially opium dissolved in wine - for those who were insomniacs... "...by reason of their continual cares, fears, sorrows, dry brains [which] is a symptom that much crucifies melancholy men..." Indeed opium was probably the world's first authentic antidepressant. Unlike other pain-relieving agents such as ethyl alcohol, ether or the barbiturates, opium doesn't impair sensory perception, the intellect or motor co-ordination. Pain ceases to be threatening, intrusive and distressing; but it can still be sensed and avoided. In low doses, opium may sometimes be pleasantly stimulating rather than soporific. In the East, opium was typically treated as a social drug; and opium-smoking was a tool for conviviality. Nowadays a life of habitual opioid use evokes images of stupor and mindless oblivion, yet ironically Coleridge coined the word intensify to describe opium's effects on consciousness. A significant advance in opium-processing occurred in the sixteenth century. In freebase form, the alkaloids found in opium are significantly less soluble in water than in alcohol. Philippus Aureolus Theophrastus Bombastus von Hohenheim (1490-1541), better known as Paracelsus, claimed: "I possess a secret remedy which I call laudanum and which is superior to all other heroic remedies". He concocted laudanum [literally: "something to be praised"] by extracting opium into brandy, thus producing, in effect, tincture of morphine. His original witches' brew contained extra ingredients such as crushed pearls, henbane and frog-spawn. It was steeped in alchemical mumbo-jumbo: Paracelsus called opium itself "the stone of immortality". Thomas Sydenham, however, went on to standardise laudanum in the now classic formulation: 2 ounces of opium; 1 ounce of saffron; a drachm of cinnamon and cloves all dissolved in a pint of Canary wine. &nbspLaudanum can be habit-forming. Yet the sometimes spectacular ill-effects noted by early modern writers when coming off laudanum probably owed more to its ethyl alcohol content than its opium. As their opioid tolerance increased, so did users' consumption of tinctures: De Quincey's florid withdrawal signs on abstaining... "I was stared at, hooted at, grinned at, chattered at, by monkeys, by paroquets, by cockatoos. I ran into pagodas, and was fixed, for centuries, at the summit, or in secret rooms: I was the idol; I was the priest; I was worshipped; I was sacrificed. I fled from the wrath of Brama through all the forests of Asia: Vishnu hated me; Seva laid wait for me. I came suddenly upon Isis and Osiris: I had done a deed, they said, which the ibis and the crocodile trembled at. I was buried for a thousand years, in stone coffins, with mummies and sphinxes, in narrow chambers at the heart of eternal pyramids. I was kissed, with cancerous kisses, by crocodiles; and laid, confounded with all unuttemble slimy things, amongst reeds and Nilotic mud..." ...suggest an alcoholic's delirium tremens rather than a junky's cold-turkey. By the nineteenth century, vials of laudanum and raw opium were freely available at any English pharmacy or grocery store. One nineteenth-century author declared: "[Laudanum] Drops, you are darling! If I love nothing else, I love you." Another user, the English gentleman quoted in Jim Hogshire's Opium for the Masses (1994), enthused that opium felt akin to a gentle and constant orgasm. British opium imports rose from a brisk 91,000lb in 1830 to an astonishing 280,000lb in 1860. Despite British control of Indian production, most domestic imports came from Turkey. This was because of the superior morphine content - 10-13% - of Turkish opium; opium's varying potency depends on its particular growing conditions. For obscure reasons,

opium was most popular among the rural peasantry of the Fens. The British Medical Association estimated that sparsely populated Cambridgeshire and its environs consumed around half of Britain's annual opium imports. This consumption was topped up by generous use of poppy-tea brewed from homegrown poppies. Youngsters were introduced to the pleasures of opiates at their mothers' breast. Harassed baby-minders - and overworked parents - found opium-based preparations were a dependable way to keep their kids happy and docile; this was an era before Ritalin. Sales of Godfrey's Cordial, a soothing syrup of opium tincture effective against colic, were prodigious. But Godfrey's Cordial had its competitors: Street's Infants' Quietness, Atkinson's Infants' Preservative, and Mrs Winslow's Soothing Syrup. Opium was viewed as a medicine, not a drug of abuse. Contemporary medical theory didn't allow that one could become addicted to a cure. However, the chemists and physicians most actively investigating the properties of opium were also its dedicated consumers; and this may conceivably have coloured their judgement. Writers of distinction certainly consumed opium in copious quantities. Samuel Taylor Coleridge (1772-1834) wrote Kubla Khan in a dream-like trance while under its spell; opium promotes vivid dreams and rich visual imagery as well as gentle euphoria... "In Xanadu did Kubla Khan A stately pleasure-dome decree Where Alph, the sacred river, ran Down to a sunless sea ... I would build that dome in air, That sunny dome, those caves of ice! And all who heard should see them there, And all should cry, Beware! Beware! His flashing eyes, his floating hair! Weave a circle round him thrice, And close your eyes with holy dread, For he on honey-dew hath fed, And drunk the milk of Paradise." Fellow English author Thomas de Quincey (1785-1859) writes of "the marvellous agency of opium, whether for pleasure or for pain". De Quincey seems to have treated opium as a mood-brightening smart-drug. The author of Confessions of an English Opium-Eater (1821) draws invidious comparisons with alcohol. He attributes a heightening of his mental powers to opium use... "Whereas wine disorders the mental faculties, opium introduces amongst them the most exquisite order, legislation and harmony. Wine robs a man of self-possession; opium greatly invigorates it....Wine constantly leads a man to the brink of absurdity and extravagance; and, beyond a certain point, it is sure to volatilize and disperse the intellectual energies; whereas opium seems to compose what has been agitated, and to concentrate what had been distracted. ...A man who is inebriated...is often...brutal; but the opium eater...feels that the diviner part of his nature is paramount; that is, the moral affections are in a state of cloudless serenity; and over all is the great light of majestic intellect...." De Quincey states that not he himself, but opium, should be regarded as the true hero of his essay. Opium was his "Divine Poppy-juice, as indispensable as breathing". By reputation, opium users have dull wits, idle lives and diminished sensibility. This was not de Quincey's verdict. He made a habit of going to the opera under its influence - and found his experience of music delightfully enhanced... "Now opium, by greatly increasing the activity of the mind, generally increases, of necessity, that particular mode of its activity by which we are able to construct out of the raw material of organic sound an elaborate intellectual pleasure...It is sufficient to say, that a chorus, etc of elaborate harmony displayed before me, as in a piece of arras work, the whole of my past life - not as if recalled by an act of memory, but as if present and incarnated in the music; no longer painful to dwell upon, but the detail of its incidents removed...and its passions exalted, spiritualized, and sublimed..." Opium induces gentle, subtle, dream-like hallucinations very different from the fierce and unpredictable weirdness of LSD. Charles Baudelaire (1821-1867) likens opium to a woman friend, "...an old and terrible friend, and, alas! like them all, full of caresses and deceptions." Across the Atlantic, in 1842, William Blair describes his experiences with opium in a New York magazine... "While I was sitting at tea, I felt a strange sensation, totally unlike any thing I had ever felt before; a gradual creeping thrill, which in a few minutes occupied every part of my body, lulling to sleep the before-mentioned racking pain, producing a pleasing glow from head to foot, and inducing a sensation of dreamy exhilaration (if the phrase be intelligible to others as it is to me) similar in nature but not in degree to the drowsiness caused by wine, though not inclining me to sleep; in fact far from it, that I longed to engage in some active exercise; to sing, dance, or leap...so vividly did I feel my vitality - for in this state of delicious exhilaration even mere excitement seemed absolute elysium - that I could not resist the tendency to break out in the strangest vagaries, until my companions thought me deranged...After I had been seated [at the play I was attending] a few minutes, the nature of the excitement changed, and a 'waking sleep' succeeded. The actors on the stage vanished; the stage itself lost its reality; and before my entranced sight magnificent halls stretched out in endless succession with galley above gallery, while the roof was blazing with gems, like stars whose rays alone illumined the whole building, which was tinged with strange, gigantic figures, like the wild possessors of lost globe...I will not attempt farther to describe the magnificent vision which a little pill of 'brown gum' had conjured up from the realm of ideal being. No words that I can command would do justice to its Titanian splendour and immensity..." Opium was also well known in Chinese antiquity. One 10th century poem celebrates how the opium poppy can be made into a drink "fit for Buddha". Ancient peoples either ate parts of the flower or converted them into liquids to drink. But by the 7th century, the Turkish and Islamic cultures of western Asia had discovered that the most powerful medicinal effects could be obtained by igniting and smoking the poppy's congealed juices; and the habit spread. The widespread use of opium in China dates to tobacco-smoking in pipes introduced by the Dutch from Java via the island of Formosa in the 17th century. Whereas Indians ordinarily ate opium, the Chinese smoked it. The Chinese mixed Indian opium with tobacco, two products traded by the Dutch. Pipe-smoking was adopted throughout the region. Predictably enough, this resulted in increased opium-smoking, both with and without tobacco. Old encrusted opium-pipes were still valuable because they contained a residue of charcoal and raw opium known as "dross". Dross could be recycled with tobacco plus various adulterants and sold to the poor. Styles of opium pipe reflected the relative wealth or poverty of their owners. Pipes ranged from bejewelled, elaborately ornamented works of art to simple constructions of clay or bamboo. By the late-1700s, the British East India Company controlled the prime Indian poppy-growing areas on the Ganges plain between Patna and Benares. The company dominated the Asian opium trade; but they did not create it. "Take your opium" was a standard greeting in some Indian cities even before the Europeans arrived. By 1800, however, the British East India Company had a virtual monopoly, controlling supply and setting prices. Dealers, merchants and users alike lovingly assessed the quality and potency of their merchandise with the ardour of a wine connoisseur. According to The Chinese Repository, discerning purchasers of the raw product looked for opium of... "...moderately firm texture, capable of receiving an impression from the finger; of a dark yellow color when held in the light, but nearly black in the mass, with a strong smell, and free from grittiness..." Opium was already heavily used in China as a recreational drug. The Imperial Chinese court had banned its use and importation, but large quantities were still being smuggled into the country. In 1839, the Qing Emperor, Tao Kwang, ordered his minister Lin Tse-hs to take action. Lin petitioned Queen Victoria for help; but he was ignored. In reaction, the Emperor instructed the confiscation of 20,000 barrels of opium and detained some foreign traders. The British retaliated by attacking the port-city of Canton. Thus began the First Opium War, launched by the biggest, richest and perhaps most aggressive drug cartel the world has ever known, the British Empire. The Chinese were defeated. They were forced to sign the Treaty of Nanjing in 1842. The British required that the opium trade be allowed to continue; that the Chinese pay a large settlement and open five new ports to foreign trade; and that China cede Hong Kong to Britain.

