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    Albert Hofmann


    Can psychedelics target overly rigid brain networks?

    Dr. Carhart-Harris and his team have discovered that psychedelic drugs, such as psilocybin, may have the ability to temporarily disrupt these patterns, and when combined with a controlled psychotherapeutic experience, may produce changes in perception and behavior that persist long after the drug has worn off.

    Through use of fMRI (functional magnetic resonance imaging) and MEG (magnetoencephalography) scanning, Dr. Carhart-Harris and colleagues have been able to study the stability of functional brain networks, such as the normally competitive relationship between the default mode network and the task-positive network. Studies suggest that psilocybin disrupts this normal competitive pattern.

    The task positive network is a problem solving, externally focused network comprised of the salience network (which determines what needs to be dealt with in the environment) and executive network (which determines what to do with this information). The structures involved with these networks, represented by the dorsolateral prefrontal cortex, lateral parietal cortex, and subgenual anterior cingular cortex, lie laterally in the brain.

    Along the midline, the default mode network is more inwardly directed and is activated when we are introspective, engaged in theory of mind (empathy), or navigating complex social interactions. These midline structures consist of the mediotemporal lobe, the posterior cingulate cortex, the ventromedial prefrontal cortex, and the dorsomedial prefrontal cortex.

    It is important to understand that these two networks normally work in opposition to one another, so that when one is turned up, the other is turned down, like two sides of a seesaw.
    In a non-depressed brain, the ability to shift between these networks should be relatively easy.

    For example, when one is lost in one's work, the dominance of the task positive network over the default mode network is evident. Conversely, when one is engaged in inward-focused activity, such as meditation or reminiscing, there is little external work being done.

    In the context of depression it appears the introspective capacity of the default mode network becomes stuck in a ruminative mode, and that this rigidity prevents the task positive network from working normally. I translate this to patients with depression by explaining that this is why they can spend all day thinking negatively about themselves, but cannot shift focus and respond to all those emails that have been piling up. This hijacking of the DMN by rumination has been called pathological introspection and this rigidity of network activity in depression has been referred to as overstability.

    Dissolving the ego doesn't happen once and for all. The DMN will resume its duties, and it can be hard to stay in touch with alternative states of consciousness. The epiphanies some people experience on drugs, then, offer a touchstone to which we can return when the brain's default mode is on.

    https://www.psychcongress.com/blog/c...brain-networks
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    Tripping out of depression: Overcoming mental health disorders with psychedelic drugs


    You’re in a hut in the jungle, the music of wildlife and aroma of smoking herbs permeating the air. The shaman, dressed in traditional Amazonian garb, hands you the brownish sludgy concoction called ayahuasca. As you drink it – the nastiest, most foul-smelling thing you’ve ever had – the shaman begins singing, calling out to the “spirits of the jungle”. The purging begins: your stomach churns, you sweat profusely and vomit intensely, your skin burning like literal hell. And then it hits. You see yourself melting away, dissolving into the universe, and you relive your life, re-experiencing all your childhood traumas and repressed emotions, the past fusing with the present, until there is no more sense of time nor self. In what feels like multiple lifetimes, you finally awaken a few hours later with a sense of overwhelming tranquility and bliss the likes of which you’ve never felt before…

    Such an experience may seem an unconventional and perhaps “unscientific” method of treatment for mental health disorders. Yet psychedelic drugs have recently garnered renewed interest in both the public and scientific communities for their potential therapeutic effects on major depressive disorders (MDD), anxiety disorders, and addictions. The allure of these “enlightenment” drugs is certainly understandable, given the growing incidence and awareness of mental health disorders coupled with the inefficacy of current medications.

