Withdrawal from Benzodiazepines and SSRIs

Paul L. Reller L.Ac. / Last Updated: August 03, 2017

Benzo withdrawal and withdrawal syndromes from SSRIs and SSNRIs have become a widespread problem in our population. The marketing of these anti-anxiety and anti-depressant medications resulted in an apparent belief that the standard differential diagnosis and application of specific treatments to correct the causes of anxiety and depression could now be ignored by prescribing a class of drugs that would alter neurotransmitter metabolism and relieve symptoms, regardless of the underlying cause. Overprescription and ignoring of warnings of drug dependence and withdrawal problems became the norm. Consequently, a large number of patients were prescribed medications that were of limited or short term benefit, and many patients decided that the adverse effects outweighed the benefits, opting to stop the medications. They also realized that their actual medical problem had not been corrected and that very significant problems of additive anxiety and depression now resulted from the discontinuation of these drugs. The withdrawal and rebound symptoms often became alarming, with both psychological and physical symptoms that were unexpectedly harsh. In essence, the manufacturers of these drugs had once again succeeded, as they did in the past with the drug Valium, a 'classic' benzodiazepine derivative, in creating drugs of addiction. While we are led to believe that benzodiazapine dependence and withdrawal syndromes are a relatively recent phenomenon, studies have warned of this problem for decades. A 1991 study at St. George's Hospital Medical School, at the University of London in the UK found that intensive treatment for benzodiazepine withdrawal was common and problematic, with just 38 percent of patients describing a "good" outcome at 6 months, and problems with withdrawal, including suicide, were common, especially in older patients, leading these psychiatrists to recommend in 1991 that maintaining the benzodiazepine treatment at a lower dose may be preferable to discontinuation, and that benzodiazepine withdrawal appeared to cause depression (PMID: 1675899). In the 25 years since this study, there has been an explosive growth in the prescription of these drugs, and still no clear guidelines for treatment of drug dependence, adverse effects, withdrawal syndromes, or post-withdrawal syndromes. This is clearly unacceptable, yet it is widely accepted in standard medicine.

Benzodiazepines are a class of drugs that include lorazepam (Ativan), clonazepam (Paxam), flurazapam (Dalmane), alprazolam (Xanax), nitrazepam (Insoma). SSRIs and SSNRIs are a class of selective serotonin and norepinephrine reuptake inhibitors that include fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft) and citalopram (Celexa), as well as duloxetine (Cymbalta), venlafaxine (Effexor), escitalopram (Lexapro) and others. With the now widespread use of atypical antipsychotics, often for off-label purposes (not FDA approved), or added to an SSNRI protocol when the depression and anxiety mood disorder is no longer well controlled, a growing concern over withdrawal and rebound syndromes with these drugs is occurring as well. The often alarming adverse effects of atypical antipsychotics have led to switching drug therapy or discontinuing the drugs in many cases, further complicating the pattern and incidence of withdrawal and rebound syndromes. The prescription of additive combinations combining benzodiazepines, antidepressants and antipsychotic drugs has also heavily marketed and prevalent, and numerous studies now show that the adverse health effects from this practice is quite alarming. This tactic of adding prescriptions is marketed under the logic that these drugs are just not working over time for most patients, so we just need to add drugs to the mix to achieve better results. If the drugs are not working well to control the symptoms of anxiety, depression, anxiety combined with depression (bipolar mood disorders), or other psychological disease, we may need to look to integration of a different strategy, though, not just increased blocking of neurotransmitter expression and neurotransmitter receptors.

It may be time to integrate a more conservative and restorative treatment protocol to correct the multifactorial pathologies of anxiety and depression, rather than a strategy to just add more drugs to a cocktail or switch prescriptions to a drug in the same class of drugs. First trying a protocol with less risk of adverse effects and rebound withdrawal for patients whenever possible, with a more holistic approach, integrating specialties, may be more work than just taking a pill or pills, but may also result in the resolution of underlying factors that create these symptoms and syndromes and stop the chronic drug dependency. Complementary and Integrative Medicine and Traditional Chinese Medicine (CIM/TCM) offers an array of treatment protocols that are supported by an increasing body of evidence and may be individualized to meet the needs and desires of each patient, and short courses of treatment with TCM physicians and Cognitive and Behavioral Therapists, along with more prolonged and persistent use of herbal and nutrient medicine and improved cognitive and behavioral habits, will result in healthier outcomes and less need to worry about problematic rebound withdrawal syndromes and adverse health effects.

Atypical antipsychotics are a class of drugs that include olanzapine (Zyprexa), quetiapine (Seroquel), aripiprazole (Abilify), clozapine (Clozaril), risperidine (Risperdal), ziprasidone (Geodon), olanzapine/fluoxetine (Symbyax), and are approved for some types of bipolar depression, schizophrenia, psychotic agitation and mania, and generally block dopamine pathways and receptors, but the exact mechanisms of action are still unknown and vary greatly from drug to drug. These atypical variants of antipsychotic medications were designed to decrease the severe extrapyramidal effects of the first generation antipsychotics, but now are well known to cause metabolic dysfunction over time in many cases, with onset of diabetes, obesity, and decreased insulin sensitivity, as well as cognitive decline, and kidney dysfunction. By 2012, these atypical antipsychotics became one of the most widely prescribed drugs in the United States, prescribed 54 million times in 2011, largely driven by advertising. Numerous large studies, such as the landmark Catie trial, showed that this new class of antipsychotics did not work better than the older class of the drug, or have fewer adverse effects overall, despite a market-driven belief. Incidence of movement disorders, such as tardive dyskinesia, which is implicated in the rising incidence of nocturnal bruxism and restless leg syndrome, are well known side effects of these drugs, and have increased in the population.

By 2013, this large sudden increase in the prescription of atypical antipsychotic medications, and the habit of switching to another type of atypical antipsychotic medication when adverse effects were reported, finally emerged as a significant health problem with many patients experiencing a rebound addiction syndrome. Experts at the Ludwig Maximillian University School of Medicine, in Munich, Germany, outlined the emerging problems in 2013, noting that this class of drugs varied substantially in biochemical effects, and that frequent switching to avoid adverse effects was resulting in substantial reports of withdrawal and rebound syndromes. These drugs all block dopamine type 2 receptors, and most block serotonin 5HT2A receptors, but a wide array of blocking effects on neurochemical receptors of dopamine, serotonin, adrenalin, histamine, muscarine, and other chemical mediators make them unpredictable. These experts acknowledged that in 2013 there were very few studies evaluating these withdrawal and rebound syndromes, and potential remedies (PMID: 23821039). Researchers in 2011, at the University Medical Center Utrecht, The Netherlands, noted that studies showed a neurodegenerative state with decreases in volume of certain key centers of the brain after withdrawal of atypical antipsychotics (PMID: 21346618).

A sensible individualized approach to withdrawal syndromes from benzodiazpines, antidepressants and antipsychotic medications must be found, and must address the broad spectrum of manifestations and types of symptom syndromes. A gradual restoration of homeostatic balance between neurotransmitters and their receptor types may be needed in many cases, and so a pragmatic persistence is needed, gradually reducing the drugs and dosage, and integrating an array of Complementary protocols to achieve a step-by-step process of restoration. For some patients, a very low dose of the drugs may be desirable for some time, but a continuing process of restoration of neurohormonal function, with a holistic perspective, is needed. Decades of avoidance of this integrative approach with safe and proven therapies in CIM/TCM has resulted in an expensive failure in the realm of treatment for these withdrawal syndromes, compounded by much misinformation regarding the proper protocol in Complementary and Integrative Medicine (CIM). For many patients, a more complex and holistic step-by-step approach is needed, with the intelligent combination of safe and effective therapeutic tools. If the resolution to the withdrawal and rebound syndrome is relatively quick, this is great, but for many patients it is not, and there is no magic simple cure.

Restoration of healthy function and balance in these syndromes must involve both persistent bioavailability of neurotransmitters and precursors, as well as stimulation to achieve restoration of growth and function in the brain, and achieve a balanced homeostatic expresson of receptor types for these neurotransmitters, while also providing some relief from symptoms that these atypical antipsychotics may have decreased. Of course, this is a complex treatment protocol that will have some flux of symptoms during the course. Nevertheless, the research that we have clearly shows that this holistic approach is needed to recover, and that the treatment may need to persist for some patients. The psychological state and the nature of the withdrawal and rebound syndromes present great feelings of uncertainty and mood difficulty for these patients, making this treatment even more difficult, but a sensible patient will try to be objective, overcome subjective and emotional responses, and simply decide to do what is objectively the right thing in choosing this protocol of recovery. The first step is to objectively understand the basic pathophysiology to get a sense of what needs to be accomplished.

In 2015, concerned that patients still were not being advised by prescribing doctors of the findings of widespread problems with dependency and withdrawal of benzodiazepines, antipsychotics, and anti-depressant medications, a number of studies investigated the actual extent of these problems. For instance, in 2015, a study by pharmacists in Piscina Manna, Italy was published in the International Journal of Clinical Pharmacology which evaluated the prescription of benzodiazepines for insomnia in 8 community pharmacies after the 2012 updated Beers Criteria recommended that benzodiazepine use in the elderly often involved more risk than benefit, and should be curtailed. This study interviewed 181 participants, with 62 percent being in the older age bracket, finding that about half were prescribed benzodiazepines for insomnia, with 64 percent of these patients prescribed benzodiazepines for more than 3 years. Of these 52 patients prescribed benzos for insomnia with long-term use, 33 patients were in favor of discontinuation of the drug, and had tried unsuccessfully to stop. The incidence of dependency and withdrawal problems was very high, yet still largely ignored by the standard medical community. These experts cited the "risk of tolerance to effects, dependence, and an increased risk of adverse events" with chronic use of benzodiazepines, especially in the older population, as significant reasons for a more rational evidence-based use of hypnotics and sedatives (PMID: 26198541). Clearly, patients need to be treated for the underlying causes of health problems such as insomnia and anxiety, these drugs should not be prescribed to as many patients as possible, and integration of a more holistic treatment protocol with Complementary and Integrative Medicine (CIM/TCM) should be provided to achieve the difficult task of discontinuation of the drugs, decrease in withdrawal and rebound symptoms, and even restorative medicine to help with the post-withdrawal syndromes that so many patients experience. As of 2015, there are no approved pharmacological therapies for benzodiazepine use disorder treatment, and optimal treatment strategies are still unclear.

By 2016, another emerging problem had become evident. A study at the Albert Einstein College of Medicine in New York, New York, U.S.A. headed by Dr. Marcus Bachhuber and printed in The American Journal of Public Health found that despite the risks and warnings of benzodiazepine dependence, withdrawal and rebound syndromes, and adverse health effects with chronic use, that prescriptions for these drugs rose 67 percent between 1996 and 2013, and that the rate of overdose deaths with benzodiazepines rose more than fourfold, to 3.07 per 100,000 adults in 2013. The rate of overdose deaths from opioid pain medications, considered an epidemic now, was 6.8 per 100,000 for non-Hispanic white persons, and for Black and Hispanic individuals in the United States was now 2.5 per 100,000. The U.S. Centers for Disease Control and Prevention reported that in 2014, 44 people die of the result of prescription opioid overdose every day. The present statistics for such cause of death from the many now addicted to benzodiazepines is thus about 20 people per day, yet this statistic is largely ignored. Medical Doctors and patients continue to take benzodiazepines for anxiety and sleep without thought of the consequences. To see this study of benzodiazepine overdose deaths, click here: http://www.einstein.yu.edu/news/releases/1155/overdose-deaths-from-common-sedatives-have-surged-new-study-finds/ . To see the report in comparison of opioid medication overdose deaths from the U.S. CDC, click here: http://www.cdc.gov/drugoverdose/data/overdose.html . The time has come to start using Complementary and Integrative Medicine and Traditional Chinese Medicine (CIM/TCM) to treat anxiety, insomnia and pain, resolving underlying health causes, and to decrease the enormous public health problems with these drugs.

The incidence of withdrawal syndromes associated with SSRI antidepressants is also not a recent medical concern. A 1996 article in the Journal of Clinical Psychopharmacology (Coupland et al) noted that a retrospective study of 352 patients treated for SSRI withdrawal experienced lowered mood (depressed affect), lethargy, paresthesia, vivid dreams (insomnia), irritability, dizziness and nausea as the most common symptoms, and treatment averaged 28 weeks with some SSRI medications (e.g. paroxetine Paxil or fluvoxamine Sarafem). The majority of these cases occurred despite slow tapering of the drug. The symptoms of withdrawal were not relieved by prescribing benzodiazepines, although this was the common treatment for decades after this study, and still is. The role of serotonin in coordinating autonomic function and sensation with motor function was hypothesized as the focus of this withdrawal pathophysiology.