Peace didn't last. The Second Opium War began and ended in 1856 over western demands that opium markets be expanded. The Chinese were again defeated. In 1858, by the Treaty of Tientsin, opium importation to China was formally legalised. God-fearing British traders claimed that the hard-working Chinese were entitled to "a harmless luxury"; the opium trade in less respectable hands would be taken over by "desperadoes, pirates and marauders". Soon opium poured into China in unprecedented quantities. By the end of the nineteenth century, it has been estimated that over a quarter of the adult male Chinese population were addicted. In 1893, a Royal Commission on Opium was established to investigate the use of opium in the British Indian Empire. Many Protestants had begun to demonise opium; and Britain's Liberal Party hoped to see the drug banned for non-medical use. The Commission held seventy days of public hearings and called hundreds of witnesses. Its final Report ran to seven volumes totalling some 2500 pages. The Commission concluded that the use of opium in India was not a cause of "extensive moral or physical degradation." Opium was no worse than alcohol. The medical and non-medical use of opium were impossible to distinguish in practice. An effective ban would be infeasible. The Report was welcomed by an editorial published in the British medical journal The Lancet in April 1895. The Report's findings "dealt a crushing blow to the anti-opium faddists". Prohibitionist claims were "...either ridiculously exaggerated or even altogether unfounded." In North America, the initial history of Papaver somniferum was somewhat more peaceful than in Asia. During the first few centuries of European settlement, opium poppies were widely cultivated. Early settlers dissolved the resin in whisky to relieve coughs, aches and pains. The plant had further uses. Papaver somniferum produces lots of small black seeds. Poppy-seeds are an ingredient of typical bird-seed and a common garnish on rolls. Poppyseeds can also be ground into flour; used in salad-dressings; added to sauces as flavouring or thickening-agents; and the oil can be expressed and used in cooking. Poppy-heads are infused to make a traditional sedative drink. Many distinguished early Americans grew Papaver somniferum. Rightly or wrongly, they would today be treated as felons. Thomas Jefferson cultivated opium poppies at his garden in Monticello. The seeds from its plants, including the poppies, were sold at the gift-shop of Thomas Jefferson Center for Historic Plants until 1991 - when a drug-bust at the nearby University of Virginia panicked the Board of Directors into ripping up the plants and burning the seeds. The cultivation of Papaver somniferum is banned in the USA under the Opium Poppy Control Act of 1942. Amateur horticulturists, however, continue to value the beautiful red, yellow and white flowers as an adornment to their gardens. Until the nineteenth century, the only opioids used medicinally or recreationally took the form of crude opium. Opium is a complex chemical cocktail containing sugars, proteins, fats, water, meconic acid, plant wax, latex, gums, ammonia, sulphuric and lactic acids, and numerous alkaloids, most notably morphine (10%-15%), codeine (1%-3%), noscapine (4%8%), papaverine (1%-3%), and thebaine (1%-2%). All of the latter, apart from thebaine, are used medicinally as analgesics. The opioid analgesics are of inestimable value because they reduce or abolish pain without causing a loss of consciousness. They also relieve coughs, spasms, fevers and diarrhea. Even thebaine, though without analgesic effect, is of immense pharmaceutical worth. This is because it can be used to produce semi-synthetic opioid morphine analogues such as oxycodone (Percodan), dihydromorphenone (Dilaudid), hydrocodone (Vicodin) and etorphine (Immobilon). Classes of morphine analogue include the diphenylpropylamines (e.g. methadone), the 4-phenylpiperidines (e.g. meperidine), the morphinans (e.g. levorphanol) and 6,7-benzomorphans (e.g. metazocine). Although seemingly structurally diverse, all these compounds either possess a piperidine ring or contain the critical part of its ring structure. Etorphine, for instance, is a very potent analogue of morphine. On one occasion a team of researchers, working in the 1960s under Professor Bentley of Macfarlan Smith and Co, drank mid-morning tea that had been stirred with a contaminated rod. They were soon laid out. The scientists had unwittingly drunk a drug later developed as etorphine. Etorphine is over 1000 times more powerful than morphine; it is used in dart-guns as Immobilon to subdue elephants and rhinos. Fortunately the scientists recovered. Morphine was first isolated from opium in 1805 by a German pharmacist, Wilhelm Sertrner (1783-1841). Sertrner described it as the Principium Somniferum. He named it morphium - after Morpheus, the Greek god of dreams. Today morphine is isolated from opium in substantially larger quantities - over 1000 tons per year - although most commercial opium is converted into codeine by methylation. On the illicit market, opium gum is filtered into morphine base and then synthesized into heroin. Doctors had long hunted for effective ways to administer drugs without ingesting them. Taken orally, opium is liable to cause unpleasant gastric side-effects. The development of the hypodermic syringe in the mid-nineteenth century allowed the injection of pure morphine. Both in Europe and America, members of high society and middle-class professionals alike would jack up daily; poor folk couldn't afford to inject drugs. Morphinism became rampant in the USA after its extensive use by injured soldiers on both sides of the Civil War. In late nineteenth-century America, opiates were cheap, legal and abundant. In the judgement of one historian, America became "a dope fiend's paradise". Moreover it was believed that injecting morphine wasn't addictive. Quitting habitual opium use can cause malaise, flu-like symptoms, and depression; morphine seemed an excellent cure. In China, for instance, early twentieth century missionaries handed out anti-opium remedies in such profusion that the pills became known as "Jesus Opium"; their active ingredient was morphine. Soldiers, missionaries and patent-medicine salesmen were not alone in eulogising its properties. A leading American medical textbook (1868) revealed that opiates... "...cause a feeling of delicious ease and comfort, with an elevation of the whole moral and intellectual nature...There is not the same uncontrollable excitement as from alcohol, but an exaltation of our better mental qualities, a warmer glow of benevolence, a disposition to do great things, but nobly and beneficently, a higher devotional spirit, and withal a stronger self-reliance, and consciousness of power. Nor is this consciousness altogether mistaken. For the intellectual and imaginative faculties are raised to the highest point compatible with individual capacity...Opium seems to make the individual, for a time, a better and greater man...." Early optimism about morphine's non-addictive nature proved sadly misplaced. Women in particular came to be seen as especially vulnerable to opiate dependence. The most likely candidate for addiction, according to American doctor R Batholow, was... "...a delicate female, having light blue eyes and flaxen hair, [who] possesses, according to my observations, the maximum susceptibility..." Racist stereotypes, rampant xenophobia and lurid images of white slave-traders abounded too. In the 1850s and 1860s, tens of thousands of Chinese had emigrated to the USA to help build the western railroads and work the California mines. Opium-smoking was an integral part of Chinese culture; and its effects offered a merciful relief from dirty and backbreaking work. But the medical tide was turning. Dr Hamilton Wright, newly appointed US opium commissioner, blamed "the Chinese vice" for corrupting the nation's youth.... "One of the most unfortunate phases of the habit of smoking opium in this country [was] the large number of women who have become involved and were living as common-law wives or cohabiting with Chinese in the Chinatowns of our various cities..." Meanwhile Dr John Witherspoon, later President of the American Medical Association, exhorted the medical community to... "...save our people from the clutches of this hydra-headed monster which stalks abroad through the civilized world, wrecking lives and happy homes, filling our jails and lunatic asylums, and taking from these unfortunates, the precious promise of eternal life..." So the search began for a powerful non-addictive alternative to opium and morphine. In 1874, English pharmacist C.R. Alder Wright (1844-1894) had boiled morphine and acetic acid to produce diacetylmorphine, C17H17NO (C2H3O2)2. Diacetylmorphine was synthesized and marketed commercially by the German pharmaceutical giant, Bayer. In 1898, Bayer launched the best-selling drug-brand of all time, Heroin.