    The difficulty in finding effective medication for mental health disorders stems from our weak understanding of the pathophysiology of these conditions. For example, there currently exist multiple theories for depression, including monoamine deficiency, neuroinflammation, and dysfunction of the neuroendocrine system. Medications aim to address each of these biological pathways in a rather reductive manner. Despite their low efficacy and plethora of adverse effects, selective serotonin reuptake inhibitors (SSRIs) are still the first line treatment for MDD. In fact, traditional antidepressants have either no effect or adverse ones in a whopping 1 of every 3 patients. Furthermore, depression is not simply a neurological disorder; social and psychological determinants play a significant, if not primary, role in its pathogenesis. Studies have shown strong correlations between childhood trauma and adult onset MDD, as psychologists suggest that patients develop ingrained behavioural patterns that contribute to depression. Certainly, the heterogeneity of depression itself presents additional challenges not only in how we diagnose it, but also in patients’ responses to different treatments.

    Enter psychedelic drugs, which proponents tout as a potential cure for mental health disorders. In contrast to harmful drugs such as alcohol, cocaine, or heroin, psychedelics are neither addictive nor acutely toxic. Human brain functional magnetic resonance imaging (fMRI) studies indicate that psychedelics function by fundamentally changing the architecture of the prefrontal cortex via neurogenesis and induction of novel neural pathways. However, how these changes alter mood and induce hallucinations remains unclear. Some studies suggest neuronal excitation creating transient neural scaffolds is involved, while others demonstrate decreased activity in the brain’s key connector hubs to enable unrestrained cognition.

    Of course, the hallmark of psychedelic drugs lies not in its pharmacological actions, but in its phenomenological effects on the user. Despite their similar mechanisms, each type of psychedelic has different methods of administration, hallucinogenic effects, and public perceptions, all of which influence the experience itself and post-trip outcomes. It is important, then, to differentiate the history and uses of each drug for a more nuanced understanding of their therapeutic potential in different mental health disorders.

    LSD) was first synthesized in 1938 by Swiss chemist Albert Hofmann. Its psychedelic effects were uncovered after the chemist accidentally ingested it, and in 1947, LSD was introduced as a psychiatric drug to treat alcoholism, neurosis, and schizophrenia. Since then, the drug has been used in an infamous CIA mind control program Project MKUltra, endorsed as a route towards consciousness expansion, touted as “the next big thing” in psychiatry, and prominently featured in the arts and music scene of the 1960s. During this period, LSD became a popular recreational drug, and its association with the counterculture hippie movement prompted the United States government to outlaw the drug in 1968, despite its therapeutic potential and lack of harm or abuse risk. The turn of the 21st century saw a resurgence of research into LSD for psychedelic therapy.

    LSD is typically processed into strips that can be placed on the tongue for ingestion. Trips start within 20-30 minutes of ingestion and can last from 6 to 12 hours in a dose-dependent manner. While trips are highly variable and context-dependent, an early clinical study describes them as “psychic states in which the subject becomes aware of repressed memories and other unconscious material”, and anecdotal reports include descriptions of visual hallucinations, synesthesia, and ego dissolution. In terms of medical efficacy, randomized controlled trials have shown beneficial effects of LSD-assisted psychotherapy on alcoholism and on anxiety associated with life-threatening diseases, without any acute or chronic side effects.

    Of course, LSD can sometimes provoke “bad trips”, during which users commonly experience anxiety, panic, and despair. Such experiences sometimes induce psychotic reactions and suicide attempts. In recent years LSD microdosing became a popular method of avoiding bad trips while still harnessing the drug’s stimulatory effects. While the jury is still out on the effectiveness of microdosing, anecdotal reports describe it as enhancing overall wellbeing, reducing stress and anxiety, and improving creativity and concentration. What this also implies though is that LSD’s synthetic nature will make it easier to administer in purified form and accurately measure dosage, thereby enabling a potentially smoother transition towards becoming a prescription drug.

    Psychedelic mushrooms, colloquially known as mushrooms or shrooms, are a group of fungi that contain psychoactive compounds such as psilocybin, psilocin, and baeocystin. Mushrooms became popularized in modern Western culture after the American mycologist R. Gordon Wasson participated in an indigenous psilocybin ritual in Mexico and publicized his experience in 1957. As with LSD, psilocybin was heavily studied in the 1960s for its therapeutic potential and similarly outlawed by the end of the decade.

