OPIATE ADDICTION – Pathophysiology and Herbal Interventions

OPIATE ADDICTION
PATHOPHYSIOLOGY AND HERBAL INTERVENTIONS
Dr Jillian Stansbury

CHASING THE DRAGON
Opiate addiction is an enormous and devastating health problem worldwide, with over 4 million active addicts in the US alone, and over 1.5 million heroin addicts undergoing treatment each year. And not only the addict is affected as of course, marriages suffer or are ruined, jobs are lost, meaningful relationships to people, other hobbies, nature, and the world at large are lost, and most of all, the mind and body are destroyed bit by bit from heroin use. Many addicts become homeless once loved ones can no longer tolerate the thefts and behaviors, and employers cannot forgive the absenteeism. The homeless population is subject to its own vast litany of problems, being at risk for violent deaths among them.
Prescriptions for opiate-based analgesics has skyrocketed in the last decade according to DEA statistics , which many people report is an inciting factor that ultimately leads to heroin addiction. The opiate industry itself is almost nothing but dark – troubled by the limited availability of raw material, low yields, and the by-product of toxic wastes, in addition to the addiction, crime association, and high mortality and morbidity. Furthermore, an attempt to gain access to poppy raw materials the US may be a hidden agenda in US’s efforts to muscle its presence into Afghanistan. Canadian economics professor, Michel Chossudovsky reported that “Heroin is a multibillion dollar business supported by powerful interests, which requires a steady and secure commodity flow. One of the “hidden” objectives of the war [in Afghanastan] was precisely to restore the CIA sponsored drug trade to its historical levels and exert direct control over the drug routes.”

OPIATE MAINTENANCE THERAPY (OMT)
The Rockefeller Institute performed research on possible pharmacotherapies for long term opiate addiction in the 1960s beginning the search for successful therapies for heroin addiction. Professor Vincent P. Dole and his team hypothesized that heroin addiction is a disease of the brain with behavioral manifestations, and not merely a personality disorder or criminal behavior. Research was begun to discover whether a long-acting opioid agonist could improve successful heroine abstinence, however due to political social stigma reasons, the FDA did not support the development of such pharmaco-therapies for nearly 40 years. It was not until the turn of the millennia, following the release of an NIH report supporting long acting opiates such as methadone maintenance, that the fruits of the Rockefeller research was finally implemented.
The heroin replacement therapies, commonly referred to as Opiate Maintenance Therapy (OMT) involve the supply of an opioid agonist, such as methadone, with the rationale of decreasing excruciating cravings for heroin, alleviating devastating withdrawal symptoms, and mitigating the need to beg, borrow, and steal the money necessary to maintain the heroin habit, yet delivered at a controlled dosage below the euphoria threshold. Opiate replacement therapies can improve social and familial functioning and support general survival. Because so many heroin addicts die from not only overdose, but a variety of causes including greatly accelerated aging, and from diseases associated with IV drug use including AIDS, hepatitis induced liver failure, and endocarditis and heart failure, OMT can help reduce such risks.

HERBAL OPTIONS AS OPIATE REPLACEMENT THERAPIES
Most of the current therapies for opiate withdrawal involve replacing the short acting opiates such as heroin with a long acting opiate that reduces craving without producing the euphoric effect. While these opiate maintenance therapies may have many benefits for addicts, a big drawback is that they maintain the up-regulated opioid circuitry in the brain. Non-Opiate therapies may include GABA and herbs that bind GABA, agents that affect noradrenaline, dopamine, serotonin and other pathways outside of the opiates, and agents that regulate stress pathways of the HPA axis. Following are herbal suggestions for opiate replacement options, as well as non-opiate options to include in but acute withdrawal and long term maintenance therapies for heroin addicts.