Potentiation
Practically everyone who digs antihistamines and other anticholinergics is going to get an even bigger kick out of the various opiates if they have the chance to experience them. Here are, based on more than a decade of experiments conducted by myself and others, some recipes for enhancing the effects of oral doses of codeine and hydrocodone. Except as noted the same effects which are shown for hydrocodone also apply to oxycodone. The effects of dihydrocodeine (Synalgos DC) are to an extent like a half again stronger version of codeine, but the euphoria has some hydrocodone elements to it, about a 60-40 split. For example, it is a warm and fuzzy feeling in general but there is the potential for the speeding exhilaration of codeine as well, especially right as the drug is entering ones system. In this document, the term "normal dose" refers to the dose used to produce euphoria without boosters, and "therapeutic dose" refers to the recommended dose for medical use. I would not recommend trying these mixtures until you are familiar with the effects of the components by themselves, and as always, err on the side of caution when dosing. A. Dealing With Troublesome Side Effects:

1. The "itchies" affect users of oral narcotics above moderate doses and can be reduced in intensity by taking a tablet of clemastine furmarate (Tavist), the new non-drowsy antihistamines Allegra or Claritin, or meclizine hydrochloride (Dramamine II) an hour before taking the dose of opiates, then using an old fashioned drowsiness producing antihistamine with moderate to strong anticholinergic action like diphenhydramine (Benadryl), dimenhydrinate (Original Dramamine), or brompheniramine (Dimetapp) to boost the effect of the opiate, and using topical creams containing antihistamines to knock down the worst itching. The itchies can be intensified by the inert and non-psychoactive ingredients of cough syrups coming out of one's pores and being deposited on the skin, so having a shower if you are not too blasted to walk a straight line can be a good idea in the middle of a long hydrocodone run. Codeine is for most people the itchiest narcotic. 2. Constipation is best dealt with by having tomatoes, tomato juice, or Metamucil before the opiate session and taking a tablet of senna 90 or more minutes before ingesting the opiates. [Eating fruit regularly is also a great help.] Keeping hydrated by drinking lots of water and fluids with electrolytes, especially on hydrocodone, also helps the problem from getting as bad as it could. Particularly with hydrocodone, the user should either avoid acidic materials before the opiate session or consume a solution of sodium bicarbonate to send their system pH back up before consuming the opiates. Many people experience an initial bout of diarrhoea on codeine, although they and others almost invariably wind up dealing with constipation even worse than oxycodone in the end. 3. Nausea is best counteracted with a combination of a carbonated beverage such as 7up or Alka Seltzer, the long-acting anti-nauseant meclizine and a shorter-acting drug such as diphenhydramine or promethazine etc. If you somehow come upon the anti-nauseant Compazine you would do well to flush it down the toilet because it has about half a dozen different ways to kill you. 4. The hangover from a combined opiate and anticholinergic session is almost completely the result of the anticholinergics and is best chased away with nicotine, either a low dose for non-smokers or some chain-smoking for smokers, and its effectiveness ranges from moderate for dimenhydrinate to virtually complete for the muscle relaxant cyclobenzaprine, the normal dose of which is equivalent to the anticholinergic effect of 70 mg of diphenhydramine. The usual dental precautions for anticholinergics such as using ice chips or artificial saliva for cotton mouth and avoiding acidic beverages until a fair amount of saliva is back in the mouth apply. B. Tips For Ingestion:

1. The efficacy of codeine, hydrocodone, oxycodone, and dihydrocodeine can be increased by at least 10% by taking them rectally. Inconclusive results have been obtained by heating hydrocodone and codeine cough syrups to 80 degrees Centigrade to boil off the alcohol, and it is suspected that these temperatures may result in the decomposition of the drug. On the other hand the best method for obtaining an opiate solution would be by using Cold Water Extraction on painkiller tablets. This liquid can be shot up the asshole with a plain syringe [no needle!] or medicine dropper or formed into colloids or solids for anal insertion by the addition of corn starch, oatmeal, or baking soda. 2. Purified powders of hydrocodone and oxycodone produced by evaporation (avoid boiling, see above) of the liquids generated by cold water extraction can be snorted (or the liquid put in a nasal sprayer), a concentrated solution or slurry added to chewing gum with a liquid centre, the liquid added to sugar cubes or antacid tablets for sublingual use or absorbed by other mucous membranes by other methods. Bulk can be added to these powders as needed by the addition of Nutrasweet, confectioner's sugar, or baby formula. Because of the way in which it is metabolised, oral administration is the optimal route for codeine. All of the oral codeine-based narcotics are bad news when used IV but can be skin-popped (injected subcutaneously) with effects marginally better than swallowing. If you are concentrating or boiling off solutions, diluting etc. it is imperative that you use precisely calibrated measuring equipment and keep some kind of record so there is no uncertainty about dosage. Reports have circulated about a method for obtaining a smokable freebase form of codeine, but this has not been verified. Snorting powdered codeine is assumed to be ineffective for metabolic reasons. The above-listed methods are theoretically workable for hydromorphone (Dilaudid) and oxymorphone (Numorphan) to an equal or greater extent. 3. The orally effective narcotics have much in common with alcohol as far as absorption goes, and the following methods have been demonstrated to have at least some effectiveness in getting the drug into the system more quickly: a. Mixing cough syrup or solutions of drug with carbonated beverages b. Mixing cough syrup or solutions of drug with Gatorade c. Mixing cough syrup or solutions of drug with warm brandy d. Using one form or another of the opiate to fortify an over-the-counter cough syrup e. Preparing a sodium bicarbonate solution or capsule containing the drug f. Dissolving/mixing the drug in soup or chocolate pudding g. Mixing codeine cough syrup or liquid into tonic water 4. Mixing liquid forms of the narcotics with antacids or sodium bicarbonate solution has proved to be effective at lengthening the high, although taking them separately has the same effect. There are bound to be tactical reasons for doing it this way -- for example, there are places where a bottle of Maalox is OK but a big bottle of cough syrup with a roman numeral five inside a C or a bottle of pills would raise suspicion. 5. Only so much codeine can be metabolised at one time - if you get above 400 mg, you are wasting it. This does not apply to hydrocodone, morphine, or the other natural or semisynthetic opiates. C. Boosting Opiates with Cytochrome P450 Inhibitors And Other Metabolism Issues

1. A dose of Tagamet an hour before a hydrocodone/oxycodone session will make the drug last longer and have a better effect. Antacids should be taken at least 45 minutes after the Tagamet otherwise absorption of the Tagamet will be impaired. Grapefruit juice also has the same type of impact on liver enzymes; use a Maalox chaser to neutralise any systemic acidification effect from the grapefruit juice. Tagamet should not be taken with codeine because it impairs the metabolism into morphine necessary for it to have any real effect. 2. Quinine and quinidine accentuate the buzz of opiates but only directly help with codeine metabolism by boosting the amount changed into morphine. The prescription antihistamine promethazine (Phenergan) helps out codeine even more, and is found with codeine in the Schedule V cough syrup Phenergan VC With Codeine. Quinine will tend to have its effect without impairing hydrocodone but does seem to burn off the buzz more quickly and may flatten the dose-to-response curve.