In order to resolve the problems with withdrawal syndrome from benzodiazepines and selective serotonin and norepinephrine reuptake inhibitors, as well as atypical antipsychotics, the patient needs to confront a number of issues. The first issue is to gain an understanding of the mechanisms of these drugs and how they create a chemical dependency. The second issue is how to alleviate the symptoms of the withdrawal by means of safe and benign treatment methods that achieve some of the same metabolic goals of the drugs themselves, while following a protocol of controlled and tapered withdrawal. Lastly, the patient must achieve a more sound diagnosis and understanding of the cause of their anxiety and depression so that these underlying causes may be resolved. Complementary Medicine must play a significant role in this process. Whether prescribing Medical Doctors will someday realize the need to fully integrate with the Complementary Physician, working together to achieve a smooth transition with tapering drug dosages is the question. More and more patients are asking for this help and cooperation, and many are now desperate.

The reasons behind discontinuation of these drugs include not only the obvious side effects of chronic use and the failure in many cases to achieve the medical goals, especially as the patient's body adapts to the drugs and the effect is decreased over time, but also the new body of research findings into the complexity of harm potentially caused by chronic use of these medications. This subject has been the focus of many medical doctors and researchers around the world as the clinical reports of health problems associated with the drugs' use have reached alarming levels, and reports concerning the alarming symptoms of withdrawal of the drugs poses extreme challenges to the medical system. In addition, many cases of temporary mood and emotional disorder, normally requiring psychological counseling rather than drug dependency, were instead treated with these drugs that resulted in chemical dependency. In 2015, a multicenter study of benzodiazepine dependence and difficulty with discontinuation, by experts at the Columbia University Medical Center, in New York, New York, U.S.A. and the Psychiatric University Hospital, in Zurich, Switzerland, found that the reasons cited for patient decisions to discontinue the drugs included health concerns, feelings of addiction, and social concerns with adverse effects on mood and behavior. These psychiatrists found that discontinuation attempts were frequent in the studied population, and not very successful, often with a fast relapse of the symptoms for which the drugs were prescribed, and that these patients clearly preferred a gradual reduction of the drug to a more abrupt discontinuation. No specific types of benzodiazepines presented preferences for treatment of withdrawal difficulty, indicating that all type of benzodiazepines presented equivalent problems (PMID: 25968120).

A large number of patients experience a varied degree of severity in syndromes associated with use of hypnotic benzodiazepines, SSRI and SSNRI medications of anxiety and depression, and atypical antipsychotics, and many of these patients find that they now have a chemical dependency as well. Much research has been devoted to this complex subject, and presents a wealth of usable information, which is often overwhelming for patients with chronic and sometimes debilitating anxiety mood disorders, severe insomnia, and neurohormonal dysfunction. While standard medicine still just prescribes more drugs to treat these disorders related to the adverse effects and withdrawal syndromes caused by these drugs, many experts have shown that a persistent step-by-step protocol with cognitive and behavioral sleep hygiene and addiction modifications are most successful in this treatment, and usually results in the cessation of drug use and dependency. The integration of Complementary Medicine into such a multidisciplinary approach presents an array of advantages, many of which are now proven in both laboratory and human clinical studies to work. While this treatment protocol seems complicated and daunting, and is often not readily available in standard medicine, more and more intelligent patients are understanding that utilization of these resources need not be costly and overwhelming if a proactive approach is taken. The first step in managing your syndrome of benzodiazepine, SSRI/SSNRI, and/or atypical antipsychotic drug dependency and achieving of withdrawal and restoration of neurohormonal homeostasis is to gain a better understanding of your problem. Utilization of a knowledgeable Licensed Acupuncturist and herbalist in this protocol could be the key to success.

History and science of withdrawal physiology and pharmakodynamics of benzodiazepines and selective serotonin reuptake inhibitors (SSRIs)

Benzodiazepines were perhaps the most widely prescribed drugs in therapeutic use during the 1990s, able to calm anxiety, produce sedative and hypnotic effects, relax muscle firing, and calm convulsion. When problems became apparent with adverse effects, chemical dependency (addiction), and withdrawal syndrome became evident with such widespread prescription, the practice of prescribing benzodiazepines so readily, and for long periods of time, was discouraged. Benzodiazepines, as well as barbituates, potentiate gamma-aminobutyric acid (GABA) receptors thought to be located near glutamate receptors in the brain. GABA is the chief known inhibitory neurotransmitter in our central nervous system, which is made up of the brain, brainstem and spinal cord. GABA is active at 20-40% of all neuronal synapses, and is active in many other functions in the brain beside neuroinhibition. GABA is an excitatory neurotransmitter as well, and is also directly responsible for regulation of muscle tone. Benzodiazepine receptors are allosteric (activating protein enzyme function) modulatory sites on GABA type A (GABAA) receptors, affected by a number of pharmaceutical drugs, as well as naturally occurring chemicals, and ethanol (alcohol). The various chemical binding sites on the GABA type A benzodiazepine receptor interact with each other in a complicated manner, enhancing or reducing this GABA neurotransmission, making it clear to experts that the GABA type A benzodiazepine receptor is a highly regulated and complex structure on brain cell membranes.

GABA works by binding to neuroreceptors and opening ion, or charged molecule, channels to trigger neural firing, or by releasing G-proteins to affect the ion channels. The inhibitory or excitatory action of GABA depends on a number of factors, especially the magnitude of the ionic current, or levels of potassium and chloride in or outside of the cells, and whether the neurological cell is receiving a signal or giving off a signal (afferent or efferent). In a child, GABA predominantly plays an excitatory role, whereas in the adult, the predominant role in the brain is inhibitory. This is important as we examine the prescription of benzodiazepines to children. It is also important as we look at the development of glutamate metabolism in the adult brain and its role in regulating our mood and mood swings. The action of benzodiazepines, and other chemicals that affect the benzodiazepine receptors, increases sensitivity of the receptor to GABA, and often results in a decrease in circulating GABA. Benzodiazepines also increase the frequency of opening of chloride ion channels, and their activity of inhibition on the cell firing in key areas of the brain, such as the hippocampus. The wrong dosage of benzodiazepine, interaction with other drugs that affect the GABA type A receptor, accumulative concentration of benzodiazepine, changes in sensitivity to the benzodiazepine, and/or changes in the expression of GABA receptors types, may create adverse effects. Since GABA receptors are potentially affected by a wide range of chemicals, various neurohormonal imbalances may also have an adverse effect on benzodiazepine action. Metabolites of pregnenolone and corticosterone are known to have modulatory effects at GABA type A receptors, and use of a bioidentical pregnenolone cream, as well as therapy to treat adrenal health with Complementary Medicine may be effective in the therapeutic protocol.

GABA plays a significant role in other important aspects of our neurological health other than regulation of mood and inhibition of anxiety. GABA regulates the health and growth of our central nervous system, controlling the proliferation of new neural progenitor cells, neural stem cells, differentiation and migration of neurites, or connecting axons and dendrites, and the formation of synapses. Benzodiazepines are thought to work by potentiating the chloride ion channels and stimulating mainly inhibitory actions, rather than the potassium ion channels. There are 3 known types of GABA receptor, and GABA receptors type A and B may be manipulated by benzodiazepines, while type C may not be affected. GABA type A receptors resemble receptors for acetylcholine and 5HTP (5HT3) in protein structure, and affect chloride ion channels in the neuron membrane, while GABA type B receptors resemble glutamate receptors in protein structure and affect calcium and potassium ion channels. We see that benzodiazepines predominantly affect GABA type A receptors, but that the system has a number of ways to achieve affects with GABA, and that chronic use of benzodiazepines may change this mix of neurotransmitter effects by overstimulating one type of GABA receptor and thus decrease the need for GABA in circulation.

Simply replacing GABA as one discontinues the benzodiazepine may not have enough effect to correct this complex system of regulation, and a more holistic approach to restoration of function needs to be considered. This means that we may need to provide bioavailability of precursor chemicals, improve cell membrane health, and stimulate new and healthy neuron growth to repair the system. GABA type A receptors may also be modulated by steroid hormones, and hormonal imbalance may play a role in symptoms associated with this GABA dysfunction, or the difficulties in reestablishing a normal GABA homeostasis after discontinuing benzodiazepines. Various hormones in the brain may be reduced with 3-alpha reductase and form metabolites that are shown to enhance GABA at GABA type A receptors and exert anxiolytic effects. GABA type B receptors produce a slow and steady inhibition at the neuron, and may need to be encouraged during the benzo withdrawal, perhaps with supplementation with the mineral ions calcium and potassium, in the form of Calcium AEP and a Magnesium and Potassium aspartate supplement. Studies have shown that specific acupuncture stimulation may also provide a modulating and selective balancing effect on the GABA type A and B receptors, contributing to the gradual restoration of balance of receptor expression. Treatment that addresses adrenal and hormonal health, mineral balance and sufficiency, and kidney health may play an important role in recovering from chronic benzodiazepine use.

Benzodiazepines have negative consequences for a number of reasons. Studies show that benzodiazepines produce significant immediate decreases in circulating plasma GABA levels in anxiety disorder patients, but increased cerebral spinal fluid levels of GABA in neurologically ill patients undergoing a spinal tap. This was an indication to researchers that benzodiazepines have varied effects on various types of patients, and could explain why some patients are affected to a greater extent by benzo withdrawal syndrome. Benzodiazepine effects in the central nervous system have been shown to be greater in patients that do not suffer from the deficiency of the glutamate decarboxylase enzyme that is perhaps a genetic trait, and prescription of benzodiazepines to a patient without a true panic disorder problem could result in a greater rebound effect when the patient tries to stop taking the drug. All of these aspects of the benzodiazepine and benzodiazepine receptor functions make the subject of treatment of benzodiazepine withdrawal syndrome difficult.

The effects of benzodiazepines are broader than the complex GABA system, though. A 1993 study at the Emory University School of Medicine, in Atlanta, Georgia, noted that chronic use of benzodiazepines resulted in significant decrease in corticotropin-releasing factor (CRF) in the hypothalamus-pituitary, which is responsible for integration of the endocrine, autonomic and behavioral responses to stress. Suppression of this neuroendocrine system appeared to be the action by which the benzodiazepines worked. Abrupt withdrawal of the benzodiazepine resulted in an immediate increase of CRF, as well as increased ACTH (adrenal corticotropic hormone) and corticosterone (cortisol) concentrations, but decreased concentration of CRF in the receptors of the anterior pituitary, "profoundly activating the hypothalamus-pituitary axis". These experts noted that "these actions of alprazolam (benzodiazapine) on CRF neurons are opposite to those observed following acute or chronic stress" (PMID: 8145178). In other words, benzodiazepines suppress the adrenal responses and the hypothalamus-adrenal axis, which would have broad implications for the autonomic and hormonal systems in the body beyond simple decrease in the level of anxiety.

Since this complex system is a feedback system, altering it would present obvious problems when the body tries to adapt to sudden changes in drug withdrawal. Obviously, adrenal support and restorative balance of the autonomic responses and hormonal health may be needed during the withdrawal of benzodiazepines. A followup study of these effects by the Emory University School of Medicine, in 2004, noted that abundant research now identifies CRF of the hypothalamic-pituitary neurohormonal system as a key factor in the normal stress response, and hyperactivity of the CRF receptors in the pathophysiology of depression and anxiety. Chronic use of benzodiazepines was shown to reduce CRF and CRF receptor type 1 function, while increasing CRF receptor type 2 function. Spontaneous withdrawal of the benzodiazepine resulted in marked activation of the hypothalamus-adrenal axis, accounting for some of the sensations of alarm seen in withdrawal. More importantly, though, this study showed that CRF mRNA expression was increased in the cerebral cortex over 300 percent during withdrawal! The researchers concluded: "The marked increase in CRFergic neurotransmission is hypothesized to play a major role in benzodiazepine withdrawal" (PMID: 15496666). Study in 2000 at the Emory University School of Medicine showed that chronic use of benzodiazepines markedly decreased not only hypothalamus-adrenal activity, but also CRF mRNA expression in the amygdala, and CRF receptor type 1 function in the amygdala (PMID: 10648728). It appears that the chemical suppression from benzodiazepines is broad, and when this suppression is take away, one can imagine the responses. Obviously, a broad restorative treatment is needed to regain CNS function and control of stress response, mood, and autonomic responses. The use of Gabapentin and anti-psychotic medications is absurd. Research has shown the potential for specific acupuncture and electroacupuncture stimulation to modulate amygdala function and connectivity, as well as the CRF receptor balance, and a holistic treatment protocol that includes herbal and nutrient medicine as well will help restore the adrenal axis and healthy CNS function. A number of scientific studies of proof of these effects are cited below in Additional Information.