Corydalis species: C. yanhusuo, C. bungeana, Corydalis humosa
Corydalis is a genus in the Poppy family (Papaveracea) long used as sedatives and analgesics and contains constituents including many isoquinoline alkaloids such as tetrahydropalmatine, corydaline, protopine, berberine, palmatine, jatrorrhizine, coptisine, and dehydrocorydaline , that may affect limbic and reward pathways. These alkaloids are also referred to as protoberberine alkaloids and some including palmatine, jatrorrhizine, coptisine, and dehydrocorydaline may also act as cholinersterase inhibitors, serving to promote acetylcholine and parasympathetic tone. Corydalis cava may promote adrenaline breakdown and metabolism, as well as the synthesis of melanine from dihydroxy-phenylalanine (DOPA). The half-life of phenolase enzymes is greatly lengthened by Corydalis.
The alkaloid tetrahydropalmatine occurs in both Corydalis and Stephania species and both plants are mentioned as being helpful for opiate addictions. Tetrahydropalamatine has been produced into a prescription drug in China marketed under the name Rotundine. Tetrahydropalmatine has been shown to bind to dopamine receptors and act as an antagonist at D1 and D2 and agonist at D3, α adrenergic and serotonin receptors. L-tetrahydropalmatine has been shown to decrease self-administration of heroin in animal models of addiction, and prevent heroin-driven changes in the nucleus accumbens and ventral tegemental area. Levo-tetrahydropalmatine has been found to diminish activation of the reward pathway in animal models of methamphetamine addiction, suggesting balancing effects on the limbic system. Levo-tetrahydropalmatine may also protect the limbic system from stress-induced changes in gene expression. Levo-tetrahydropalmatine may also bind GABA receptors.
L-isocorypalmine is a methylated analog of L-tetrahydropalmatine also found to bind dopamine receptors and act as a partial agonist at D1 and antagonist at D2 receptors, serving to mitigate cocaine withdrawal symptoms. Acetylchorynoline is another an alkaloid in C. bungeana shown to prevent dopaminergic degeneration in Parkinson’s disease models. Another Corydalis root constituent, the isoquinoline alkaloid tetrahydroberberine may help correct the digestive suppression induce by opiate drugs by upregulating GI motility via dopaminergic effects at D2 receptors and serotonergic receptor agonism.

Eschscholzia californica, the California Poppy is in the Poppy Family and native to the west coast of North America where it was used as a sleep aid and pain remedy by indigenous people of the region. Eschscholzia remains in common use as a gentle nervine and may be considered in herbal formulas for easing opiate withdrawal symptoms, and possibly long-term maintenance therapies to reduce the cravings. Eschscholtzia may inhibit the enzymatic degradation of catecholamine as well as inhibit the synthesis of adrenaline. Inhibition of diamine oxidases and monoamine oxidase are among the mechanisms of action.

Harpagophytum procumbens – Devil’s Claw has shown efficacy in reducing arthritic pain and reducing the need for other pain medications. The plant may be anti-inflammatory when applied topically. Some research has suggested that in addition to anti-inflammatory effects, Harpagophytum may be pain relieving via opiate pathways. This plant might especially be considered in formulas for those seeking to wean from opiate prescriptions for pain management.

Hypericum perforatum – St. Johnswort is a well-known herb used for depression and anxiety. Extensive research on the plant shows it to have a broad effect on numerous neurotransmitters including serotonin, GABA, and dopamine. Animal studies suggest it may also help ease the symptoms of acute morphine withdrawal. Hypericum was shown to be as effective as clonidine for the symptoms of opiate withdrawal in animal models of addiction. Other researchers report Hypericum perforatum to reduce abdominal spasm and diarrhea in animal models of acute opiate withdrawal. ,

Jitai Tablets And Jinnui Capsules – Jitai tablet are TCM an herbal marine product combo with a dozen ingredients traditionally used for detoxification and acute opiate withdrawal symptoms. In TCM such symptoms are described as being poison-blood stasis, cold and heat complex, and spleen and kidney weakness. Jitai tablets contain amygdalin, danshensu, ferulic acid, hydroxysafflor yellow A, and salvianolic acids A and B. The effects of Jitai tablets are similar to those of clonidine in controlling the withdrawal symptoms of morphine-dependent animals. Clinical studies have further confirmed that Jitai tablet has good efficacy in controlling both acute and protracted opiate withdrawal symptoms. One clinical trial reported equal efficacy to lofexidine for acute heroin withdrawal. , Adverse herb reactions are mild and can be reduced during the treatment or after drug reduction. No significant adverse effects have been found on the liver and kidney function in patients.