3. With all this liver magic going on and the acetaminophen content of a number of the drugs in question, the concurrent use of any alcohol at all with any of these mixtures should be thoroughly researched ahead of time. For example, washing down 5 Percocets with a vodka gimlet is not a good idea even if you have a massive tolerance to the narcotic. Also in many people moderate to large amounts of alcohol can change the subjective nature of the high for the worse and bring on sleep before the user intends. Anything more than 20 ml pure alcohol equivalent is likely to create trouble. D. Mixtures of Narcotics With Other Substances Note: Several other drugs are discussed under the headings below; if you do not see one you are looking for, use the find function on your reader to see if it is in the document. 1. Orphenadrine Citrate (Banflex, Norflex, Norgesic) -- This muscle relaxant works by much the same mechanism as scopolamine and the ethanolamine antihistamines and by itself is a mild euphoriant, although this euphoria is mainly appreciated by experienced anticholinergic users. Orphenadrine has many of the same systemic effects as cyclobenzaprine but tends to metabolise more quickly. It can be used, by itself or with a standard dose of a strong antihistamine like diphenhydramine, to enhance the euphoria of both codeine and hydrocodone to equal extents, and it is assumed oxycodone as well. A full dose of orphenadrine should be taken with an 80% dose of narcotic; if available, a half-dose of scopolamine, or 75 mg of diphenhydramine, provides a massive boost to the above mixture. Alcohol in low to moderate amounts does tend to increase the overall euphoria but should be added in small amounts after the full effect of the two or three other drugs is known. 2. Cyclobenzaprine (Flexeril) -- This muscle relaxant is generally a rotten medication but does have some impact on opiates and is a crucial ingredient in a late-afternoon snack involving Tylenol With Codeine. The user prepares for the set by taking a 200 mg caffeine tablet and an antacid and then about 30 minutes later taking a naproxen tablet, a effective dose of Tylenol (or aspirin or ibuprofen) with Codeine and the Cyclobenzaprine. If taken on an otherwise empty stomach the feeling of euphoria rapidly overtakes the user. Cyclobenzaprine is a tricyclic and the usual interaction warnings apply. Vicodin had been substituted for codeine with less success and it is assumed oxycodone preparations will have a similar effect. Alcohol will cause stomach problems if consumed with this mixture. In general, Cyclobenzaprine has been found to steepen the dose-to-response curve of codeine but have a negligible impact on other opiates, and mixes very poorly with many synthetics such as Darvon. 3. Diazepam (Valium) & Other Benzodiazepines -- This drug and other benzodiazepine tranquillisers have the effect of making codeine, oxycodone and especially hydrocodone highs cosier and preventing the insomnia that moderate to high narcotic doses can cause. A full therapeutic dose of the benzodiazepine should be taken with a dose of the narcotic starting at 70% of the usual. Alcohol must not be consumed with benzodiazepine tranquillisers under any circumstances. Not only does alcohol in low doses spoil the positive effects of the drug, but practically all benzodiazepine-related deaths have something to do with alcohol. It is assumed that oxycodone, paregoric, and opium doses should be started even lower if taken with Valium, Xanax, Librium etc. 4. Meprobamate (Miltown) -- This sedative-hypnotic can be used to boost codeine pain pills into a much higher level of euphoria, and along with quinine the combination can approach the intensity of morphine. However, Meprobamate spoils a hydrocodone high by making it harsher although the onset is more intense. A usual therapeutic dose of 200-600 mg of Meprobamate combined with 60% of the usual narcotic dose is a good place to start, with booster doses of opiate following no sooner than an hour later. Alcohol of any type should not be combined with these. 5. Barbiturates & Other Depressants -- The only research I or others have done with barbiturates has involved the use of low doses of hydrocodone to lift the hangover remaining after the primary effects had worn off. It is assumed that practically nothing in the realm of narcotics, depressants, or anticholinergics can be safely mixed with barbiturates at any dose. Non-barbiturate sedative-hypnotics have lesser but still significant dangers and concomitant dosing should not be attempted unless one has a good deal of experience with the effects of the sedative by itself. A therapeutic dose of methyprylon (Noludar) combined with 60 mg of codeine significantly strengthened both. Another piperidine-derived drug reportedly sold with codeine for concurrent use, glutethemide (Doriden), could not be obtained and is apparently no longer manufactured for US distribution. The depressant ethchlorvynol (Placidyl) is similar in many respects to barbiturates. Unconfirmed reports of a half dose of codeine cough syrup taking the rough edge of the recommended hypnotic dose of Chloral Hydrate have circulated, and codeine has the same effect on downer hangover that it does on alcohol hangover. 6. Promethazine (Phenergan) Phenergan VC With Codeine Cough Syrup is a pleasant night time substance which can be enhanced with the green-label Alka Seltzer Night-Time Cold Medicine or diphenhydramine. See notes under metabolic enhancers - this drug theoretically will burn off a hydrocodone/oxycodone buzz faster while increasing sedation. 7. Trazadone -- Effects are somewhat similar to cyclobenzaprine, both of which cannot be taken if the user has been taking MAO inhibitors in the last two weeks. Trazadone's anticholinergic activity is much less than Cyclobenzaprine and Trazadone has a horrible side effect profile including priapism or impotence and so forth. 8. Belladonna Alkaloids - These three alkaloids, scopolamine, hyoscyamine and atropine are used as antispasmodics and anticholinergics and have indirect additive effects on natural and semi-synthetic opiates when taken by mouth. The belladonna-paregoric mixture Donnagel PG has a crazy rushing high to it when taken at 150% of the therapeutic dose. Similar effects have resulted with combining the therapeutic dose with normal doses of codeine and dihydrocodeine. Of the alkaloids considered singly, therapeutic doses of scopolamine help out the opiates, hyoscyamine theoretically would have no direct impact, and atropine has variable antagonist activity, and its impact on opiates generally is a wash with the exception of some synthetics, which it directly wipes out. Diphenhydramine is basically synthetic scopolamine, the antiparkinsonism agent Trihexyphenidyl (Artane) is an atropine equivalent that does not appear to have the opiate-antagonist properties of atropine, and chlorpheniramine has many atropine-like effects (and a very similar dose-to-response curve) with no known opiate-antagonist activity. In all cases starting with the therapeutic dose of both the opiate and the anticholinergic are recommended, with increases in the anticholinergic needing to be capped at double the therapeutic dosage. In contrast to the belladonna alkaloids, the mentioned antihistamines have negligible gastro-intestinal effects, and Artane is closer to the antihistamines than atropine in this regard. 9. Diphenhydramine (Benadryl) -- This antihistamine increases the effects of opiates more or less evenly across the board, and the effect seems to be similar for all natural and semisynthetic opiates. A normal dose of the opiate can be taken with 25 to 75 mg of diphenhydramine. This mixture should be taken with a bronchodialator/decongestant because diphenhydramine is also a cough suppressant. The green label version of Alka Seltzer cold medicine contains a sufficient dose of decongestant and sodium bicarbonate (which slows metabolism). If the diphenhydramine product contains alcohol, the loading dose of the opiate should be reduced by 30% and the any booster doses should be taken no sooner than an hour afterwards. Those who take larger doses of antihistamines or other anticholinergics for the euphoriant properties should not take opiates along with them; needless to say, the mixing of opiates with the much higher deliriant doses of anticholinergics can be assumed to invariably have catastrophic effects because of the combination of respiratory depression and thickening of bronchial secretions caused by these drugs. It is assumed that any dose of diphenhydramine above 125 mg cannot be safely mixed with any quantity of opiate. 10. Dimenhydrinate -- Basically a pro-drug of diphenhydramine, see that section, doses are a 2:1 ratio. 11. Phenyltoloxamine Citrate - This is an antihistamine found in "enhanced pain relievers" available over-the-counter and has effects midway between brompheniramine and orphenadrine. It will make the euphoria of hydrocodone warmer and have a similar impact on codeine and dihydrocodeine. A normal dose of the opiate can be combined with up to 175% of the therapeutic dose of the phenyltoloxamine product (beware of total acetaminophen consumption) to start with. 12. Doxylamine Succinate -- This antihistamine is the active ingredient in NyQuil and some over-the-counter sleeping pills. Its sedative effects are similar to diphenhydramine and it has about 65-75% of the anticholinergic strength. It works nicely with codeine and about as well with hydrocodone. A normal dose of the opiate can be combined with a therapeutic dose of the doxylamine product to start out with, unless the doxylamine product contains a large amount of alcohol, in which case the opiate should be divided between a 70% dose initially and the other 30% no less than 30 minutes later with booster doses done at the usual interval but equal to or more than of the usual size.

13. Brompheniramine Maleate (Dimetapp) - This antihistamine is a drowsier version of Chlor-Trimeton which adds directly to most of the effects of opiates, with its contribution to codeine being the most significant. More than one person has reported a feeling of exhilaration similar to 150 mg of codeine when taking Dimetapp with 25 mg of hydrocodone. The sedative effect of brompheniramine is about 80% that of diphenhydramine with 75-80% of the anticholinergic potency. At therapeutic doses of brompheniramine the normal dose of the opiate can be taken; with anything above twice that (max should be four times) the initial dose of the opiate should be reduced by 20-35% and booster doses started no sooner than 45 minutes later, and then, at least initially, smaller than usual. Any brompheniramine product being used with opiates which contains alcohol should be taken at no more than 150% of the therapeutic dose with an initial dose of the opiate reduced by 25%. 14. Dextromethorphan Hydrobromide - Therapeutic doses of dextromethorphan tend to smooth out a codeine buzz and add calmness to the buzz of hydrocodone, oxycodone, and dihydrocodeine. Anything above this amount may not be a good idea because of the respiratory effects. Dextromethorphan is technically an opioid in the same chemical class as LevoDromoran, without a lot of the same effects, of course. 15. Meclizine (Dramamine II) - This is effective at reducing the nausea of opiates in a lot of people and at therapeutic doses will cause some across-the-board increase in the effects of opiates (about 35% that of diphenhydramine) and has been demonstrated to steepen or move out the dose-to-response curve of opiates, hydrocodone particularly. The antihistamines cyclizine (Marezine) and tripelennamine (PBZ, Pelamine) also have similar effects. The latter is a strong anticholinergic and was famous for being mixed with pentazocine (Talwin) back in the old days before they started mixing it with Narcan. All of these can be taken in the therapeutic doses along with the normal dose of the opiate. 16. Clemastine (Tavist) - This is an antihistamine in the same chemical class as diphenhydramine with a much longer half-life and about 55% of the sedative strength and 30% of the anticholinergic potency. The antihistamine triprolidine (Actifed) is a shorter acting antihistamine of the same type, albeit in another chemical category, that has stronger anticholinergic effects, about 60% those of diphenhydramine. Tavist is better ranked with Allegra and Claritin as being good medicines for pre-empting the itchies, although it has a similar effect to meclizine in compounding the effects of opiates, 35-45% that of diphenhydramine. These can be taken in the therapeutic doses along with the normal dose of the opiate. 17. NyQuil (Doxylamine & Dextromethorphan + other items) - See the dextromethorphan and doxylamine sections for details on how these act separately. This mixture is a good potentiator of practically all narcotics and has a particularly pleasing impact on hydrocodone. Because of the alcohol content, a therapeutic dose of NyQuil should be taken with an initial opiate dose reduced by 25% if it is the only item added or 25-45% if a third agent (the best are ONE of the following at one time): a.Orphenadrine, therapeutic dose, best with any b.Chlorpheniramine, therapeutic dose, best with codeine c.Diazepam, no more than 50% of the therapeutic dose with a 5mg maximum, somewhat better with hydrocodone. In this case, the dose of NyQuil should also be cut by 25%, as well as basically halving the initial opiate dose and then taking the other half about 45 minutes later, and no more alcohol consumed in any form. 18. Valerian - This is a good agent for dealing with insomnia at the end of an opiate session but really doesn't do much for the opiate. Chamomile tea has similar effects. 19. St. John's Wort - This has seemed to help some of the stimulant effects of opiates, codeine in particular, along. The difference varies quite a bit from person to person, and the fact that St. John's Wort is reportedly a soft Monoamine Oxidase Inhibitor should be considered when getting ready to mix things. 20. Sljivovica (100 proof plum brandy) - Of the alcoholic beverages, this was the best to mix with opiates, although no more than about > of an ounce should be used by those with no tolerance, and probably not that much more for others. It had an across-the-board impact on codeine but tended to harshen hydrocodone and oxycodone buzzes. In matters other than flavour and aesthetics, vodka is interchangeable with this beverage. 21. Gin - The same 15-20 ml pure-alcohol equivalent limit applies for this, and it's negative effects on the hydrocodone and oxycodone buzzes seemed to be somewhat greater than vodka, Sljivovica, and pure reagent-grade ethanol (thus it can be assumed Everclear) 22. White Wine: The co-generics present in wine make it an all or nothing thing as far as how well it mixes with opiates. Red wine will generally be worse. For a lot of people it won't be an improvement. The same goes for beer and a lot of whiskey. 23. Naproxen (Aleve): This non-steroidal anti-inflammatory will increase the analgesia of all opiates and can add some warmth to a hydrocodone buzz. It is very tough on the digestive system when taken on an empty stomach. 24. Multi-Narcotic Mixtures: The natural and semi-synthetic opiates by themselves steepen the dose-toresponse curve of other opiates of the same class. Whether this is the most efficient use of them depends on one's supply situation. 25. Chlorpheniramine (Chlor-Trimeton) - This antihistamine with about 60% of the anticholinergic strength and less than a quarter of the sedative activity of diphenhydramine markedly increases the exhilaration of codeine. Both are taken at the normal dosages, and mixtures of chlorpheniramine and phenylpropanolamine (Ornade etc) seem to work even better. The mixture can in turn be mixed with a normal dose of orphenadrine for an enhanced body buzz. The effects of chlorpheniramine seem to go on independent of a hydrocodone buzz without much in the way of enhancement, subjective change, or metabolic changes. 26. Loperamide (Immodium): This drug is related to meperidine/pethidine (Demerol) but does not cross the blood-brain barrier in sufficient quantities to cause euphoria. However, the consumption of doses of 150-300% of the therapeutic dose when mixed with high doses of codeine or meprobamate have been reported to produce a weak Darvon-like buzz aside from the effects of the other drugs.