The imbalance over time of the expression of GABA receptor types and CRF receptor types appears to be the biggest hurdle in regaining a healthy homeostatic function, and may take a gradual persistent step-by-step to reverse and restore. This may carry over to the gastrointestinal tract as well, as both GABA and CRF have been shown to regulate the GI function, and imbalances in receptor types may affect not only the brain, but the GI tract regulation, and the effects of benzodiazepines are not confined to the brain. One only needs to look at the most common side effects of many psych drugs to see that they affect the GI tract. A study in 2015, at the Asahikawa Medical University Medical School, in Midorigaoka Higashi, Japan, found that Irritable Bowel Syndrome (IBS), which has increased in incidence greatly in the last decades, is partially caused by the imbalance of signaling between the CRF receptor types 1 and 2, which need to exert a balanced response to stress. If the CRF signaling balance is abnormally shifted to the CRF1 responses, enhanced visceral sensitization and colonic motility results (PMID: 25962711). It is clear to IBS patients that stress flares symptoms in IBS, but what is not clear for many of these patients, who have an anxiety mood or sleep disorder, is that chronic use of benzodiazepines may be worsening their condition.

Other common side effects of benzodiazepines include dryness of the mouth and membranes, and constipation, as well as increased mouth and bronchial secretions and diarrhea, implying problems with autonomic regulation in the body. Loss of libido and erectile dysfunction, visual changes, nagging nausea, and problems with urination also imply a negative effect on the autonomic nervous system. Psychological effects include a false sense of well-being, unusual tiredness, anxiety and confusion, irritability, as well as memory problems and mental depression, which were reported with some frequency. In a small percentage of patients, abnormal thoughts, confusion, delusion and a loss of a sense of reality were reported, as well as paresthesias and tremors. Clinically, these symptoms were often reported by the patients that sought to stop taking the drugs but found that the withdrawal syndrome, which includes acutely rising blood pressure and a sense of profound panic and autonomic disorder, prevented them from stopping the drug regimen. A 2015 randomized controlled clinical study at the University of Aix-Marseille and Montpelier University, in France, showed that these adverse effects on cognitive function were measurable even in patients who took lorazepam prior to surgery to calm anxiety, with adverse effects on cognitive recovery significantly worse than the placebo and no premedication groups (PMID: 2574733).

In the study of pharmacology in medical schools, benzodiazepines present some of the greatest warnings concerning side effects. Extra-pyramidal side effect symptoms of are particular concern. The extrapyramidal system in the brain is a neural network that includes much of the brainstem, the pons and medulla, as well as key areas of the cerebellum, the basal ganglia, cerebral cortex, vestibular nuclei and substantium nigrum, all of which act together to control our movement and muscle control. Extrapyramidal symptoms include movement disorders (akathisia), such as facial twitch, tremor, restless leg movements, and muscle spasms, as well as psychological disorder, and were first noticed when drugs that reduced dopamine in the brain were used widely, such as tricyclic antidepressants. Parkinsons-like syndromes may also be induced by drugs with extrapyramidal side effects. What is confusing is that benzodiazepines are actually prescribed to treat some types of extrapyramidal side effects, and often do show efficacy.

Standard Treatment for Benzodiazepine and SSRI Withdrawal Uses Antipsychotic Drugs that are also proving to have rebound, addicting and withdrawal effects, as well as negative long-term adverse effects

Although modern medicine is loathe to fully acknowledge the extent of benzodiazepine withdrawal syndromes, there are clinics specializing in this therapy around the world today. Of course, a typical cure for a drug withdrawal syndrome is another drug, as exemplified by the use of a synthetic narcotic, methodone, to treat narcotic addiction and withdrawal, which has now become a popular drug of abusers and presents a syndrome of addiction and withdrawal itself. With benzodiazepine withdrawal, Pregabalin (Lyrica) is popularly prescribed, which is an anti-seizure medication found useful for neuropathic pain in seizure disorders, but is now marketed also as an adjunct therapy in generalized anxiety disorder, fibromyalgia, and more difficult depression and anxiety disorders not well controlled with standard medication. Lyrica, or pregabalin, is structurally and pharmacologically related to its predecessor, Neurontin, or gabapentin, which presents alarming neurological side effects for a high percentage of patients. Unfortunately, the widespread prescription of Lyrica has now generated considerable clinical concern that this drug too is addictive with chronic use, and that sensations of both euphoria and CNS depression have prompted abuse, with multiple prescriptions sought, and increased dosage. Lyrica is one of the 4 drugs cited by the U.S. FDA that was illegally marketed by a subsidiary of Pfizer, Pharmacia and Upjohn, in 2009, resulting in a settlement to avoid prosecution of $2.3 billion (yes, billion) for "intent to defraud or mislead". Lyrica is also categorized as a Schedule 5 drug and CNS depressant, with concern that it is sold as a street drug, and like benzodiazepines, ground into powder and combined with other CNS drugs to achieve a euphoric high. Pregabalin acts like a benzodiazepine, binding to calcium channels on neuron cells, decreasing glutamate and norepinephrine (adrenalin), but does not bind to GABA receptors. Side effect of pregabalin, or Lyrica, that occur in more than 10 percent of patients in clinical trials, include drowsiness, dizziness and CNS depression, and in just under 10 percent of patients reportedly at the normal dose, euphoria, increased appetite, confusion, fatigue, asthenia, vivid dreams, changes in libido, attention changes, memory impairment, drunkeness, and weight gain.

With these negative scientific findings and warnings concerning pregabalin, or Lyrica, including the 2006 findings of a Stanford University study (Micheva et al; PMID: 16641316), that pregabalin action depends on NMDA glutamate receptor activation, reduces the activity of synaptic vesicles from hippocampal neurons, and may impede synaptic function, many prescribing medical doctors returned to the prescription of its predecessor Neurontin, or gabapentin, to treat withdrawal from benzodiazepines. Once again, using a problematic drug to treat withdrawal from another problematic drug is somewhat of a last resort, and does not seem like a protocol to restore normal brain function. Since pregabalin and gabapentin are almost the same drug, structurally and in pharmacological effects, this choice between Lyrica and Neurontin may seem like a significant choice to the patient, but in reality does not present a significant change in treatment protocol. Research at Stanford University (Ben Barnes, Cagla Eroglu et al; Cell Oct.8, 2009) found that a major mechanism of gabapentin, or Neurontin, involves the binding to a neuron receptor A2D1, inhibiting the receptor, and inhibiting the chemical thrombosponin from binding, which is used to stimulate new synapse formations in the brain. By inhibiting new synapse formation, gabapentin impedes pain signals, and excess neural activity, as in seizure disorders involving excess synaptic connections, but also inhibits neural adaptation, and regrowth in neurodegeneration. Prior to this study, the mechanisms of Neurontin eluded understanding.

FDA warnings concerning Gabapentin involve negative mood, cognitive, and behavioral changes, and multiorgan hypersensitivity, as well as problems with abrupt withdrawal. The most common side effects in clinical trials were somnolence, dizziness, and peripheral edema, and adverse events that prompted discontinuation of the drug during clinical trials included abnormal thinking, memory impairment, diminished physical sensation, incoordination, ataxia, and impaired vision. A frequent clinical complaint with the use of Neurontin or Lyrica in benzodiazepine withdrawal is that it seemed to cause some of the same alarming neurological problems that the benzodiazepine withdrawal syndrome caused. Since the action of Lyrica depends upon NMDA receptor activation, depressed glutamate activity, associated with benzodiazepine use, may also inhibit its aid to decrease anxiety. Agonists of NMDA receptors include glutamate, aspartate, L-phenylalanine, and quinolinic acid (a metabolite of tryptophan). Mood support nutrient medicines include the precursors to glutamate (L-glutamine, P5P, and inositol hexacotinate), magnesium and potassium aspartate, L-phenylalanine, and L-tryptophan. It may be healthier to first try these nutrient medicines, and benzodiazepine-like and anxiolytic herbal chemicals, than to take another problematic drug with cognitive, behavioral and mood altering adverse effects that comes with a warning about problems with abrupt withdrawal as well. While Gabapentin came to mind for prescribing doctors treating a GABA dysfunction, there is no actual proof that Neurontin potentiates GABA, despite its name.

SSRI (selective serotonin reuptake inhibitors), and the more complex SSNRI (selective serotonin and norepinephrine (adrenalin) reuptake inhibitors), have also been shown to produce withdrawal and rebound syndromes with chronic use that are quite alarming to many patients, and thus create a chemical dependency. The exact mechanisms of these withdrawal symptoms, which include anxiety, agitation, aggression (mania), decreased concentration and memory, confusion, lowered mood, depersonalization, light-headedness, loss of appetite, nausea, fatigue, lethargy, malaise, heart palpitations, headache, insomnia, vivid dreams, and even sometimes parasthesia (numbness and tingling), dysesthesia (pins and needles sensation), and tremor, remain unclear, despite much study and investigation. A number of books have been published on the subject of SSRI withdrawal and dependency, and a widespread knowledge of the importance of slowly tapering from these drugs is apparent. Nevertheless, SSRI and SSNRI medications are still routinely prescribed with little workup of the individual, or discussion of these potential adverse effects, by medical doctors outside of the specialty of psychiatry. The incidence of withdrawal symptoms in a number of studies was estimated at between 28 to 50 percent of patients, depending on the type of SSRI. The array of symptoms from withdrawal of the drug implies that a number of mechanisms exist for SSRI withdrawal syndrome, including upregulation of the effects of the neurotransmitter acetylcholine due to the anticholinergic effects of SSRIs and subsequent increase in cholinergic stimulation when the drug is withdrawn, the obvious decline in serotonergic transmission when reuptake is withdrawn, believed to be caused by desensitization of the 5HT receptors, and affects on the serotonin/dopamine balance, and the effects on the number of serotonin, or 5HT, receptors expressed when chronic use of a selective serotonin reuptake inhibitor is used. Rates of elimination of the drug from the body, which vary from 21 hours to several days, or more, and the effects of liver function on these rates of elimination, also play a role on the severity of the withdrawal symptoms.

Patients most susceptible to SSRI withdrawal syndromes are those with anxiety and panic disorders, those patients prescribed a higher dosage, and those patients taking the SSRI for longer periods of time. Also, studies have indicated that at least 10 percent of patients prescribed SSRI medications may be slow metabolizers due to decreased liver function, liver stress, or concurrent prescription of other medications that utilize the P450 CYP2D6 liver enzymatic pathway to break down the drug (this occurs more often than one would expect, since pharmacological guidelines warn against such drug contraindications). The many common medications that use the CYP2D6 catabolic liver pathway include all tricyclic antidepressants, opioid pain medications, antipsychotics, beta-blockers, antiarrhythmics, stimulants such as ADHD drugs, antihistamines, and some antifungals. These contraindications are largely ignored in prescription. Obviously, many patients with anxiety and panic disorders are prescribed both the SSRI and benzodiazepine medications as well, despite the increased potential of difficult withdrawal syndromes. Since patients with depression, anxiety, and chemical dependency proclivities often utilize other drugs and alcohol to stimulate the feelings of reward and well-being as well, many patients that are prescribed SSRI medication also use addictive drugs and alcohol as well, which eventually complicates the brain systems involved in addiction and withdrawal. All of these factors make the treatment of SSRI, SSNRI, and benzodiazepine withdrawal complex, and patients need to accept that knowledgeable guidance, sometimes by more than one type of physician, may be needed, as well as patience, perseverance, and understanding of the need for an intelligent step-by-step process in withdrawal. Attempts at making the withdrawal overly simplified often results in a chronic state of withdrawal symptoms occurring, and this syndrome may take on a life of its own and present even more complexities in the health imbalances. It may be advisable for patients wanting to discontinue these drugs to seek intelligent guidance sooner rather than later, and integrating a knowledgeable Complementary Medicine physician into this treatment plan, such as an experienced Licensed Acupuncturist and herbalist, may be very important.

Atypical antipsychotic prescription tripled from 1995 to 2006, and off-label prescribing, for conditions not approved by the U.S. FDA, more than doubled, reaching an estimated 9 million prescriptions in 2008 in the United States. This was largely driven by advertising and promotion, with at least 20 variant drugs with such appealing names as Abilify, Seroquel and Zyprexa, and some names that were easily confused with other drugs in the class of SSRI and SSNRI antidepressants and benzodiazepines. Enormous promotion of these drugs to medical doctors in the form of large free samples, expensive restaurant promotions, promotional office gifts, and paid consulting fees and educational seminars accompanied these television, print and internet advertisements. This has become somewhat of a scandal, and congressional investigations have resulted in enormous fines and settlements from drug companies and changes in the laws regarding marketing practices and declarations of income by medical doctors, researchers and heads of organizations that form treatment guidelines. Despite this now enormous controversy, there was little decrease in the number of prescriptions, or the easy acceptance by patients of these drugs in therapy.