Mitragyna speciosa – Kratom/Khratom, Ketum is an Asian plant, often sought after by those looking for a drug-like effect as word has spread of this use by villagers in Thailand and Malaysia. Mitragyna leaves contain mitragynine and related alkaloids having both opiate and cocaine-like effects and legislation was passed in Malaysia in 2004 to outlaw its sale and consumption, more due to concerns of it being a “gateway” drug than any real toxicity or abuse issues. One ethnobotanical survey reported many rural villages ingest Mitragyna extracts as tea on a daily basis with reported effects including simple social and recreational effects, increased stamina and physical endurance, pain relief and improved sexual performance. Many users reported difficulty in abstaining from consuming the tea so frequently. At the same time, many heroin addicts in Thailand and Maylasia report Mitragyna to have helped them wean off heroin. Animal studies suggest that Mitragyna induces cytochrome enzymes in the liver and speeds up metabolism of many drugs also metabolized via this pathway.

Salvia divinorum – The plant is sometimes referred to as “Magic Mint” even though it is a perennial sage, however it is a member of the Mint or Labaitae family, not a family known for its psychadelics as are the Poppy and Cactus families. Salvia divinorum is native to the Oaxaca area of Mexico where it has been a long standing sacred plant used in rituals. Salvia divinorum has been used as a treatment for the “semimagical” disease panzón de borrego. The Mazatec people of Mexico also used Salvia divinorum for rituals and to treat gastrointestinal disorders.
The effects of Salvia divinorum come on quickly, within one minute following ingestion and last for a relatively short period of time. Researchers report that the effects may be so rapid due to the ability of salvinorin A to modulate the P-glycoprotein transporter and gain rapid transport through the blood brain barrier. Human investigations report no cognitive deficits, changes to vital signs with use, but spikes in prolactin and cortisol occur transiently. Other than talking, laughing, and moving more often, no untoward physical symptoms were observed in clinical placebo controlled trials of    Salvia divinorum ingestion. Salvinorin A did not significantly increase heart rate or blood pressure. Participant narratives indicated intense experiences characterized by disruptions in vestibular and interoceptive signals (e.g., change in spatial orientation, pressure on the body) and unusual and sometimes recurring themes across sessions such as revisiting childhood memories, cartoon-like imagery, and contact with entities.
Salvia divinorum’s most studied constituents are its diterpenes. Salvinorin diterpenes are classified as neoclerodane, and said to be the first identified non-nitrogenous ligand of the opiate receptor , and the diterpene salvinorin A shown to be a kappa-opioid agonist and the first reported psychoactive diterpene known to exist in nature. Other naturally occurring neoclerodanes from a variety of Salvia species may have an affinity for opioid receptors, albeit not with a very strong binding affinity as seen with salvinorin. Salvinorin may act via both opiate and cannabinoid receptors to mitigate both stress and pain pathways. Animal research suggests that Salvinorin may reverse depression associated with chronic stress. Researchers also report that the ability to limit negative emotional consequences may also cause chronic use of Salvia divinorum to impair memory formation in general and affect learning. Isolated Salvinorin A has therapeutic potential as a treatment for pain, mood and personality disorders, substance abuse, and gastrointestinal disturbances , and suggests that nonalkaloids are potential scaffolds for drug development for aminergic G-protein coupled receptors.
Like many opiate agonists, S. divinorum affects colonic function. Salvinorin A inhibits gastrointestinal peristalsis and reduces neurogenic ion channel transport when overstimulated due to the presence of endotoxins, explaining its historical use for intestinal disorders. Salvinorin A inhibits intestinal motility through activation of kappa-opioid receptors. Additionally, intestinal inflammation upregulates cannabinoid receptors and endogenous cannabinoids, and salvinorin A may improve gastrointestinal symptoms through cannabinoid pathways as well.
Because there are cannabinoid receptors on immune cells and lymphatic tissue, some of the anti-inflammatory effects of marijuana and Salvia divinorum may be via binding these receptors. Salvia divinorum has been found to have modulating effects on activated macrophages, for example.