CWE
IMHO the secret of improving CWE is finding a solvent with a lower boiling point than H2O Whilst messing around with codeine paracetamol tablets I tried the following: Added 96 10mg codeine 500mg+ rubbish tablets to 200ml cold tap water and left for 10mins or so to dissolve CP. I then decided to warm the solution before filtering. So I heated the solution in a hot water bath to about 45 or 50 deg.C. I then filtered the solution and it filtered in a fraction of the time it usually does with cold water. This gives a clear solution and without vacuum filtration you only lose about 5ml instead of 1/3 filtering cold solution. This is then placed in the freezer until it almost freezes, by which time almost all of the paracetamol dissolved, crystalizes out in lovely large needle shaped crystals. This near frozen solution is then filtered, which is also fast as paracetamol crystals are now large. This solution is now safe to drink containing approx. 5mg/ml,codeine phosphate or you can extract the codeine base and convert etc. see other threads.I found with the cold extraction and cold filtration method clogged up filters as the paracetamol was so powdery this method seems to work better and the final product was stronger than anything Ive had previously keeping everything cold?? But dont go over 60deg.C as CP apparently degrades then! :D Anyone noticed the 6 keto on hydrocodone? That will form a complex with bisulfite or NaI just fine, but I havn't got any solubility data FOR said complex. Since complex formation is a common way for MDMA cooks to cleen their MDP2P, it's probably a good way to clean hydrocodone as well. Failing that, ACAP (Paracetamol) had a phenolic group. Forming the insoluable calcium salt (this is how morphine is extracted from opium, letting the codeine - or in this case hydrocodone, stay in solution. Well, If you add some calcium hydroxide (lime) or calcium oxide (quicklime) to an APAP/Hydrocodone solution, the APAP will form the calcium salt, the freebase hydrocodone will stay in solution. If you distill off the water, you end up with SMOKABLE hydrocodone freebase. To form the bisulfite complex, add sodium bisulfite (or sodium metabisulfite) to a solution of hydrocodone & junk; the hydrocodone drops out - Add NaI to form the sodium iodide complex. To free from said complex, strain out complex & dump into a sodium hydroxide (NaOH) solution. You can then add sulfuric/hydrochloric acid until the pH is below 2.5 to form the salt of the hydrocodone. Add acetone until hydrocodone drops out...

Opium PoppiesHarvesting Opium * Morphine extraction * Heroin Synthesis * Dried Poppies * Poppy Seed Tea
Opium contains morphine and codeine. It can be made into heroin, morphine, or smoked. Opium can be obtained by growing Papaver Somniforum, there are several different varieties, I recommend the Persian white. Poppies are legal to grow and possess, but its illegal to use them with intent to produce opium, therefore its probably best to keep it private. They are often dried and used in floral arrangements. Poppy seeds are the only part of the plant that is not considered a schedule II substance under the Controlled Substance act of 1970.

Dried Poppies- Dried poppies (seed capsules, chopped flower petals, leaves,
Stems, etc) contain around 1mg of opiates in a gram. You can buy Papaver Somniforum from florists (make sure they dont have preservatives), or dry the plant material from poppies after youve harvested opium. Boil them then dink the liquid for psychoactive effects. This tea is VERY strong. Trade or possession of dried Papaver Somniforum is actually illegal; its not commonly prosecuted because of its decorative purposes.

Poppy Seed Tea- Poppy seeds contain the same alkaloids as opium except for morphine, and sometimes opium residue is left on the seeds. You can make tea by soaking about
350 grams of poppy seeds in lemon juice for 15 minutes, then soak them in hot water for another 15 minutes, then boil the liquid down until it makes about a cup. Be careful with poppy seed tea because the amount of alkaloids in the seeds vary it can be easy to overdo it, so drink it slowly and wait to feel the effects before raising your dose.

Harvesting and Smoking Opium- Poppy pods are ready to harvest when the petals have fallen off and they are firm, if they are not firm yet give them a few more days. Make
several close shallow cuts on the pods, from top to bottom. The opium will go into the pod if you cut too deep so be gentle. Let dry until it gets tarry, then scrape the tar off with a knife and store in the fridge. The poppy will produce opium for four days after being harvested.

Opium Morphine
10g Opium 500ml Demineralized Water 60 g Calcium Chloride 200ml Concentrated Ammonia (anhydrous is not necessary) 4 Coffee Filters Heat Opium to around 180 in Demineralized Water stir until latex dissolves Remove from heat Stir & pour through coffee filter Discard filter and return liquid to heat( around 180) stirring it When it begins to steam add ammonia until crystals stop forming Pour through coffee filter you should have white crystals Allow Crystals*** <3 to dry overnight Remember it may contain impurities so its best not to inject

Heroin Heroin is acetylated morphine (=diacetylmorphine is the chemical name for heroin). Its very easy (much much easier than the demethylation of codeine to morphine) to make
heroine from morphine, when you get acetic anhydride. This are the common ways to get H: opium - codeine - morphine - heroin opium - morphine heroin *College level chem. *acetic anhydride (concentrated acetic acid) should only be used by experienced ppl & is on DEA most watched list 10g morphineH CI: 15 grams of acetic acid 50 grams sodium carbonate 200 ml water 50 gramsa ctivatedc arbon 200 ml chloroform 200 ml ethyl alcohol 200 ml muriatic acid 200 ml ethyl ether 4 coffee filters Step Number I Add equal amounts of morphine and acetic anhydride and bring the tenperature to 185' F. Use caution if you don't live in a rural area, as acetic acid is what gives the "smell" to vinegar,a nd is closet o unbearableif the chemist is not cooking in a barn or other well-ventilated area.

One keepst he temperaturec onstanta nd stirs periodically for a period of no less than six hours. At this point, the chemist has bonded the acid to the opiate to form a crude heroin (diacetyl morPhine). Step Number 2 The product is mixed vigorously with water and chloroform (l:l rvater:chloroform) and drained off. This extracts any unreacted products or impurities. Pour off the waterchloroform mixture and add sodium carbonate to the heroin solution. This will cause heroin crystals to form and fall out of the solution. Step Number 3 Filter the solution through a couple of coffee filters to collect the heroin crystals. Dry the crystals overnight and then add them to a portion of alcohol and activated charcoal chips. Shake vigorously for a couple of minutes and filter chips through coffee filter. Evaporate alcohol off with a low heat. The product remaining is known as Nunr ber 3 Heroin. It can be used in this form or further purified to 99Vo in step number 4. Step Number 4 This step takes the heroin and turns it into super-potent, super-pure crystals. The purity will vary, but even an average chemist can realize a product that is 75Vo pure! The dangers of acetic anhydride are mild compared to the precipitator in this case: ether. Dissolve heroin crystals in a portion of alcohol and add simultaneously: muriatic (HCl) acid and ethyl ether. This will precipitate the Number 4 Heroin. Filter the crystals as in the previous step and spread them on a glass plate. position a standard 40-watt light bulb 16 inches above the plate and allow to dry overnight. When the crystals are dry and crunchy, they can be used accordingly.

OPIOIDS GLOSSARY
Abstinence syndrome = withdrawal symptoms Affinity = in crude terms, the "strength" of the interaction between a ligand and a receptor. When two ligands exist at equimolar concentration, the ligand whose affinity is higher will tend to displace the other from a receptor, assuming the low-affinity ligand is bound reversibly to the receptor. Agonist = a compound that will bind to a receptor to form a complex which elicits a full pharmacological response, peculiar to the nature of the receptor involved. Antagonist = a compound that will bind to a receptor to form a complex which does not give rise to any response, as if the receptor were unoccupied.