While official guidelines and advertising of medications must adhere to official FDA approval guidelines, Medical Doctors are free to prescribe these medications for any purpose, and the intense marketing practices have of course increased this off-label prescriptions greatly, despite the alarming adverse effects, and now the increasing concern over complex withdrawal and rebound syndromes. The off-label prescription of atypical antipsychotics for anxiety and depressive mood disorders, neurodegenerative disorders, behavioral disorders, neuropathies, and other symptoms and syndromes is now common practice. Since there is so much variance in effects and individual reactions to these drugs, the prescription is often changed to achieve better results. Since the mechanism of action is still largely unknown in this class of drugs, and the chronic and acute adverse side effects are varied, and include such unexpected symptoms as weight gain, obesity, Metabolic Syndrome with insulin resistance, diabetes, sexual dysfunction, urinary difficulties, cognitive decline, cognitive changes, and even cardiovascular symptoms, the prescription may be changed multiple times. With a placebo effect, it may become difficult for the patient to distinguish the actual benefits of the drugs, and there is some concern that switching medications often temporarily provides a sense of improvement in the condition that is a placebo effect. Widespread prescription in nursing homes to control behavior has also been a concern, especially with proof of cognitive decline and increased incidence of falls and injuries associated with these drugs. While the withdrawal and rebound syndromes have not been studied as much as those of benzodiazepines, SSRI and SSNRI antidepressants, there is a growing chorus of concern in the medical community, especially in Europe.

Modern research and revelations about the mechanisms of depression and anxiety

The World Health Organization (WHO) now estimates that depression is one of, or perhaps the most prevalent health problems in the world today. In 2003, the WHO estimated that 1% of European GDP, or gross domestic product, was spent on treatment of depression and anxiety, and this number is rising. Clinical depression was estimated as affecting over 120 million people globally. In 2013, studies are finally being conducted to assess the current spending and efficacy of standard treatment, and it is expected that changes will be made in standard medical care. For many patients, anxiety is linked to an underlying health issue that is seldom explored by treating Medical Doctors, and may be resolved by treating the underlying health problem or problems. The Mayo Clinic lists these well known physical causes of anxiety mood disorders: withdrawal from benzodiazepines, drug abuse, alcohol withdrawal, thyroid problems (both subclinical and clinical, hypo and hyper), chronic muscle spasms or cramps, asthma, heart disease, diabetes, and tumors affecting the adrenal-pituitary-hypothalamus axis. Simply prescribing benzodiazepines and SSRI and SSNRI medications without assessing these potential underlying physical causes of anxiety has been a major mistake in modern medicine. Traditional Chinese Medicine, or Complementary Medicine, always looks for underlying causes of disease and disorder, and addresses these in a holistic treatment protocol.

A number of theories concerning the mechanisms of depression have emerged from scientific study. One is that the there is a reduced nerve cell volume in parts of the brain, especially the prefrontal cortex and hippocampus, that harms the ability to control mood and regulate GABA production. A 2007 fMRI study of monozygotic, or identical, twins, with high risk of for anxiety and depression did not show a distinct pattern of reduced nerve volume in the temporal lobe and posterior hippocampus, which suggests that this reduced nerve volume seen in studies is probably specific to an environmental, rather than genetic cause. Accumulating data in scientific study has shown that herbal medicine is effective both as a neuroprotective agent and as a means of promoting neurite growth, and combined in a holistic protocol to decrease the environmental causes of neuronal degeneration, may present a better alternative to GABA inhibition or inhibition of serotonin and norepinephrine reuptake in the cure of anxiety or depression, especially if herbal and nutrient medicine could in part play a significant role in providing increased bioavailability of GABA, serotonin and norepinephrine. Abundant research now proves that acupuncture stimulation both modulates brain cell functions and stimulates proliferation of stem cells in the brain, and a concerted effort to further map the specific effects of acupuncture points is ongoing, greatly contributing to the efficacy of the Licensed Acupuncturist and herbalist. Go to the article on this website entitled Brain Health and Function: utilizing Complementary Medicine to better understand how herbal and nutrient medicine in coordination with acupuncture stimulation presents enormous potential for not only neuro-protective but neuro-regenerating effects.

Bipolar disorder is a syndrome of difficulty in control of mood swing resulting in periods of hyperactive mood suddenly turning to depression. Many researchers believe that bipolar disorder is also a GABAergic dysfunction, and that increasing DNA demethylation results in a positive change in regulation of GABA production. As with Depressive Mood Disorder, Bipolar Disorder has also been shown to involve neurodegeneration in specific areas of the brain. A 2013 study at the University of Oslo Institute of Clinical Medicine, in Oslo, Norway, found that "Bipolar II Disorder is associated with thinning of prefrontal and temporal cortices that are implicated in the expression and regulation of negative and positive affect" (PMID: 23980618). Patients and physicians must do more to provide neuro-restorative protocols in these disorders. Simply taking drugs that inhibit neurotransmitter metabolism does not address the neurobiological damage.

Physical causes of depression include subclinical hyperparathyroidism with elevated blood calcium and parathyroid hormone, sometime stimulated by a period of calcium deficiency, Vitamin D3 deficiency, magnesium deficiency, or other metabolic and nutritional deficiencies. Although the study of the long-term impact of synthetic hormone contraceptives on human psychology has been vastly under-researched, large studies have confirmed higher rates of depression in women with long-term use of synthetic hormonal contraceptives, and starting these synthetic hormonal therapies in women at a young age, when the endocrine system is still developing, may have long-term impact on future anxiety and depression. Hormonal balancing and restoration of hormonal homeostasis may be an important factor in reversing the biochemical causes of anxiety and depressive mood disorders. Mood disorder is well known as the most prevalent adverse effect causing discontinuation of synthetic hormonal contraceptives, but there has been very little study of the long-term consequences. Chronic pain, gastrointestinal problems, sleep disturbances, and chronic fatigue have all been highly associated with depressive mood disorders, but little research has explored the potential of resolution of these physical symptoms in the treatment of depression. A 2002 study presented to the annual meeting of the American Psychiatric Association (Denninger JW et al) presented evidence of the strong relationship between somatic symptoms and depression, but did little to change treatment protocols.

In 2004, a meta-review of scientific study of this mind-body relationship by Dr. Madhukar H. Trivedi MD, of the University of Texas Southwest Medical School, in Dallas, Texas, concluded that: "Because depression and pain share a common neuro-chemical pathway in that they are both influenced by serotonin and norepinephrine, depression and associated painful physical symptoms must be treated together in order to achieve remission. In fact, research has shown that physical symptoms improvement was correlated with the improvement of other depressive symptoms, which suggests that the patient's ability to achieve depression remission may be directly related to the reduction of painful physical symptoms." Further study in 2010, at the Cedars-Sinai Medical Center in Los Angeles, California, utilized randomized controlled human clinical trial to determine the benefits of deep tissue physiotherapy, and the admittedly skeptical head researcher, Dr. Mark Rapaport, chairman of the department of psychiatry and behavioral neurosciences at Cedars-Sinai, was amazed at the array of benefits from deep tissue physiotherapy, remarking that this would alter his future opinion of the correct course of therapeutic protocol in psychotherapy (see the article on this website entitled Deep Tissue Massage and it's many benefits). All of these underlying causes must be considered in the holistic therapeutic protocol, and may indeed be vital to the remission of anxiety and depressive mood disorders, as well as resolution of the withdrawal and rebound syndromes from benzodiazepines, SSRI and SSNRI anti-depressants, and atypic antipsychotic medications.

How herbal formulas and nutritional supplements may have a positive effect on GABA metabolism and help control anxiety disorder safely, enhanced by acupuncture and healthy routines, such as yoga

In the adult, GABA is synthesized from glutamate, or glutamic acid, using cofactors derived from pyroxidine, or Vitamin B6 (P5P), and an enzyme derived from the glutamic acid metabolism, which is affected by the amino acid L-glutamine. L-glutamine readily crosses the blood brain barrier in circulation and is converted to glutamic acid and increases bioavailability of GABA. A formula of nutrient supplements potentially has a beneficial effect on increasing GABA bioavailability, whose need increases with periods of poorly controlled anxiety. L-glutamine, Vitamin B6 (P5P is the bioactive form), inositol (inositol hexacotinate is the bioactive form), choline (GDP choline and phosphatidylcholine / phosphotidylserine are the most useful forms), and nicotinic acid, or niacin (niacinamide has none of the alarming flushing effects), has this effect on many patients. Since GABA primarily has an effect to control sudden mood swings, the patient with poor control of anxiety, or sudden episodes, will benefit from this course more than the patient with constant anxiety, or an anxious depression. GABA itself is a nutrient supplement, but many patients do not experience a positive effect from taking this supplement in pill form. GABA has been well studied and shown to not cross the brain-blood barrier when taken as a supplement. The brain-blood barrier is decreased in small parts of the brain, such as the hypothalamic pituitary complex, but since GABA is produced within the cells, and has its main effects within the neural cells, supplementation with GABA will achieve little real restoration of brain homeostasis. While GABA supplementation is widely used in therapy, the effects may be due to a placebo effect, or due to alteration of the GABA type A receptor functions in the hypothalamus alone.

Numerous studies point to the intracellular production and storage of GABA as the main regulator of GABA function in the brain, and GABA levels within the postsynaptic cell, as well as levels of chloride ion within the cell, are the main regulators of GABA type A receptor functions. In addition, GABA is a peripheral neurotransmitter affecting the gastrointestinal function, as well as the reproductive functions, and supplementation with GABA directly may not be the best strategy. While the precursor formula above aids bioavailability, GABA supplement in excess dosage may cause increased anxiety, as well as mild shortness of breath and tingling in the extremities. Foods that contain GABA may be of some benefit, though, and include oranges and mandarin oranges, as well as pumpkin seed and shitake mushroom. Herbs that contain GABA include Dang gui, ginseng, valerian, bitter melon, and the food herb tarragon. As medications that affect the GABA system are withdrawn there will be fluctuation of the mood regulation and other inhibitory mechanisms which GABA regulates in the brain, but by supplying the brain with the chemical bioavailability to restore the normal biochemical balance, these symptoms that result from the drug tapering have a much better chance of being corrected. The symptoms experienced during this process will not be caused by simple nutrient and herbal medicines, such as common amino acids L-glutamine or L-tryptophan, or common vitamins, choline in low dosage of herbs such as St. John's Wort, California Poppy or Magnolia (Hou pou), but still the process will involve fluctuating symptoms until a balance is restored during this withdrawal process. Trust in the process and a pragmatic attitude is important. Many patients experiencing this withdrawal process naturally are anxious about taking any medication, no matter how benign and proven it is, and need to use an objective approach and become educated to this process to overcome the anxiety and fear induced by the chronic use of benzodiazepines and other psych drugs, and the heightening of these emotional states druing withdrawal. Avoiding sensible treatment protocols that are proven and proven benign is not a logical approach. Also, jumping from one oversimplified and overadvertised protocol to another is not the way to achieve success.

In 2008, study at McMaster University, in Ontario, Canada, and the University College Cork, in Ireland, led by John Cryan, showed that the health of the gut Biome is important in neuropsyche regulation and bioavailability of of neurotransmitters and hormones as well. These scientists showed that laboratory animals with induced stress produced more GABA when a sufficient amount of Lactobacillus rhamnosus occurred in their Biome. Thus the field of psychobiotics emerged. In the laboratory, gut bacterial reacted highly to norepinephrine (adrenaline) and produced various chemicals that helped the organism adapt to stress. Laboratory animals with overgrowth of pathological bacteria, such as Camphylobacter jejuni, were more anxious and fearful, according to the researcher Dr. Mark Lyte, at Texas Tech University, in Abilene, Texas, U.S.A. A remarkable symbiotic relationship has evolved between the gut Biome and the human organism, and is important for neuropsyche health. Dr. Lyte was a 2008 finalist in the U.S. NIH Pioneer Award competition. Since 2008, research by Sarkis Mazmanian of the California Institute of Technology confirmed that these symbiotic gut bacteria produce necessary bioidentical neurohormones and unique metabolites that affect behavior, the immune complement system, membrane functions, and neural cross-talk. Dr. Michael Fischbach of the University of California in San Francisco (UCSF) stated that "the scientific community has a way of remaining skeptical until every last arrow has been drawn, and until the picture is colored in". It appears that the picture is now completed, and the scientific community has finally conceded that a very complex holistic relationship exists between the bacterial colony and the Biome and the human organism itself, and that restoration of this biotic balance and homeostasis could actually produce some of the greatest cures and treatments we have ever seen. While standard medicine has derided this approach, it is clear that attention to the holistic approach is important, and should not be ignored in treating Benzodiazepine Withdrawal Syndrome and other syndromes of withdrawal from psyche drugs. Of course, restoration of healthy GI function and the human Biome is just one part of the overall treatment strategy in these disorders.