Scopalamine – Scopalamine is a tropane alkaloid found in many nightshades family members such as Atropa belladonna, Hyoscyamus, and Datura. Isolated scopolamine has been used for decades as a topical patch to prevent acute motion sickness is susceptible individuals. Recent research looked at Scopolamine using a therapy termed scopolamine detoxification technique (SDT) compared to methadone for acute heroin withdrawal symptoms. While all patients received methadone from 1 to 3 days, half were switched to SDT for the subsequent 3 days. SDT involves the IV administration of both scopolamine and chlorpromazine for 4 to 6 hours each day. Study participants reported their withdrawal symptoms on a daily basis. Urine samples were collected twice a week following discharge and a questionnaire to report reasons for relapse was collected following opiate positive urinalyses. Although groups did not differ on retention or the percentage of opioid-positive urine samples, the SDT group reported less heroin craving, depression, and anxiety compared with the methadone group. Datura leaves are an ingredient in the traditional Chineses Jitai formula discussed above.

Withania somnifera – Ashwaghanda or Indian Ginseng has been reported to mitigate the effects of morphine on the CNS and is thereby considered a possible tool in the treatment of opiate addiction. Withania has effects on GABA receptors (γ-aminobutyric acid) and may also have weak binding at µ-opioid receptors.
Withania has also had numerous studies showing the ability to support protection and regeneration of neurons in various disease and inflammatory models over recent decades. Withania has been shown to reduce heroin withdrawal symptoms if given chronically prior to withdrawal, but not to ease the symptoms when given upon initial abstinence in animal models of heroin addiction and withdrawal. Further, long term ingestion of Withania has been shown to fully prevent the loss of dopaminergic density in the nucleus procumbens that typically happens upon opiate withdrawal. This suggest that pretreatment with Withania, prior to withdrawal has possible therapeutic benefits to heroin addicts.

FROM OPIUM TO MORPHINE TO HEROIN
The English physician Thomas Sydenham developed a remedy easier to administer than crude opium, with the advent of an opiate tincture called laudanum, in 1683. Laudanum became the leading pharmaceutical for pain for several hundred years . Paracelsus, however, used the term “laudanum” 150 years prior for his own opiate-based pain remedy, and chose the name from the Latin verb “laudare”, meaning to praise.
Morphine is said to be the first ever plant alkaloid to be purified and was isolated in 1804 by Friedrich Sertürner. He distributed the substance as an analgesic himself for a decade until it began to be produced and sold commercially by a small independent chemists’ apothecary that has since grown into the pharmaceutical giant Merck. The sale of Morphine became even more popular after the development of the hypodermic needle in 1857. Heroin was first synthesized from Morphine in 1874 and bought to market by Bayer in 1898. It became possible to synthesize morphine from petrochemicals in the 1950s.
Upon its initial discovery, morphine was thought helpful for opium addiction and alcoholism but was quickly realized to be more addictive than either opium or alcohol. Morphine was used widely during the American Civil Was and resulted in some 400,000 soldiers with morphine addiction. Thomas de Quincey published Confessions of an English Opium-Eater in 1821, inciting a national debate on opiate drugs.

PLANTS THAT CONTAIN OPIATES

OR OTHER MOLECULES THAT BIND OPIATE RECEPTORS
These botanicals that bind opiate receptors can help reduce opiate withdrawal symptoms, and can be part of long term maintenance protocols for heroin and prescription opiate addiction.