Delta receptors = a term used collectively to refer to two characterised subtypes of opioid receptors (delta-1, delta-2) that possess numerous features in common which are not present in the mu receptors or kappa receptors. Dynorphin = an endogenous peptide which functions as a selective agonist for the kappa opioid receptors. Endorphin(s), beta-endorphin = an endogenous peptide which functions as a selective agonist for the mu-opioid receptors. Endomorphin = a term which refers to two small (5 amino-acids) endogenous peptides, known as endomorphin-1 and endomorphin-2, which function as mu-agonists with greater selectivity than beta-endorphin. Enkephalin = one of a number of endogenous peptides which function as selective agonists for the delta-opioid receptors. Full agonist = see "agonist" Inverse agonist = in the context of receptors which exert some basic signalling activity even the absence of an agonist (characteristic known as "constitutive activity"), an agent which binds to a receptor, suppressing this activity to some degree. Intrinsic activity = a measure of the maximum response to an agonist. Kappa receptors = a term used collectively to refer to three characterised subtypes of opioid receptors (kappa-1, kappa-2, kappa-3) that possess numerous features in common which are not present in the mu receptors or delta receptors. Ligand = molecule which binds to a receptor to form a complex. MMT (methadone maintenence therapy) = medical treatment of addiction with the (less euphorigenic) opioid methadone Mixed agonist-antagonist = see "partial agonist" Morphinan = compound with the structural core or pharmacophore possesed by morphine and other opiates - not restricted to opiates Narcotic = literally "sleep/stupor-inducing agent". Term usually applied indiscriminately to describe any exogenous compound with a "sedating" profile. Use of the term with reference to the opioids is not recommended, due to its ambiguity, and arguably negative connotation. Neurotransmitter = any endogenous compound that plays a role in synaptic nervous transmission. Opiate = compound containing the fundamental morphine or thebaine structure possessing some affinity to any, or all, of the opioid receptor subtypes. Examples are heroin, buprenorphine and naltrexone. Opioid = any compound, peptide or otherwise, which, while not containing the fundamental morphine or thebaine structure, possesses some affinity for any, or all, of the opioid receptor subtypes. Common opioids are endorphin, fentanyl and methadone. Partial agonist = a compound which possesses affinity for a receptor, but unlike a full agonist, will elicit only a small degree of the pharmacological response peculiar to the nature of the receptor involved, even if a high proportion of receptors are occupied by the compound. Pharmacophore = the minimum functionality, or 3-D configuration of specific atoms or groups, that a molecule must have in order to exhibit biological activity. SAR (structure activity relationship) = the relationship between the chemical structure of a psychoactive compound to its strength and/or effects Selectivity = the relationship between the affinity of a compound for a particular receptor and its affinity for other types of opioid receptor. For instance, a compound that will bind with high affinity to the mu-receptors, but with very low affinity to kappa and delta receptors, is said to possess high selectivity for mu. Semi-synthetic opiate/opioid = a compound with some opioid receptor affinity, synthesised by functional modification of a product extracted from opium. Synthetic opiate/opioid = a compound with some opioid receptor affinity, synthesised using no products extracted from opium.

Timeline
.3400 B.C. The opium poppy is cultivated in lower Mesopotamia. The Sumerians refer to it as Hul Gil, the 'joy plant.' The Sumerians would soon pass along the plant and its euphoric effects to the Assyrians. The art of opium poppy-culling would continue from the Assyrians to the Babylonians who in turn would pass their knowledge onto the Egyptians. c.1300 B.C. In the capital city of Thebes, Egyptians begin cultivation of opium thebaicum, grown in their famous poppy fields. The opium trade flourishes during the reign of Thutmose IV, Akhenaton and King Tutankhamen. The trade route included the Phoenicians and Minoans who move the profitable item across the Mediterranean Sea into Greece, Carthage, and Europe. c.1100 B.C. On the island of Cyprus, the "Peoples of the Sea" craft surgical-quality culling knives to harvest opium, which they would cultivate, trade and smoke before the fall of Troy. c. 460 B.C. Hippocrates, "the father of medicine", dismisses the magical attributes of opium but acknowledges its usefulness as a narcotic and styptic in treating internal diseases, diseases of women and epidemics. 330 B.C. Alexander the Great introduces opium to the people of Persia and India. A.D. 400 Opium thebaicum, from the Egyptian fields at Thebes, is first introduced to China by Arab traders.

1020 Avicenna of Persia teaches that opium is "the most powerful of stupefacients." A.D. 1200 Ancient Indian medical treatises The Shodal Gadanigrah and Sharangdhar Samahita describe the use of opium for diarrohea and sexual debility. The Dhanvantri Nighantu also describes the medical properties of opium. 1300s Opium disappears for two hundred years from European historical record. Opium had become a taboo subject for those in circles of learning during the Holy Inquisition. In the eyes of the Inquisition, anything from the East was linked to the Devil. 1500 The Portuguese, while trading along the East China Sea, initiate the smoking of opium. The effects were instantaneous as they discovered but it was a practice the Chinese considered barbaric and subversive. 1527 During the height of the Reformation, opium is reintroduced into European medical literature by Paracelsus as laudanum. These black pills or "Stones of Immortality" were made of opium thebaicum, citrus juice and quintessence of gold and prescribed as painkillers. 1600s Residents of Persia and India begin eating and drinking opium mixtures for recreational use. Portuguese merchants carrying cargoes of Indian opium through Macao direct its trade flow into China. 1601 Ships chartered by Elizabeth I are instructed to purchase the finest Indian opium and transport it back to England. 1620s -1670s Rajput troops fighting for the Mughals introduce the habit of taking opium to Assam. Opium is given daily to Rajput soldiers. From 1637 onwards Opium becomes the main commodity of British trade with China. 1680 English apothecary, Thomas Sydenham, introduces Sydenham's Laudanum, a compound of opium, sherry wine and herbs. His pills along with others of the time become popular remedies for numerous ailments. 1700 The Dutch export shipments of Indian opium to China and the islands of Southeast Asia; the Dutch introduce the practice of smoking opium in a tobacco pipe to the Chinese. 1729 Chinese emperor, Yung Cheng, issues an edict prohibiting the smoking of opium and its domestic sale, except under license for use as medicine. 1750 The British East India Company assumes control of Bengal and Bihar, opium-growing districts of India. British shipping dominates the opium trade out of Calcutta to China. 1753 Linnaeus, the father of botany, first classifies the poppy, Papaver somniferum - 'sleep-inducing', in his book Genera Plantarum. 1767 The British East India Company's import of opium to China reaches a staggering two thousand chests of opium per year. 1773 East India Company assumes monopoly over all the opium produced in Bengal, Bihar and Orissa. Warren Hastings introduces system of contracts. Contracts for dealing in opium were awarded through auction. 1793 The British East India Company establishes a monopoly on the opium trade. All poppy growers in India were forbidden to sell opium to competitor trading companies. 1796 The import of opium into China becomes a contraband trade. Silver was smuggled out to pay for smuggling opium in. 1797 East India Company introduced Bengal Regulation IV to enable appointment of Opium Agents for purchase of opium from cultivators and its processing at factories owned by the company at Patna and Ghazipur 1799 China's emperor, Kia King, bans opium completely, making trade and poppy cultivation illegal. 1800 The British Levant Company purchases nearly half of all of the opium coming out of Smyrna, Turkey strictly for importation to Europe and the United States. 1803 Friedrich Sertrner of Paderborn, Germany discovers the active ingredient of opium by dissolving it in acid then neutralizing it with ammonia. The result: alkaloids - Principium somniferum or morphine. Physicians believe that opium had finally been perfected and tamed. Morphine is lauded as "God's own medicine" for its reliability, long-lasting effects and safety. 1805 A smuggler from Boston, Massachusetts, Charles Cabot, attempts to purchase opium from the British, then smuggle it into China under the auspices of British smugglers. 1812 American John Cushing, under the employ of his uncles' business, James and Thomas H. Perkins Company of Boston, acquires his wealth from smuggling Turkish opium to Canton.