A sensible combination of therapeutic protocols is needed to overcome these difficult withdrawal syndromes. In addition to herbs and supplements, researchers at the Boston University School of Medicine found that the practice of yoga elevates brain GABA levels, reducing anxiety and depression (see the article in information resources below). As always, a comprehensive and holistic treatment protocol will insure the best outcome. Acupuncture is well known as a treatment to relieve anxiety and depression as well, and should be included in the protocol. Various studies have measured the effects of specific acupuncture stimulations on GABA metabolism. A 2010 study at Daegu Haany University in South Korea (cited below as well) found that acupuncture stimulation at a single point (HT7) significantly modulated GABA neuron excitability in the ventral tegmental area of the brain and decreased harmful effects of alcohol withdrawal by normalizing GABA effects and dopamine release. As with many such studies, acupuncture has been proven to exert modulating homeostatic effects, rather than the allopathic alterations achieved by drug use. In other words, acupuncture stimulation works to normalize the healthy balancing that the body is always programmed to achieve, which we call homeostasis. Research has revealed that a number of acupuncture point stimulations modulate GABA metabolism in the brain, including P5-6, ST36, GB37-39, K6 and UB62, and SI5. Further research is sure to better define the specific effects of acupuncture stimulation. Research concerning acupuncture stimulation has also revealed that acupuncture techniques that elicit the reactions classically called de qi, and electroacupuncture stimulations, affect the deeper areas of the brain, while simple needle insertion without manipulating effects generally affect only the cortex.

Certain herbs have been studied and found to have proven benzodiazepine effects, without side effects. These include magnolia (Hou pou) and California poppy (Escholzia californum), as well as Ganoderma lucida (Ling zhi mushroom aqueous extract, or Reishi), and even chamomile. Other herbs are well known to have positive effects on GABA receptors, acting as GABA analogues or GABA production stimulators. These include Kava-kava (kavalactones), valerian, and skullcap (baicalin from scutellaria lateriflora, or Huang qin, or the aerial parts of skullcap). Some of these herbal medicines need to be taken in low dosage so as not to overstimulate, and starting with too low of dosage, and increasing the dosage until the desired effect is achieved is the correct protocol. Diazepam is a benzodiazepine derivative and MAO inhibitor found in wheat sprouts and potatoes, and was synthetically derived to form Valium. The basis for many of these synthesized benzodiazepine drugs originated in herbal and nutrient medicine, and many patients are going back to the more natural forms of the chemicals to avoid side effects. Alcohol and glycerite extracts of some of these herbs, such as California poppy and Skullcap, may provide significant GABA modulation with a very low dosage. Once again, these low dosage gentle herbs have no proven adverse side effects, and do not act like a synthetic benzodiazepine, and fear of simple nutrient and herbal remedies are thus attributable to the expected fluctuations of mood and anxiety involved in the withdrawal from the drugs. Many patients are too anxious to trust any therapy, and of course, reluctant to add pills, but an objective analysis will show that providing some natural effects to offset the stopping of GABA receptor agonists with herbal and nutrient is sensible to smooth the biochemical transition.

There are herbs with known anxiolytic effects such as MAO inhibition, a focus of another type of antidepressant and anti-anxiety drug. Magnolia stem, or Hou po, in Chinese medicine, not only has benzodiazepine activity, but also contains honokiol, which has an MAO inhibition. St. John's Wort, or Hypericum perforatum, has the active ingredient hypericin, which acts as an MAO inhibitor and is anxiolytic. Apigenin is also an herbal chemical with this effect and is found in Passiflora incarnata, Gingko biloba, yarrow, scullcap, Qing hao (artemesia), Bo he (field mint), Ge gen (kudzu), Huang qin (Scutellaria baicalensis), chamomile, Echinacea, saw palmetto, and milk thistle, as well as foods such as alfalfa sprouts, cilantro, tea (camellia), rosemary, and thyme. Of course, concentrations of these active chemicals in these common foods and herbs are relatively small, but professional herbal extracts contain a sufficient dosage to exert the right effect. Each patient may need a somewhat different dosage to have the best effect, though, and a Licensed Acupuncturist and herbalist will often start at the lowest effective dosage and gradually increase the dosage for the individual when the appropriate effect is achieved. Self-medication and purchase of products from the health food or drug store may be problematic due to lack of FDA regulation and marketing of products without the actual herbal ingredients listed on the label, or the right dosage. Use of professional products is recommended to insure content and dosage.

Passiflora incarnata, or passionflower, contains not only apigenin, but other active chemicals that exert MAO inhibition and positive CNS effects, and has been well studied in Europe. Passiflora contains harmaline, harmalol, harmane, and harmine, all MAO inhbitors that are also shownt to modulate dopamine metabolism, and scopoletin, an anticholinergic, CNS effector, MAO inhibitor, and muscle relaxant. In addition, passiflora contains some potent antioxidants, such as quercetin, luteolin, kaempferol, and anti-inflammatory ingredients as well. The wide array of chemicals in passiflora exert a balanced effect, and this herb is now well studies and approved by the Commission E in Germany for insomnia and anxiety disorders. As we see, there are now a wide varity of herbal medicines that can be useful, and the patient and physician needs to try various combinations until the right individualized protocol is achieved.

As of 2010, there still has not been a large number of sufficiently funded studies of herbal chemicals to treat anxiety in human clinical trials yet. Still, as this meta-analysis from the Universidade Fereral do Parana in Brazil shows, there have been sound studies demonstrating the effectiveness of Passiflora incarnata, Valeriana officianalis, Gingko biloba, and Matricaria recutita. Click here to see the study link: http://www.ncbi.nlm.nih.gov/pubmed/21308265. In Germany, the official government Commission E (founded in 1985) approved Passiflora for the treatment of insomnia, and in 2011, the NIH MedlinePlus database lists the effectiveness ratings for Passiflora (as determined by the Natural Medicines Comprehensive Database) as proven as effective as some prescription medications for anxiety, as effective in combination with clonidine to relieve symptoms of narcotic drug withdrawal, and effective in relieving symptoms of adjustment disorder with anxious mood when used in combination with other herbs, such as Valerian, crataegus, and ballota. Passiflora was in fact given FDA approval as an over-the-counter sleep aid and sedative in the U.S. in 1977, but was taken off the market in 1978 when pharmaceutical companies objected that its safety and effectiveness had not been sufficiently proven in rigorous human clinical trials. Of course, 35 years is not an unreasonable time period to conduct such studies, I guess, especially when talking about a flower extract that has been used safely for centuries. We see from such history that modern medical science has tightly controlled both the published scientific study and government regulation of herbal medicine, and that the mere lack of published scientific information does not negate the efficacy of herbal medicine, as is widely reported.

The most well known nutrient substance with anxiolytic, or antianxiety, effects is L-tryptophan, an essential amino acid found in all meats and many vegetables and grains. Tryptophan may also act as a precursor to serotonin, if serotonin is deficient and there is demand. Like many herbs and supplements, the body responds to these chemicals in a modulatory manner that is different from the responses to synthetic chemicals. Because of this, the synthetic drugs are more powerful even when they are not needed by the metabolism, but also are able to produce more unwanted effects. Tryptophan was one of the most popular nutrient supplements in world history until and incidence of manufacturing contamination prompted the cautionary banning of its sale in the United States in 1996. The CDC investigation immediately proved that the problems from the supplement product were tied to a rare bacteria contaminating a batch of L-Tryptophan, but pharmaceutical lobbying insured that the FDA did not lift the ban on this nutrient supplement for over ten years in order to decrease the competition and insure greater use of pharmaceutical anti-anxiety and anti-depressant drugs. During this time, the amino acid precursor, 5-HTP, or hydroxy-tryptophan-precursor, became popular, and this supplement is often a key ingredient in the treatment protocol of withdrawal syndrome from SSRIs, along with Sam-E, a type of methionine that aids the action of 5HTP, aids neurotransmitter transformation and bioavailability, and aid liver and glutamate metabolism. Tryptophan is found in many foods and herbs, including spinach, asparagus, potato, corn, oats, amaranth, fenugreek, sesame seed, thyme, lotus seed, Gingko biloba seed, sunflower oil, evening primrose oil, and watercress.

5HTP, an extract from Griffonia seed, is a bioidentical chemical to the tryptophan precursor found in the human body. 5-Hydroxytryptophan, or 5HTP, is a naturally occurring amino acid that the body utilizes as a precursor to both trypthophan and melatonin. Tryptophan is a bioactive amino acid that may be utilized in the body as a precursor to serotonin, melatonin, niacin, N-acetlytransferase, 5-hydroxyindole-O-methyltransferase, and Auxin. In addition, there are many 5HT receptors in the cells of the body as well, with 5HTP potentially exerting direct effects. This all adds up to the ability of 5HTP to be utilized to create an improved bioavailability for a number of important neurotransmitters and enzymes that regulate neurotransmitters. 5HTP may have immediate effects, with many patients noticing sound sleep and less anxiety related insomnia with a short course of 5HTP. On the other hand, studies show that the best effects of 5HTP therapy come after prolonged use, with about 2 months of taking a mild dose improving mood and sleep quality considerably. Since 5HTP is a precursor chemical, allowing better bioavailability of neurotransmitter production in the brain, studies have also found that this herbal and food chemical works well in tandom with other related herbs and nutrients. The formula that combines a low dosage of 5HTP with active Vitamin B6 (P5P), melatonin, and St. Johns Wort extract, provides the brain with a combination of effectors that allow for increased chance of homeostatic balance. This product is available from Vitamin Research, and called Positrol.

Widespread warnings that 5HTP could potentially cause a condition termed "serotonin syndrome" when combined with SSRI medication or MAO inhibitors have been disseminated. The key words here are potentially and theoretically as searches reveal no actual cases of serotonin syndrome induced by concurrent 5HTP usage, despite the widespread use of 5HTP by patients with concurrent use of SSRI medication. These warnings are based on one small laboratory study where a high dose of 5HTP was combined with an MAO inhibitor in laboratory animals, and induced an apparent serotonin crisis, or excess accumulation of serotonin. Most of the theoretical potentiality of this herbal chemical causing serotonin syndrome was derived from studies of pharmaceutical interactions causing this syndrome, which are well documented, but rarely warned against. The concurrent prescription of MAO inhibitors with SSRI medications or other serotonergic meds carries interaction warnings common to all prescribing manuals, yet is often ignored by MDs. The occurrence of serotonin syndrome is relatively rare. The dosage of 5HTP by a professional herbalist is small in almost all circumstances. Tryptophan itself is found in all meats and a wide variety of foods, and obviously, tryptophan, the serotonin precursor, is eaten by all patients taking SSRI medications. Still, the level of caution in the herbal profession almost always precludes the prescription of 5HTP concurrently with SSRI medication. 5HTP is useful, though, in the withdrawal syndrome of SSRI medication, as a precipitous drop in serotonin bioavailability occurs with SSRI withdrawal, and is thought to be responsible for the alarming symptoms that may occur. The text Encyclopedia of Dietary Supplements by the reknowned Paul M. Coates, states that "To our knowledge, there are no published cases of serotonin syndrome linked to 5HTP consumption." This was published in 2005. Dr. Coates was appointed the Director of the Office of Dietary Supplements (ODS) at the NIH in 1999, and prior to this was on the faculty of the University of Pennsylvania School of Medicine. His knowledge can be trusted.

Some nutritional supplements have some effect on GABA but are highly regulated in the body and so mainly affect the GABA system when they are deficient, not when the patient takes in an abundance of the supplement. One of these nutrients is manganese, which has a GABA stimulating effect in its natural form in the body, and is a cofactor for many enzymatic activities, as well as a necessary part of the mitochondria, or oxygen metabolizers, in our central nervous system cells. Manganese is an important constituent of the powerful antioxidant super oxide dismutase (SOD), and the type of SOD with manganese is an important part of our brain cells, protecting the cell from the oxidant superoxide, which is toxic to the cell. Deficiency of manganese-SOD may be a key component to neurodegeneration. While manganese is an essential trace nutrient to all forms of life, certain isotopes and compounds of manganese are toxic, especially those that are generated by smelters and coal fired power plants, which form organic manganese compounds that permeate our air, and are ingested in the water and food that are exposed. These toxic manganese compounds are very small and light, and difficult to break down, even entering our air via the water that we shower with. This type of toxic manganese compound is neurotoxic and has been linked to cognitive disorders and Parkinson-like neurodegenerative disease, like the compounds of mercury and lead from the coal-fired power plants and smelters. The nutrient manganese is a much different molecule, and is not toxic, but, like all charged minerals in the body, is highly regulated, and taking the supplement will aid defiency but will probably not stimulate a GABA mechanism if one is not deficient in manganese. It would be best to insure that manganese is obtained from the diet, but mild dosage in supplementation may be warranted for some patients. It may be best to take manganese in a professional Essential Minerals formula. Do not expect a noticeable effect on regulation of mood like one observes for the anxiolytic herbs, but nervertheless, manganese may be an important aid to patients with neurodegenerative disease, thyroid deficiency, and other deficiencies related to mood disorders.