  • Actaea racemosa – Black Cohosh (formerly Cimicifuga racemosa) is a poppy family plant is commonly used as a nervine, hormone regulator in menopausal complaints, and for nervous and musculoskeletal hypersentivity in anxiety states and for fibromyalgia. Actaea extracts have been shown to bind mu opiate receptors and thereby affect hormones and nerve sensitivity.
  • Corydalyis species – A poppy family genus is discussed in detail in this document.
  • Eschscholtzia californica – The California Poppy is also discussed in detail in this document.
  • Maytenus rigida – the stem bark may bind opiate receptors and provide analgesia, based on the evidence that its effects are block by the opiate antagonist naloxone.
  • Mitrigyna speciosa – Kratom contains the opiate agonist mitragynine.
  • Papaver somniferum and other Papaver species
  • Parastrephia lepidophylla – An aster family plant from Chile is folkloric analgesic believed to have activity at opiate receptors.
  • Trifolium pratense – not commonly thought of by herbalists or naturopathic physicians as a nervine, sedative or source of opiate, but Trifolium indeed binds mu and delta opiate receptors, the mu receptors with a very high affinity. This may be another mechanism, besides the isoflavones whereby Trifolium helps control menopausal symptoms due the regulating effects opiate pathways have on temperature, mood, and hormones.

THE REWARD PATHWAY
The reward pathway is part of an ancient neurotransmitter system that encourages animals to seek food and enjoy sexual activity in manners that support the survival of an individual and the perpetuation of a species. Simply put, the reward system helps us to enjoy and seek out activities and experiences that are good for us. However, drugs of abuse offer a false reward – a fleeting euphoria that not only does nothing to enhance survival, challenges it. In fact, drugs’ effects on the reward system are so powerful that they are able to override other generally gratifying reinforcers: money, safety, loved ones, and morality. Even one’s survival becomes less important to the abuser than obtaining and using. Thus drugs offer a greater reward than the evolution of the reward system was intended to reinforce.
Dopamine is considered to be the primary neurotransmitter or the “reward pathway”, but because many other neurotransmitters and many drug of abuse affect dopamine via complex mechanisms, many other neurotransmitters and pathways are involved the brain’s reward system. Dopamine is inextricably intertwined with serotonin, GABA, and the opiates. Each of these neurotransmitters has its own personality and the combination, dominance, up and down regulation of each contributes to the personality, mood, and affect of an individual. Agents that bind dopamine and promote “normal” levels of dopamine have been shown to decrease the consumption of alcohol and possibly other drugs of abuse, by limiting the euphoria produced by the excessive release of dopamine obtained from such drugs. Stimulants such as cocaine, amphetamines, caffeine and nicotine all stimulate the brain reward pathway via various mechanisms and promote dopamine to varying degrees.
Serotonin plays a role in person’s motivation to work and the amount of energy one is willing to spend to obtain a reward, or in the case of addictions, a drug. Serotonergic pathways innervate the nucleus accumbens where it helps regulate dopamine release.
GABA also helps regulate dopamine and plays a role in drug addiction cycles. GABA is a primary inhibitory neurotransmitter distributed throughout the brain. Drugs of abuse cripple GABAnergic pathways by hyperpolarizing them and reduce or inhibit altogether their ability to fire. Dopamine is not inhibited when GABAnergic neuron are disabled in this way, and excessive levels of dopamine ramp up the reward system and the associated feelings of euphoria and sedation.
Opiates inhibit GABA thereby having a stimulatory effect, or said in another way, block the inhibitory effect of GABA. Dopamine fires more rapidly under the influence of opiates. Opiates are therefore said to be a second important neurotransmitter of the reward system.  Epinephrine and amphetamines also promote dopamine by increasing neuronal release and inhibiting synaptic uptake. Via its own mechanism on adenosine, the amphetamine-like stimulant caffeine also promotes dopamine.  Acetylcholine promotes dopaminergic activity downstream at post-synaptic neuronal sites. Nicotine and nicotinic agents act in this way and therefore activates reward pathways.



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