1816 John Jacob Astor of New York City joins the opium smuggling trade. His American Fur Company purchases ten tons of Turkish opium then ships the contraband item to Canton on the Macedonian. Astor would later leave the China opium trade and sell solely to England. 1819 Writer John Keats and other English literary personalities experiment with opium intended for strict recreational use - simply for the high and taken at extended, non-addictive intervals 1821 Thomas De Quincey publishes his autobiographical account of opium addiction, Confessions of an English Opium-eater. 1827 E. Merck & Company of Darmstadt, Germany, begins commercial manufacturing of morphine. 1830 The British dependence on opium for medicinal and recreational use reaches an all time high as 22,000 pounds of opium is imported from Turkey and India. Jardine-Matheson & Company of London inherit India and its opium from the British East India Company once the mandate to rule and dictate the trade policies of British India are no longer in effect. 1837 Elizabeth Barrett Browning falls under the spell of morphine. This, however, does not impede her ability to write "poetical paragraphs." March 18, 1839 Lin Tse-Hsu, imperial Chinese commissioner in charge of suppressing the opium traffic, orders all foreign traders to surrender their opium. In response, the British send expeditionary warships to the coast of China, beginning The First Opium War. 1840 New Englanders bring 24,000 pounds of opium into the United States. This catches the attention of U.S. Customs which promptly puts a duty fee on the import. 1841 The Chinese are defeated by the British in the First Opium War. Along with paying a large indemnity, Hong Kong is ceded to the British. 1842 The Treaty of Nanking between the Queen of Great Britain and the Emperor of China. 1843 Dr. Alexander Wood of Edinburgh discovers a new technique of administering morphine, injection with a syringe. He finds the effects of morphine on his patients instantaneous and three times more potent. 1852 The British arrive in lower Burma, importing large quantities of opium from India and selling it through a government-controlled opium monopoly. 1856 The British and French renew their hostilities against China in the Second Opium War. In the aftermath of the struggle, China is forced to pay another indemnity. The importation of opium is legalized. Opium production increases along the highlands of Southeast Asia. 1874 English researcher, C.R. Wright first synthesizes heroin, or diacetylmorphine, by boiling morphine over a stove. In San Francisco, smoking opium in the city limits is banned and is confined to neighboring Chinatowns and their opium dens. 1878 Britain passes the Opium Act with hopes of reducing opium consumption. Under the new regulation, the selling of opium is restricted to registered Chinese opium smokers and Indian opium eaters while the Burmese are strictly prohibited from smoking opium. 1886 The British acquire Burma's northeast region, the Shan state. Production and smuggling of opium along the lower region of Burma thrives despite British efforts to maintain a strict monopoly on the opium trade. 1890 U.S. Congress, in its earliest law-enforcement legislation on narcotics, imposes a tax on opium and morphine. Tabloids owned by William Randolph Hearst publish stories of white women being seduced by Chinese men and their opium to invoke fear of the 'Yellow Peril', disguised as an "antidrug" campaign. 1895 Heinrich Dreser working for The Bayer Company of Elberfeld, Germany, finds that diluting morphine with acetyls produces a drug without the common morphine side effects. Bayer begins production of diacetylmorphine and coins the name "heroin." Heroin would not be introduced commercially for another three years. Early 1900s The philanthropic Saint James Society in the U.S. mounts a campaign to supply free samples of heroin through the mail to morphine addicts who are trying give up their habits. Efforts by the British and French to control opium production in Southeast Asia are successful. Nevertheless, this Southeast region, referred to as the 'Golden Triangle', eventually becomes a major player in the profitable opium trade during the 1940s. 1902 In various medical journals, physicians discuss the side effects of using heroin as a morphine step-down cure. Several physicians would argue that their patients suffered from heroin withdrawal symptoms equal to morphine addiction. 1903 Heroin addiction rises to alarming rates.

1905 U.S. Congress bans opium. 1906 China and England finally enact a treaty restricting the Sino-Indian opium trade. Several physicians experiment with treatments for heroin addiction. Dr. Alexander Lambert and Charles B. Towns tout their popular cure as the most "advanced, effective and compassionate cure" for heroin addiction. The cure consisted of a 7 day regimen, which included a five day purge of heroin from the addict's system with doses of belladonna delirium. U.S. Congress passes the Pure Food and Drug Act requiring contents labeling on patent medicines by pharmaceutical companies. As a result, the availability of opiates and opiate consumers significantly declines. 1909 The first federal drug prohibition passes in the U.S. outlawing the importation of opium. It was passed in preparation for the Shanghai Conference, at which the US presses for legislation aimed at suppressing the sale of opium to China. February 1, 1909 The International Opium Commission convenes in Shanghai. Heading the U.S. delegation are Dr. Hamilton Wright and Episcopal Bishop Henry Brent. Both would try to convince the international delegation of the immoral and evil effects of opium. 1910 After 150 years of failed attempts to rid the country of opium, the Chinese are finally successful in convincing the British to dismantle the India-China opium trade. Dec. 17, 1914 The passage of Harrison Narcotics Act which aims to curb drug (especially cocaine but also heroin) abuse and addiction. It requires doctors, pharmacists and others who prescribed narcotics to register and pay a tax. 1923 The U.S. Treasury Department's Narcotics Division (the first federal drug agency) bans all legal narcotics sales. With the prohibition of legal venues to purchase heroin, addicts are forced to buy from illegal street dealers. 1925 In the wake of the first federal ban on opium, a thriving black market opens up in New York's Chinatown. 1930s The majority of illegal heroin smuggled into the U.S. comes from China and is refined in Shanghai and Tietsin. Early 1940s During World War II, opium trade routes are blocked and the flow of opium from India and Persia is cut off. Fearful of losing their opium monopoly, the French encourage Hmong farmers to expand their opium production. 1945-1947 Burma gains its independence from Britain at the end of World War II. Opium cultivation and trade flourishes in the Shan states. 1948-1972 Corsican gangsters dominate the U.S. heroin market through their connection with Mafia drug distributors. After refining the raw Turkish opium in Marseilles laboratories, the heroin is made easily available for purchase by junkies on New York City streets. 1950s U.S. efforts to contain the spread of Communism in Asia involves forging alliances with tribes and warlords inhabiting the areas of the Golden Triangle, (an expanse covering Laos, Thailand and Burma), thus providing accessibility and protection along the southeast border of China. In order to maintain their relationship with the warlords while continuing to fund the struggle against communism, the U.S. and France supply the drug warlords and their armies with ammunition, arms and air transport for the production and sale of opium. The result: an explosion in the availability and illegal flow of heroin into the United States and into the hands of drug dealers and addicts. 1962 Burma outlaws opium. 1965-1970 U.S. involvement in Vietnam is blamed for the surge in illegal heroin being smuggled into the States. To aid U.S. allies, the Central Intelligence Agency (CIA) sets up a charter airline, Air America, to transport raw opium from Burma and Laos. As well, some of the opium would be transported to Marseilles by Corsican gangsters to be refined into heroin and shipped to the U.S via the French connection. The number of heroin addicts in the U.S. reaches an estimated 750,000. October 1970 Legendary singer, Janis Joplin, is found dead at Hollywood's Landmark Hotel, a victim of an "accidental heroin overdose." 1972 Heroin exportation from Southeast Asia's Golden Triangle, controlled by Shan warlord, Khun Sa, becomes a major source for raw opium in the profitable drug trade. Solomon Snyder and Candace Pert discover opiate receptor in the brain. July 1, 1973 President Nixon creates the DEA (Drug Enforcement Administration) under the Justice Dept. to consolidate virtually all federal powers of drug enforcement in a single agency. Mid-1970s Saigon falls. The heroin epidemic subsides. The search for a new source of raw opium yields Mexico's Sierra Madre. "Mexican Mud" would temporarily replace "China White" heroin until 1978. 1975 Hans Kosterlitz and his colleagues isolate and purify an endogenous opioid in the brain, enkephalin. 1978 The U.S. and Mexican governments find a means to eliminate the source of raw opium - by spraying poppy fields with Agent Orange. The eradication plan is termed a success as the amount of "Mexican Mud" in the U.S. drug market declines. In response to the decrease in availability of "Mexican Mud", another source of heroin is found in the Golden Crescent area Iran, Afghanistan and Pakistan, creating a dramatic upsurge in the production and trade of illegal heroin.

1982 Comedian John Belushi of Animal House fame, dies of a heroin-cocaine - "speedball" overdose. Sept. 13, 1984 U.S. State Department officials conclude, after more than a decade of crop substitution programs for Third World growers of marijuana, coca or opium poppies, that the tactic cannot work without eradication of the plants and criminal enforcement. Poor results are reported from eradication programs in Burma, Pakistan, Mexico and Peru. 1988 Opium production in Burma increases under the rule of the State Law and Order Restoration Council (SLORC), the Burmese junta regime. The single largest heroin seizure is made in Bangkok. The U.S. suspects that the 2,400-pound shipment of heroin, en route to New York City, originated from the Golden Triangle region, controlled by drug warlord, Khun Sa. 1990 A U.S. Court indicts Khun Sa, leader of the Shan United Army and reputed drug warlord, on heroin trafficking charges. The U.S. Attorney General's office charges Khun Sa with importing 3,500 pounds of heroin into New York City over the course of eighteen months, as well as holding him responsible for the source of the heroin seized in Bangkok. 1992 Colombia's drug lords are said to be introducing a high-grade form of heroin into the United States. 1993 The Thai army with support from the U.S. Drug Enforcement Agency (DEA) launches its operation to destroy thousands of acres of opium poppies from the fields of the Golden Triangle region. January 1994 Efforts to eradicate opium at its source remains unsuccessful. The Clinton Administration orders a shift in policy away from the anti- drug campaigns of previous administrations. Instead the focus includes "institution building" with the hope that by "strengthening democratic governments abroad, [it] will foster law-abiding behavior and promote legitimate economic opportunity." 1995 The Golden Triangle region of Southeast Asia is now the leader in opium production, yielding 2,500 tons annually. According to U.S. drug experts, there are new drug trafficking routes from Burma through Laos, to southern China, Cambodia and Vietnam. January 1996 Khun Sa, one of Shan state's most powerful drug warlords, "surrenders" to SLORC. The U.S. is suspicious and fears that this agreement between the ruling junta regime and Khun Sa includes a deal allowing "the opium king" to retain control of his opium trade but in exchange end his 30-year-old revolutionary war against the government. November 1996 International drug trafficking organizations, including China, Nigeria, Colombia and Mexico are said to be "aggressively marketing heroin in the United States and Europe." 1999 Bumper opium crop of 4,600 tons in Afghanistan. UN Drug Control Program estimates around 75% of world's heroin production is of Afghan origin. 2000 Taliban leader Mullah Omar bans poppy cultivation in Afghanistan; United Nations Drug Control Program confirms opium production eradicated. July 2001 Portugal decriminalizes all drugs for personal consumption. Autumn 2001 War in Afghanistan; heroin floods the Pakistan market. Taleban regime overthrown. October 2002 U.N. Drug Control and Crime Prevention Agency announces Afghanistan has regained its position as the world's largest opium producer. December 2002 UK Government health plan will make heroin available free on National Health Service "to all those with a clinical need for it". Consumers are sceptical. April 2003 State sponsored heroin trafficking: Korea's attempt to penetrate the Australian heroin market hits rocky waters. October 2003 US Food and Drug Administration (FDA) and Drug Enforcement Administration (DEA) launch special task force to curb surge in Net-based sales of narcotics from online pharmacies. January 2004 Consumer groups file a lawsuit against Oxycontin maker Purdue Pharma. The company is alleged to have used fraudulent patents and deceptive trade practices to block the prescription of cheap generic medications for patients in pain. September 2004 Singapore announces plans to execute a self-medicating heroin user, Chew Seow Leng. Under Singapore law, chronic heroin users with a high physiological tolerance to the drug are deemed to be "traffickers". Consumers face a mandatory death sentence if they take more than 15 grams (0.5 ounces) of heroin a day. September 2004 A Tasmanian company publishes details of its genetically-engineered opium poppies. Top1 [thebaine oripavine poppy 1] mutants do not produce morphine or codeine. Tasmania is the source of some 40% of the world's legal opiates; its native crop of poppies is already being re-engineered with the mutant stain. Conversely, some investigators expect that the development of genetically-engineered plants and microorganisms to manufacture potent psychoactive compounds will become widespread later in the 21st century. Research into transgenic psychotropic botanicals and microbes is controversial; genes from mutants have a habit of spreading into the wild population by accident as well as design. September 2004 The FDA grants a product license to Purdue's pain medication Palladone: high dose, extended-release hydromorphone capsules. Palladone is designed to provide "around-the-clock" pain-relief for opioid-tolerant users.