Calcium and magnesium are also nutrients that are highly regulated in the body but do have some anxiolytic or calming effects, especially if the patient is deficient in these minerals, or if there is a hypothyroid or hyperparathyroid disorder, or a hormonal deficiency of estrogen. Unfortunately, the subject of calcium supplementation is not simple, like we are led to believe. Calcium may be the most regulated molecule in the body, and is found in almost every cell. Specific hormonal systems have been evolved in the body mainly to regulate calcium metabolism in all aspects of absorption in the digestive track, utilization and transportation, storage in the bone, and resorption from the bone as needed. There are many types of calcium supplement, and each type is a molecule of calcium combined with another substance, which is the prime determinant of where it goes and how it is utilized in the body. Magnesium absorption and utilization may be partially controlled or affected by levels of calcium in the diet, local calcium concentrations in cells and tissues, and perhaps even by calcium regulating hormones. Different types of magnesium will be carried to different tissues as well, producing different effects. Since the molecule aspartate affects glutamate and GABA receptors, taking calcium and magnesium in the form or calcium and magnesium aspartate may be the best choice.

To learn more about calcium metabolism, go to the article on this website entitled Calcium Supplementation. Calcium aspartate may help the patient to calm muscle spasticity, and calcium AEP is a molecule often found to be deficient in syndromes related to hypothalamic dysfunction or hypofunction. Calcium 2-aminoethyphosphate, or Ca-AEP, is a vital component in cell membranes, and forms functional mineral complexes that improve neurological function, aiding not only the function of the hypothalamus, but the whole nervous system, and studies have shown that Ca-AEP is effective in the repair of cell membranes, in combination with antioxidants such as Co-Q10 and resveratrol. In Germany, the combination of Ca-AEP, magnesium and potassium aspartate have been declared a proven treatment for Multiple Sclerosis. These are two examples of calcium supplements, Calcium and magnesium aspartate and Ca-AEP, that may be used to normalize symptoms in a protocol to treat withdrawal syndromes. The balance of mineral ions in the brain may be of most importance, with positively charged sodium and potassium, calcium and magnesium, balanced with negatively charged chloride ions. This homeostatic electrolyte balance is tightly controlled, but may be affected by various abnormalities and dysfunctions. The voltage and ion concentration gradients of these mineral ions, calcium, magnesium, sodium, potassium and chloride across the nerve cell membrane are the chief forces governing the movement of these ions, which supply both the nerve conduction and the cellular transport. Supplementation with essential mineral complexes, as well as correction of stomach acid problems (hydrochloride ions), may have a positive effect on brain chemistry and function.

The history of negative advertising and propaganda directed toward anxiolytic herbs that were competing with benzodiazepines and SSRIs in the 1990s is a subject that has not elicited enough scrutiny. A campaign to discredit the growing popularity of St. Johns Wort, Kava kava, and the amino acid L-tryptophan, proved extremely easy for the pharmaceutical companies with the aid of standard medicine. These benign herbs and a common essential amino acid were successfully vilified and their use curbed dramatically, despite a long history of use of the herbs with almost no actual clinical ill effects, and the fact that L-tryptophan was an amino acid consumed daily throughout history by almost every human. Many articles were published citing the potential for harm from these herbs and this amino acid, all based on theoretical research that was too complicated for the average patient to understand, and having no basis in actual clinical cases of proven harm to a single patient. Nevertheless, this campaign succeeded in generating FDA warnings and the end of prescription of these herbs and this amino acid, despite no actual restriction on use in herbalism. These products were removed from the market esentially, and became difficult to obtain for a number of years. In the meantime, the many thousands of patients that were successfully relying on these herbs and this amino acid to calm anxiety disorders probably joined the lucrative market for benzodiazepines and SSRI medications.

Scientific study of acupuncture stimulation and its effects on the GABA system

In 2012, laboratory studies conducted by the Max Planck Institute for Biophysics in coordination with the Chinese Academy of Sciences and Shanghai Institutes for Biological Sciences, as well as the University of California, Irvine, discovered that acupuncture analgesic effects may be partially achieved by strengthening the inhibitory function of the GABAergic system via effects on opioid receptors and GABA transporting proteins (GAT1) (PMID: 23365600). These scientists stated: "We concluded that inhibition function of GAT1 (GABA transporter) function will strengthen the inhibitory action of the GABAergic system and hence may contribute to acupuncture-induced analgesia." In 2013, study by the University of California, Irvine campus, Susan Samueli Center for Integrative Medicine, also found that electroacupuncture at the PC5 and PC6 acupuncture points reduces sympathoexcitatory blood pressure reflex responses by effects at GABA type A receptors in the basal ganglia (rostral ventrolateral medulla etc.) (PMID: 23302958). In recent years, numerous scientific studies have been able to prove that acupuncture stimulation affects GABA type A receptors in different parts of the brain, contributing to its effects over time to relieve insomnia, anxiety, and autonomic dysfunction. These studies, effectively measuring physiological effects in laboratory animals, show that acupuncture and electroacupuncture provide homeostatic and modulatory effects that may help normalize brain activity over time. Such studies also help the acupuncturist to better refine the choices of acupuncture stimulation to achieve more specific effects. There is no longer any doubt that acupuncture and electroacupuncture achieves significant modulatory effects on the brain, and is effective in relieving anxiety, insomnia, autonomic dysfunction, and neurohormonal dysfunction over time. These studies demonstrate that the array of adverse effects and symptoms with withdrawal syndromes could be benefited by acupuncture stimulation, and that over time, the systems adversely affected in the brain can be helped to regain homeostatic health.

More recent studies in China have also demonstrated in studies of laboratory animals that specific electroacupuncture stimulations will beneficially modulate the corticotropin-releasing factor (CRF) receptor types in such a way as to normalize the expression and balance of these receptor types to restore homeostasis after withdrawal of benzodiazepines. You may see the studies and links below, that show that electroacupuncture at ST36, GB34 and SP6 achieve these results in the amygdala and other areas of the brain, and possibly the GI system as well. Of course, such therapy needs to be given time to achieve the desired results, but these studies show how important this type of acupuncture therapy could be in the long run to restore the patient to health. The use of electroacupuncture at P6, P5, ST36, GB34 and SP6 is simple and beneficial in a broad number of ways, has no adverse effects, and can be part of a more holistic protocol involving various herbal and nutrient medicines. It should be delivered in short courses of frequent treatment on a periodic basis. A 2014 study at the Mudanjiang Medical University in China, and the Daegu Haany University in South Korea confirmed that electroacupuncture at just the point ST36 inhibited the withdrawal-induced hypothalamus-pituitary-adrenal hyperactivity in study animals, with measurement of corticosterone, ACTH and CRF in blood circulation and in specific areas of the brain (PMID: 25441946). Such studies provide tangible proof that these protocols work amazingly well, and a 2015 study of this same ST36 stimulation, at the Georgetown University Medical Center in Washington DC, U.S.A., showed that it both prevented this hyperactivity with induced stress and that the effects lasted for at least 4 days after the treatment (PMID: 26196540). It is only the decades of negative propaganda that now fails to accept such scientific proof and still fails to integrate such care into standard treatment. The proof is strong, but industry opposition to integration of CIM/TCM is stronger, and this is hurting patient care and outcomes.

Other studies in recent years have used functional MRI studies with human subjects to show that specific acupuncture and electroacupuncture stimulations significantly modulate connectivity and hyperexcitation between key areas of the brain such as the amygdala and hippocampus, and the cortex, and have demonstrated with tissue staining and PCR in laboratory animals that restorative and protective effects to these areas of the brain affected by benzo withdrawal and anxiety mood disorders are achieved with acupuncture stimulation to classic points such as DU20 and DU24, sishencong, GB20 and UB10, and ear points associated with the autonomic nervous system and these areas of the brain. More and more of this evidence is accumulating, and can be resourced below, and in links to studies provided on other articles on this website, such as the articles on Anxiety and Brain function. Of course, this type of therapy needs to be utilized in short courses of frequent treatment, with 2-3 treatments per week for 2-4 weeks at a time optimally, and integrated with other therapeutic and restorative protocols. By supplying the biochemical availablity for the brain to restore neurohormonal balance while using short courses of specific acupuncture protocols during th same time period, the ability to achieve restoration of homeostasis is greatly improved. The success of treatment needs to be judged not by the immediate effect but by the long term sustained effect. The information in this article provides the patient and treating physicians with evidence and protocols to achieve the goal, and merely needs study, understanding and implementation to work. What appears to be lacking is the will to integrated these therapies to finally achieve success.

The actual cure for Benzodiazepine addiction and dependence obviously involves the need for a step-by-step comprehensive and holistic integrated treatment protocol, with a strong pro-active involvement from the patient. The nature of the disorder will understandably make this difficult, as debilitating anxiety and autonomic symptoms occur that makes the focus and persistence needed difficult. By forcing the mind to concentrate on a step-by-step systematic protocol, and avoiding the negative big picture of hopelessness, success will be achieved. One does not need to depend on a miracle cure or a single knowledgeable physician, but instead on oneself and understanding of what needs to be restored to finally relieve symptoms. Symptoms are like the tip of an iceberg, and addressing what it under the water is the concern. By correcting the causes of the symptoms with restorative medicine, utilizing CIM/TCM, the normalization of these symptoms will eventually be achieved.