October 2004 Unannounced withdrawal of newly-issued DEA guidelines to pain specialists. The guidelines had pledged that physicians wouldn't be arrested for providing adequate pain-relief to their patients. DEA drug-diversion chief Patricia Good earlier stated that the new rules were meant to eliminate an "aura of fear" that stopped doctors treating pain aggressively. December 2004 McLean pain-treatment specialist Dr William E. Hurwitz is sent to prison for allegedly "excessive" prescription of opioid painkillers to chronic pain patients. Testifying in court, Dr Hurwitz describes the abrupt stoppage of prescriptions as "tantamount to torture". May 2005 Researchers at Ernest Gallo Clinic and Research Center in Emeryville, California, inhibit expression of the AGS3 gene in the core of nucleus accumbens. Experimentally blocking the AGS3 gene curbs the desire for heroin in addicted rodents. By contrast, activation of the reward centres of the nucleus accumbens is immensely pleasurable and addictive. The possible effects of overexpression and gene amplification of AGS3 remain unexplored. December 2005 Neuroscientists close in on the (hypothetical) final common pathway of pleasure in the brain. The "hedonic hotspot" is activated by agonists of the mu opioid receptor. In rats, at least, the hedonic hotspot is located in a single cubic millimeter of tissue: the substrates of pure bliss may lie in medium spiny neurons in the rostrodorsal region of the medial shell of the nucleus accumbens. May 2006 In Mexico, Congress passes a bill legalising the private personal use of all drugs, including opium and all opiate-based drugs. President Vicente Fox promises to to sign the measure, but buckles a day later under US government pressure. The bill is referred back to Congress for changes. "We welcome the idea of Mexico reviewing the legislation to avoid the perception that drug use would be tolerated in Mexico," says the U.S. Embassy in Mexico City. June 2006 University of Southern California neuroscientist Irving Biederman publishes in the American Scientist a theory of knowledge-acquisition likening all human beings to "junkies". On this hypothesis, knowledge junkies are driven to learn more information by a craving for the brain's own natural opium-like substances. September 2006 The head of the United Nations Office on Drugs and Crime reports that Afghanistan's harvest in 2006 will be around 6,100 metric tons of opium - a world record. This figure amounts to some 92% of global opium supply. November 2006 Senior UK police officer Howard Roberts advocates legalisation of heroin and its availability without charge on National Health Service (NHS) prescription. August 2007 Afghanistan's poppy production rises an estimated 15 percent over 2006. Afghanistan now accounts for 95 percent of the world's opium poppy crop, a 3 percentage point increase over last year. The US State Department's top counternarcotics official Tom Schweich claims that Afghanistan is now "providing close to 95 percent of the world's heroin". October 2007 Death of Golden Triangle opium lord and former Shan separatist leader Khun Sa (1933-2007). At its peak, Khun Sa's narcotics empire controlled production of an estimated quarter of the world's heroin supply. March 2008 A report by The Pew Centre, a Washington think tank, reveals that over one in 100 adults in the USA is now in jail: some 2,300,000 prisoners, triple the rate in the 1980s. American prisons now hold around a quarter of the world's inmates. Nearly half of US federal prisoners are imprisoned for non-violent, drug-related "crimes". Law professor Paul Cassell of the University of Utah comments on the size of the US prison population: "it's the price of living in the most free society in the world. November 2008 Swiss voters overwhelmingly endorse a permanent and comprehensive legalized heroin program. February 2009 FDA announces plans further to restrict access to opioid-based pain-relievers by American citizens and their doctors. March 2009 According to the World Health Organization, around 80% of the worlds population does not have adequate access to pain relief. The international organisation Human Rights Watch (HRW) blames a failure of leadership, inadequate training of health care workers, and over-zealous drug control efforts. May 2010 Research published in Proceedings of the National Academy of Sciences confirms that mice (and humans?) can synthesise their own morphine.

People
Marcus Aurelius (AD 121 - 180) Charles Baudelaire (1821-1867) Elizabeth Barrett Browning (1806 - 1861) William S Burroughs (1917 - 1997) Robert Clive (1725 -1774) Samuel Taylor Coleridge (1772 - 1834) Wilkie Collins (1824 - 1889) George Crabbe (1754 - 1832) Heinrich Dreser (1860 - 1924) Galen (AD 131 - 200) William Stewart Halsted (1852 - 1922) Hippocrates (c.460 - c.377 BC) John Keats (1795 - 1821) Hans Kosterlitz (1903 - 1996) Linnaeus (1707 - 1778) Andr Malraux (1901 - 1976) Paracelsus (1490 - 1541) Candace Pert (1946 - ) Edgar Allan Poe (1809 - 1849) Thomas de Quincey (1785 - 1859) Wilhelm Sertrner (1783 - 1841) Solomon Snyder Thomas Sydenham (1624 - 1689) Warren Hastings (1732 - 1818) William Wilberforce (1759 - 1833)

Quotes

"Opium teaches only one thing, which is that aside from physical suffering, there is nothing real." Andr Malraux MAN'S FATE "I'll die young, but it's like kissing God" Lenny Bruce "If we could sniff or swallow something that would, for five or six hours each day, abolish our solitude as individuals, atone us with our fellows in a glowing exaltation of affection and make life in all its aspects seem not only worth living, but divinely beautiful and significant, and if this heavenly, worldtransfiguring drug were of such a kind that we could wake up next morning with a clear head and an undamaged constitution - then, it seems to me, all our problems (and not merely the one small problem of discovering a novel pleasure) would be wholly solved and earth would become paradise." ALDOUS HUXLEY 1894 1963 "Narcotics have been systematically scapegoated & demonized" (quote from Drugstore Cowboy) Thou hast the keys of Paradise, oh just, subtle, and mighty opium! -Thomas De Quincey Our current drug crisis is a tragedy born of a phony system of classification. For reasons that are little more than accidents of history, we have divided a group of nonfood substances into two categories: items purchasable for supposed pleasure (such as alcohol), and illicit drugs. The categories were once reversed. Opiates were legal in America before the Harrison Narcotics Act of 1914, and members of the Womens Christian Temperance Union, who campaigned against alcohol during the day, drank their valued womens tonics at night, products laced with laudanum (tincture of opium). I could abidethough I would still opposeour current intransigence if we applied the principle of total interdiction to all harmful drugs. But how can we possibly defend our current policy based on a dichotomy that encourages us to view one class of substances as a preeminent scourge while the two most dangerous and life-destroying substances by far, alcohol and tobacco, form a second class advertised in neon on every street corner of urban America? And why, moreover, should heroin be viewed with horror while chemical cognates that are no different from heroin than lemonade is from iced tea perform work of enormous compassion by relieving the pain of terminal cancer patients in their last days? -Stephen J. Gould Choose Life. Choose a job. Choose a career. Choose a family. Choose a fucking big television, choose washing machines, cars, compact disc players and electrical tin openers. Choose good health, low cholesterol, and dental insurance. Choose fixed interest mortgage repayments. Choose a starter home. Choose your friends. Choose leisurewear and matching luggage. Choose a three-piece suit on hire purchase in a range of fucking fabrics. Choose DIY and wondering who the fuck you are on Sunday morning. Choose sitting on that couch watching mind-numbing, spirit-crushing game shows, stuffing fucking junk food into your mouth. Choose rotting away at the end of it all, pissing your last in a miserable home, nothing more than an embarrassment to the selfish, fucked up brats you spawned to replace yourselves. Choose your future. Choose life... But why would I want to do a thing like that? I chose not to choose life. I chose somethin' else. And the reasons? There are no reasons. Who needs reasons when you've got heroin? Trainspotting "God's Own Medicine" Sir William Osler