Information Resource - Additional Information and Links to Scientific Studies

  1. A comprehensive report from 2006 on SSRI and benzodiazapine withdrawal syndrome: http://www.benzo.org.uk/ssri.htm
  2. A 2014 report on benzodiazepine dependence and withdrawal syndromes, and the complete lack of treatment success, as well as the inexplicable persistence in wide prescription of these drugs worldwide, by the University of Western Australia School of Medicine and School of Psychiatry, shows that because no pharmacological intervention, or any other therapy in standard practice, has proven effective to treat dependence and withdrawal syndromes, that a seldom used past drug protocol of GABA type A receptor antagonist flumazenil has been used to temper acute withdrawal symptoms, as an infusion for 4 days, and that now clinics are trying to use this infusion drug therapy for chronic cases as well. Studies in animals have shown some efficacy in sheep, and infusion pump implants are being developed, yet there is no proof of efficacy or long-term safety: http://www.ncbi.nlm.nih.gov/pubmed/23126253
  3. A comprehensive 2009 review of the scientific study in standard medicine of the incidence of common adverse effects of benzodiazepines, from the faculty of the Grigore T. Popa University Medical School, Romania, is seen in this article, showing that a majority, or near majority, of patients experience depression, anxiety, increased sweating (autonomic dysfunction), insomnia, and cognitive difficulties with chronic use. This report does not address the common problem with dependence and withdrawal, which usually produced alarming symptoms, worse with patients with comorbid health problems, panic attack syndrome and chronic use: http://www.ncbi.nlm.nih.gov/pubmed/21495303
  4. A large 2015 longitudinal population study of the cancer risk from long term benzodiazepine use, by experts from Taipei Medical University, and National Yang Mind University, in Taipei, Taiwan, found that over a 12-year period, looking at 42,500 patient records, that that increased risk for brain, colorectal, and lung cancer was evident over matching controls, varying with types of benzodiazepines, and more significant for clonazepam (Klonopin or Rivotril): http://www.ncbi.nlm.nih.gov/pubmed/25674736
  5. A 2012 U.S. multi-center report on the treatment of agitation, by the University of Californian San Diego, the University of Rochester Medical Center Department of Psychiatry, and the University of Mississippi Medical Center Department of Psychiatry, concluded that treatment of the syndrome of anxiety and agitation should be based on the careful assessment of the most likely cause, and "if agitation results from a delirium or other medical condition, clinicians should first attempt to treat the underlying cause instead of simply medicating with antipsychotics or benzodiazepines". The goal of prescription of benzodiazepines or antipsychotic medication should be to temporarily calm the patient to facilitate assessment of the medical cause, according to these experts, yet we see the universal prescription of these drugs with no assessment or treatment of the underlying disease, just chronic use of the drugs. The numerous FDA warnings are explained in this paper. These experts also state that "medication should be used to calm patients, not induce sleep": http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3298219/
  6. A 2012 study from experts at the University of Eastern Finland, Kuopio University, the University of Tampere and the Karolinksa Institute in Finland and Sweden, showed that the combination of benzodiazepines, antidepressants and antipsychotic drugs is now prevalent, with alarming adverse effects largely ignored. Here, the focus was on the treatment of schizophrenia, where this poloypharmacy approach is now the norm, but these findings can be applied to all patients. This large study found that additive with benzodiazepines increased overall mortality in the patients, especially with incidence of suicide, but that while overall mortality was not increased by combining antidepressants and antipsychotics, the adverse health effects were alarming, and recommendations that less polypharmacy and lower dosage be tried, as well as integration of less risky and harmful therapy, were made: http://archpsyc.jamanetwork.com/article.aspx?articleid=1151489#
  7. A report from Harvard Health Publications in 2015 notes that a study published in 2014 in the esteemed British Medical Journal (BMJ) showed that there is a direct causal relationship between the cumulative dosing with benzodiazepines and the risk of Alzheimer's disease onset. Large studies in both France and Canada linked the amount of benzodiazepine use to the risk of Alzhemimer's disease, and since benzodiazepines accumulate in fatty tissues, and affect older patients more due to slower metabolism, this also increases the risk of adverse health effects on the brain. Numerous studies have also shown that with repeated use, benzodiazepines have diminished effects in promoting sleep, and in 2012, the American Geriatric Society listed benzodiazepines as inappropriate medication for treating insomnia, agitation, or delirium: http://www.health.harvard.edu/blog/benzodiazepine-use-may-raise-risk-alzheimers-disease-201409107397
  8. A 2012 comprehensive meta-review study of the incidence of withdrawal syndrome from chronic benzodiazepine use, at the University of Leiden Dept. of Psychiatry, in The Netherlands, showed that the most common risk with comorbid conditions involved patients with insomnia, antidepressant use, and alcohol dependency: http://www.ncbi.nlm.nih.gov/pubmed/22703562
  9. A 1990 report from the U.S. National Institute on Alchohol Abuse and Alcoholism, in Bethesda, Maryland, U.S.A. showed that alcohol consumption increases the effects of benzodiazepines on the GABA system and that many patients with an anxiety mood disorder on benzodiazepines do therefore abuse alcohol. Even in 1990, these experts advised Medical Doctors to be aware that negative interactions between benzodiazepine and alcohol occur with social use, treatment for alcoholism, and for alcoholics, yet this advice was apparently ignored and not passed on to patients, creating enormous harm: http://www.ncbi.nlm.nih.gov/pubmed/1980691
  10. A 2014 multicenter randomized controlled human clinical study in Spain showed that treatment for benzodiazepine withdrawal using standard drug therapy produced only a 15 percent success rate after 6 months, while structured intervention, a type of guided cognitive and behavioral group therapy without drugs, produced a 45 percent success rate of complete discontinuation at 12 months, either with follow-up visits or written instructions. Integrating Complementary Medicine into such a treatment protocol is sure to achieve even better results: http://www.ncbi.nlm.nih.gov/pubmed/24526745
  11. A 2015 review of standard treatment for benzodiazepine withdrawal and post-withdrawal syndromes, by the Center for Addiction and Mental Health, in Toronto, Canada, found that "there is currently no approved pharmacotherapy for benzodiazepine use disorder treatment and optimal strategies for treatment are unclear" - the review of treatment options shows that in 2015, anti-seizure, antipsychotic, and GABA receptor antagonists (e.g. flumazenil) are used as the "gold standard", but that "but have not yet been tested appropriately". Current long-term success is still considered poor for these pharmacological strategies, and a gradual tapering of dosage combined with cognitive behavioral therapy appears to by the most successful standard strategy. Integration of restorative Complementary Medicine is still not even considered, despite abundant research to support it: http://www.ncbi.nlm.nih.gov/pubmed/26088120
  12. A 2013 meta-review of all published scientific studies of withdrawal and rebound adverse health effects from the use of atypical antipsychotics, most of which are marketed with soothing names such as Lyrica and Abilify, by the Ludwig Maximillian University School of Medicine, in Munich, Germany, found that in 2013, this problem was recognized but few studies had been conducted to accurately track these symptoms and syndromes, and instead, widespread practice of switching to different brands when patients complained of adverse symptoms occurred, maintaining chronic use of the drugs forever. The cynical recommendations to alleviate these adverse health effects and withdrawal and rebound effects from stopping the medication involved prescribing benzodiazepines and anticholinergic drugs, such as Xanax, Tagamet, Soma, and Codeine, which come with alarming adverse effects and withdrawal and rebound symptoms themselves. Surely, it is now obvious that using problematic psyche drugs to treat rebound and withdrawal from other problematic psyche drugs is not a good idea: http://www.ncbi.nlm.nih.gov/pubmed/23821039
  13. A thorough 2003 meta-review of published scientific studies of post-withdrawal effects from benzodiazepines, by experts at La Trobe University, in Australia, shows that negative cognitive effects persist after withdrawal from long-term use of benzodiazepines, with significant CNS impairment. Cessation of benzodiazepines showed some improvement in cognitive function broadly, especially in attention deficit, but long-term deficits persisted for many patients. Such study should show the need to integrate restorative medicine for the treatment of benzodiazepine post-withdrawal syndrome, but no such recommendations occur, especially concerning Complementary and Integrative Medicine and Traditional Chinese Medicine (CIM/TCM), which many studies have proven effective in this realm: http://www.sciencedirect.com/science/article/pii/S0887617703000969
  14. A 2010 article published in the journal Psychology Today, written and researched by Dr. Christopher Lane Ph.D., shows how both the pharmaceutical industry and major governmental regulatory groups, such as the British Medical Research Council, have kept their findings of the prevalence of Benzodiazepine and SSRI withdrawal and adverse health effects hidden as these drugs became the most prescribed and profitable drugs in the world: https://www.psychologytoday.com/blog/side-effects/201011/brain-damage-benzodiazepines-the-troubling-facts-risks-and-history-minor
  15. A large 2004 study at the Loughborough Sleep Research Centre at Loughborough University, United Kingdom, found that psychological treatment for chronic insomnia with comorbid use of hypnotic drugs (e.g. benzodiazepines), with average use for 13.4 years, was successful and relatively inexpensive, with success at 6 months and 1 year for a majority, and a majority of patients either with infrequent low-dose of the benzodiazepines, or zero use, and improved sleep quality and quality of life. This treatment usually consists of sleep hygiene behavioral and cognitive modifications that are individualized. Once again, the integration of Complementary Medicine into this protocol could achieve an ever better outcome: http://www.ncbi.nlm.nih.gov/pubmed/14960254
  16. A study of the effects of benzodiazepines on plasma GABA in anxious patients: http://resources.metapress.com/pdf-preview.axd?code=f73x435p413218pq&size=larger
  17. A study of benzodiazepine responses indicates that panic disorder patients have a much different response to benzodiazepines than normal patients. The study found that levels of GABA were peristently low even with chronic benzodiazepine use in these patients, and that a deficient glutamate metabolism was perhaps the key to panic or anxiety disorders: http://ajp.psychiatryonline.org/cgi/content/full/161/12/2186
  18. A 2009 study of benzodiazepine withdrawal, by King's College of London, UK, Institute of Psychiatry, concluded that the prescription and abuse of benzodiazepines and hypnotics continues to "excite controversy", with the adverse effects of chronic use extensively documented and their effectiveness questioned. These psychiatric experts conclude that discontinuation of benzodiazepines and hypnotics usually results in improved cognitive and psychomotor function, and that the potential for dependence and addiction have become ever more apparent. The cessation of use requires slow tapering, with standard treatment for benzodiazepine withdrawal utilizing from 4 weeks to 3 years of this slow tapering to avoid serious withdrawal syndrome, and these experts recommending that less than 6 months be a standard for drug tapering. Clearly, patients would benefit by integration of Complementary Medicine into this difficult withdrawal process, but of course, no such recommendation has come forth from standard medicine: http://www.ncbi.nlm.nih.gov/pubmed/19062773
  19. A 2013 monograph for gabapentin, or Neurontin, often prescribed when the patient complains of benzodiazepine withdrawal symptoms, approved by the manufacturer, Pfizer, and published as part of the drug safety watch of the U.S. FDA, warns that Neurontin, or gabapentin, may cause panic attacks, depression, anxiety, agitation, restlessness, aggressive mood, mania, and other unusual changes in behavior or mood, including suicidal thoughts and actions, the subject of numerous lawsuits: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM229208.pdf
  20. A 2013 case study of pregabalin, or Lyrica, by Ulm University, Ulm, Germany, confirmed reports from a few small studies that Lyrica has the possibility of triggering addictive behaviors, requiring caution in prescription. A prior study found that in 55 reports of Lyrica abuse or dependence were found in the German Federal Institute for Drugs and Medical Devices (BfArM) database: http://www.ncbi.nlm.nih.gov/pubmed/23519046
  21. A 2012 report by the National Institutes of Health of the United States, involving experts at the University of Chicago, and Stanford University in Palo Alto, California, showed that prescription of atypical antipsychotics more than tripled from 1995 to 2006, decreasing with enormous fines and settlements for illegal marketing practices after 2006, and off-label, or non-FDA approved prescription of these drugs more than doubling during this period, to 9 million prescriptions per year in the U.S.: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3069498/
  22. A 2012 New York Times article by the renowned Dr. Richard A. Friedman M.D., professor of Clinical Psychiatry at Cornell Medical College, called for caution in easy prescription of atypical antipsychotic medications, then prescribed off-label for over 21 percent of cases of anxiety mood disorder, usually by an M.D. that is not a psychiatriast. Dr. Friedman noted that the alarming array of serious side effects from chronic use and lack of scientific studies supporting the efficacy and safety of these drugs for generalized anxiety has been trumped by marketing. Since 2012, these drugs have only increased in prescription, with little patient awareness of the real adverse effects of chronic use: http://www.nytimes.com/2012/09/25/health/a-call-for-caution-in-the-use-of-antipsychotic-drugs.html?_r=0
  23. A 2013 report from experts at Ludwig Maximilian University, in Munich, Germany, shows that increased concern has been generated by large numbers of reports of withdrawal and rebound syndromes from atypical antipsychotics, with the complexity of the symptom presentations, and the frequent switching between drugs creating a problem of clearly identifying and studying these syndromes: http://www.ncbi.nlm.nih.gov/pubmed/23821039
  24. A 2010 report from the Oregon Health and Science University, in Portland, Oregon, U.S.A. showed that there was little evidence of differences in efficacy among the many types of these atypical antipsychotic medications, but some considerable differences in reports of adverse effects, and of discontinuation of use due to adverse effects. Some types of atypical antipsychotics showed a relatively high percentage of patients with weight gain of 6-13 pounds, new onset diabetes, and onset of tardive dyskinesia (bruxism and movement disorders, especially in sleep), as well as increased risk of seizures. Large studies of these adverse effects are sparse, though, clinical trials typically have a select patient population and study short-term side effects: http://www.ncbi.nlm.nih.gov/pubmed/21348048
  25. A 2013 report from experts at the King Faisal Specialist Hospital and Research Center, in Riyadh, Saudi Arabia, shows that secondary Parkinsonism is usually a result of chronic use of antipsychotic medications: http://www.ncbi.nlm.nih.gov/pubmed/23887211
  26. A 2006 case study from Nassau University Medical Center, in East Meadow, New York, U.S.A. explains how atypical antipsychotics like Aripriprazole (Ability) sometimes induce inexplicable suicidal and violent thoughts, in this case concurrent with onset of akathisia, a restless movement disorder: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2990567/
  27. A 2007 study by the Boston University School of Medicine and Maclean Hospital showed surprising results demonstrating that the practice of yoga could result in healthy levels of GABA: http://www.anxietyinsights.info/yoga_elevates_brain_gaba_levels_reduces_anxiety_and_depress.htm
  28. A 2014 study at Taipei Medical University, in Taiwan, found that acetylcholinesterase inhibitors have been shown to reverse benzodiazepine-induced sedation to aid in the treatment of withdrawal. While synthetic acetylcholinesterase inhibitors come with alarming side effects, herbal acetylcholinesterase inhibitors have been well studied and found to be both effective and without significant side effects. The most well studied are Huperzine A and Vinpocetine (Vinpurazine), from 2 Chinese herbs, but significant effects are found in the herbs Uncaria (Gou teng / Cat's Claw), Huang bai (Phellodendron), Ban xia (Pinellia), and Lian zi xin (Nelumbo): http://www.ncbi.nlm.nih.gov/pubmed/24774720
  29. A 2013 study at the University of Rome Sapienza, in Italy, showed that the nutrient medicine L-acetylcarnitine (LAC) facilitates regulation of glutamate receptor expression and appears to enhance epigenetic modulation of glutamate metabolism, achieving antidepressant effects. Such study reveals how this nutrient medicine could be a valuable part of the holistic treatment for SSRI withdrawal syndrome: http://www.ncbi.nlm.nih.gov/pubmed/23382250
  30. A 2007 study of neural cell volume reductions associated with anxiety and depressive disorder that appears to confirm an environmental cause, suggesting that a holistic change of environmental factors, including diet, lifestyle, phytochemical therapy, behavioral and cognitive changes is appropriate to therapeutic protocol: http://www.anxietyinsights.info/abstract_reduced_temporal_lobe_volume_in_anxiety_depressio.htm
  31. A 2007 review of research data in China shows that herbal medicine shows much potential to reverse neurodegneration as well as promote neuronal survival, addressing the issue of loss of nerve cells in the hippocampus and prefrontal cortex that has been linked to anxiety and depression: http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17691984
  32. A 2011 study in Germany showed that an extract of the herb Passiflora incarnata (Passionflower) acted as a modulator of the GABA type B receptor without negatively affecting the GABA type A receptor, helping to restore the proven pathological dysfunction in anxiety mood disorder. Sufficient dose of Passiflora extract, usually taken as an alcohol and glycerite tincture, could enhance the effects of treatment: http://www.ncbi.nlm.nih.gov/pubmed/21089181
  33. As far back as 1992, studies such as this at the University of Calcutta, in India, showed that 10 Hz electrical stimulation at key acupuncture points could potentiate and modulate the effects of benzodiazepines. We can now use this knowledge to integrate short courses of acupuncture into treatment during slow tapering withdrawal from benzodiazepines to maintain the effects at the benzodiazepine receptors at the medulla and brain stem as we withdraw the drug: http://www.ncbi.nlm.nih.gov/pubmed/1598023
  34. A 2008 study at the Southern Illinois University School of Medicine, in Springfield, Illinois, U.S.A. found that electroacupuncture stimulation in one of a set of electrical stimulations proven to activate networks in the brain, or CNS. This type of activation has been shown to compete with disease networks, and provide a therapeutic competition to pathological mechanisms, especially in areas of the brain that have neurons shown to react to a various connections between key regulatory centers, such as the amygdala, brainstem, reticular formation, and the cerebral cortex. These researchers note that drugs that enhance GABA-mediated inhibiton, such as benzodiazepine, barbituates and gabapentin, or drugs that antagonize glutamate-mediated neurons (of which there are many), can cause these networking neurons to become unresponsive. The clear deduction is that electroacupuncture provides a treatment that could enhance recovery from long-term use of such drugs as benzodiazepines, and could be useful as part of a more holistic protocol of restorative medicine. The other types of electrical stimulation in standard medicine to achieve this goal are electroshock therapy and direct electrical applicaton to local brain tissues and the vagal nerve with implants, which obviously come with considerable risk of adverse effects: http://www.ncbi.nlm.nih.gov/pubmed/18762389
  35. A 2010 study of the GABA modulating effects at the Daegu Haany University in South Korea in 2010 followed up on similar study in 2006 (Zhao et al) and found that acupuncture stimulation at a single point (HT7) effectively modulated GABA neuron excitability and dopamine release: http://www.ncbi.nlm.nih.gov/pubmed/20860620
  36. A 2012 study at the Henan College of Chinese Medicine Zhengzhou, China, found that stimulation at the acupuncture points HT7, UB62 and K6, Shenman, Shenmai, and Zhaohai, potentiated GABA expression and the expression of GABA receptors in the hypothalamus, significantly better than stimulation at P6, ST36 and SP6: http://www.ncbi.nlm.nih.gov/pubmed/23140052
  37. A clinical study in 2010, at the Catholic University of Korea, Department of Integrative Medicine, found that a 2 Hz 2mA electrical stimulation for just 10 minutes at a single acupuncture point, ST36, ameliorated physiological dysfunctions in anxiety triggered by restraint stress, such as cortisone spikes and immunoreactive expression affecting neurotransmitters, as well as decreasing anxiety-related behavioral responses: http://www.ncbi.nlm.nih.gov/pubmed/20034458
  38. A 1999 article on acupuncture and the limbic system outlines some of the early scientific observations after fMRI studies revealed how directly acupuncture stimulation affected the limbic system, and how science explains these effects: http://www.acampbell.ukfsn.org/acupuncture/articles/limbic.html
  39. A study in 2003 in Seoul, South Korea, at Kyung Hee University, found that acupuncture stimulation significantly modulated the hippocampus and neuropeptide Y, restoring functional activities. The hippocampus and neuropeptide Y have been observed to have decreased activity in patients with stress disorders, causing physical symptoms: http://www.ncbi.nlm.nih.gov/pubmed/12749995
  40. A follow-up study in South Korea to the one mentioned above found that neuropeptide Y is involved in the regulation of various physiological functions related to anxiety, and that specific acupuncture stimulations signficantly modulated the expression of both neuropeptide Y (NPY) in the amygdala, as well as the expression of NPY-immunoreactive cells. The researchers found that this may be one way that the acupuncture stimulation reduced anxiety-related symptoms in study animals following traumatic stress. http://www.ncbi.nlm.nih.gov/pubmed/15755522
  41. A 2008 study at Kyung Hee University then found that acupuncture stimulation also modulated corticotropin-releasing factor (CRF), as well as neuropeptide Y, in the limbic system, to improve physical manifestations of anxiety induced by chemical stimulation. http://www.ncbi.nlm.nih.gov/pubmed/18060697
  42. A 2012 study at the Henan College of Medicine, Zhengzhou, China, found that acupuncture stimulation at P6, ST36, HT7, SP6, K6 and UB62 increased both the expression of GABA type A receptors in the hypothalamus of laboratory animals, as well as the up-regulation of GABA at the receptors. Stimulation at points UB62 to K6 and HT7 were shown to be significantly more effective in this regard, providing information that acupuncturists can use to achieve better results with waking insomnia and anxiety: http://www.ncbi.nlm.nih.gov/pubmed/23140052
  43. A 2013 study of abuse of a drug popularly prescribed to treat benzodiazepine withdrawal, Pregabalin, or Lyrica, was conducted in 2013, in Germany, and although prescribing medical doctors are loathe to report issues of drug abuse with prescribed popular drugs, there were 55 such reports in Germany, and the investigating panel at the University Hospital of Ulm stated that each year more such reports of Lyrica abuse or dependence are being reported: http://www.ncbi.nlm.nih.gov/pubmed/23292158
  44. A 2013 followup to study of Pregabalin (Lyrica) abuse and withdrawal, but the University Hospital of Ulm, Germany, cited a clinical case where a female patient became addicted to the euphoria with Lyrica and increased her dosage over time by seeking multiple drug prescriptions, developing a withdrawal syndrome when she sought help, involving a vegetative state. These doctors felt that a more severe addiction and withdrawal syndrome was averted because she sought help within the first 4 months of abuse: http://www.ncbi.nlm.nih.gov/pubmed/23519046
  45. A 2012 study at the University of Seville, Department of Pharmacology, in Spain, found that 2 herbal extracts from Uncaria tomentosa (Cat's claw, or Gou teng), and Eucalyptus globulus, could be used safely with benzodiazepines to ameliorate some of the adverse effects, such as restless motor activity and tremor, as well as to provide antiinflammatory effects in patients with musculoskeletal disorders that use benzodiazepines: http://www.ncbi.nlm.nih.gov/pubmed/21928376
  46. A 2012 study at the Shanghai Medical College of Fudan University, Shanghai, China, found that the chemical honokiol in the Chinese herb Magnolia officianalis (Hou pou) modulated the benzodiazepine site of the GABA type A receptor. Studies have also identified benzodiazepine-like effects from other medicinal magnolia species, such as the Magnolia dealbata, native to Mexico: http://www.ncbi.nlm.nih.gov/pubmed/22537192
  47. A 2007 study at the University of Vienna Department of Pharmacology found that an active chemical in the herb Valerian, valeranic acid, significantly antagonizes and modulates GABA type A receptor activity: http://www.ncbi.nlm.nih.gov/pubmed/17585957
  48. A 2007 study at the Peking University School of Basic Medical Sciences, Beijing, China, found that the aqueous extract of the Chinese herb Ganoderma lucidum (Ling zhi mushroom) may exert its effects via a benzodiazepine-like activity: http://www.ncbi.nlm.nih.gov/pubmed/17383716
  49. A 2005 study at the Okayama University Department of Pharmaceutical Sciences, in Okayama, Japan, found that the extract of chamomile exerted significant benzodiazepine-like activity: http://www.ncbi.nlm.nih.gov/pubmed/15863883
  50. A 2015 study at Asahikawa Medical University showed that the imbalance of corticotropin releasing factor (CRF) receptor types that lies at the heart of the functional physiology of benzodiazepines, as well as their adverse effects and difficulty with stopping the drugs, is also involved in the prevalent conditions called Irritable Bowel Syndrome, and there is probably a link, as anxiety and stress are key components to IBS: http://www.ncbi.nlm.nih.gov/pubmed/25962711
  51. A 2014 study in China showed that electroacupuncture stimulation at the points ST36 and GB34 downregulated expression of CRF type 2 receptors and upregulated expression of CRF type 1 receptors in the amygdala of laboratory animals. This not only achieved pain relief, but also had positive effects on the animal affect, or mood. This same imbalance of corticotropin releasing factor (CRF) receptor types is seen in chronic use of benzodiazepines, showing that this treatment could potentially aid in benzo withdrawal over time: http://www.ncbi.nlm.nih.gov/pubmed/25632568
  52. A 2010 study at Shanghai Medical College of Fudan University, in China, also found that electroacupuncture to ST36 and SP6 improved the measurable disorder in the hypothalamus-pituitary-adrenal axis (HPA) of laboratory animals with induced traumatic stress, and normalized the balance of CRF receptor types and UCN 1 expression (urocortin). Since these imbalances are found to be at the heart of the pathology of benzodiazepine withdrawal and rebound syndromes, such study shows the potential of electroacupuncture in the holistc treatment regimen: http://www.ncbi.nlm.nih.gov/pubmed/20848889
  53. A 2014 study at the Medical College of Georgia, Georgia Regents University, U.S.A. and Southern Medical University in Guangzhou, China, showed that regulation of the fear memory involves NRG1 (neuroregulin 1) signaling in the amygdala. Obviously, the poor regulation of fear memory is a component of chronic benzodiazepine syndrome, as well as other psychological disorders, such as schizophrenia, and a holistic protocol to restore homeostasis in the amygdala and limbic system could contribute highly to the resolution of benzo withdrawal syndrome: http://www.ncbi.nlm.nih.gov/pubmed/25451196
  54. A 2015 study at the East China Normal University, Guangzhou University of Chinese Medicine, in Guanghzhou, China, with the Georgia Regents University, in Augusta, Georgia, U.S.A. showed that regulation of the neuregulin 1 (NRG1) protein in the amygdala and other areas of the brain, associated with fear memory and effects of anxiety, is linked to overexpression of a protein called calcyon, with elevated levels of calcyon stimulating excess NRG1 signaling and hyperexcitation of the GABAergic mechanisms. This excess of calcyon was linked to a variety of mechanisms, including activity of Beta-secretase and clathrin protein expression. Such study leads to a search for an allopathic drug to control fear memory in pathology, but also points to the need to affect a more holistic restoration to achieve success, using CIM/TCM: http://www.ncbi.nlm.nih.gov/pubmed/25349163
  55. A 2015 study at Jining Medical University, in Jining, China, linked the exposure to chronic stress in laboratory animals to dysregulation of the NRG1 (neuregulin 1) and ErbB pathway in the hippocampus and prefrontal cortex of the brain, creating a depressive mood disorder. Such study demonstrates that disruption of homeostatic mechanisms in the hippocampus and amygdala, related to the GABA system, is linked to these mechanisms and explain the connection between symptoms in benzo withdrawal syndrome: http://www.ncbi.nlm.nih.gov/pubmed/26626816
  56. A 2015 study in China showed that acupuncture stimulation at the points DU20 and PC6 every other day for 28 days significantly reduced inflammatory and oxidant stress in the hippocampus of laboratory animals, reducing depression. Such studies demonstrate the potential for acupuncture stimulation to help restore these key areas of mood control in the brain, integrated with a more holistic protocol: http://www.ncbi.nlm.nih.gov/pubmed/26669192
  57. A 2015 study at the Capital Medical University, in Beijing, China, using immunoflourescence staining, and PCR analysis of tissues of the hippocampus in laboratory animals, found that acupuncture stimulation exerted a profound neuroprotective effect via the Nrf2 gene expression and microglia activation: http://www.ncbi.nlm.nih.gov/pubmed/26546103
  58. A 2015 human clinical study with functional MRI in China found that electroacupuncture stimulation at the points DU20 and DU24, along with acupuncture at Sishencong and GB20, performed 3 times a week for 12 weeks, significantly restored connectivity between the hippocampus and parietal lobe in patients with PTSD, and inhibiting excess activity between the hippocampus, parahippocampal gyrus, and amygdala, relieving symptoms: http://www.ncbi.nlm.nih.gov/pubmed/26255522