    In contrast to LSD, psilocybin induces different hallucinogenic experiences. Mushrooms are typically eaten, brewed into tea, or taken in pill form, with trips lasting 3 to 6 hours. Shroom trips have been described as “more giggly than LSD”, during which visions are more saturated, “mundane aspects of life can become comical”, and one’s sense of self disintegrates. Given its relatively mild psychedelic effects and weaker social stigma, it is not surprising then that the scientific community is now turning its head towards psilocybin. Recently, open-label feasibility studies indicate one to two doses of psilocybin in conjunction with therapy can assist in treatment of alcohol dependence and treatment-resistant depression for up to nine months. Similar results were found on patients with anxiety associated with advanced-stage cancer, obsessive-compulsive disorder, and substance addictions. Nevertheless, these studies have extremely small sample sizes, and definitive conclusions cannot be made due to their absence of placebo-controlled groups. To address these issues, Imperial College London has recently established a Psychedelic Research Group, with upcoming double-blind randomized controlled trials on psilocybin treatment for MDD.

    Ayahuasca, Quechuan for “vine of the spirit”, is a psychotropic brew traditionally used for spiritual and therapeutic purposes in Amazonian indigenous populations. The concoction,
    made from the Banisteriopsis caapi vine boiled with leaves from the Psychotria viridis shrub, contains the powerful hallucinogen N,N-dimethyltryptamine (DMT) and monoamine oxidase A (MAO-A) inhibitors, which allow the former to bypass gastrointestinal degradation and enter the circulation and central nervous system. Interestingly, DMT is the only known psychoactive compound that is naturally found, albeit at low levels, in the human brain.

    Unlike LSD and mushrooms, Ayahuasca-induced psychedelic experiences seem much stronger and more spiritual in nature, with stories of users going through “hell”, seeing horrific visions, reliving traumas, and talking to the plant itself, before emerging with a sense of bliss and newfound understanding of one’s place in the world. Physically, Ayahuasca users usually undergo vomiting, diarrhea, and tachycardia, considered to be a necessary purging. Although the Ayahuasca experience may not appear to be a very pleasant one, multiple self-reports of long-lasting psychological improvements suggest the plant may be worth a deeper look.

    Psychological guidance is a major part of Ayahuasca ceremonies, with a shaman typically guiding users physically and emotionally. This guidance throughout and after the Ayahuasca experience is vital for the healing process and has been implemented in the clinic. In 2010-2011, Canadian physician Dr. Gabor Mate successfully treated multiple addiction patients at his Vancouver-based clinic with Ayahuasca and guided therapy, helping them to work out their past traumas to get to what he believes is the root cause of many addictions. This approach is widely used in many Ayahuasca retreats in South America, where the drug is legal for spiritual use. To date, researchers from the University of Barcelona and University of Sao Paulo have found significant improvements in addiction patients who received Ayahuasca treatment in preliminary studies. These findings have prompted neuroscientists in the United States to seek government approval to bring this traditional brew to patients in North America.

    While preliminary research into psychedelic therapy looks promising, these results should not be interpreted as an endorsement for psychedelic drugs as self-medication nor as recreational use. Most studies so far have been small open-label trials that often do not include placebo controls, have extensive exclusion criteria, and have not measured the long-term outcomes of psychedelic treatment. Appropriate administration, psychological guidance, and extensive support, both during and after the experience, are extremely important; it’s been shown that the psychological context and expectations during the acute psychedelic experience can predict long-term outcomes on mental health.

    What this ultimately points to, however, is the need for further research, which is currently restricted by social stigma and the legal status of these drugs. A common thread in the most researched psychedelic drugs is the experience of reliving past traumas and integrating those reflections into reinventing oneself. It is crucial that we look past preconceived notions of these psychotropic plants, which have arguably co-existed with, and helped, us since prehistoric times. In a society that is growing evermore disconnected with the world, perhaps it is time we look deep into our roots and journey back into our interconnected experience of life with nature.

    http://www.immpressmagazine.com/trip...hedelic-drugs/
    Last edited by mr peabody; 28-01-2019 at 13:01.
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    For me, mushrooms have positive affects over all. I can be in the worst mood before I take them, and afterwards I have a more positive outlook on life. In the days following, I feel so much better emotionally and mentally. It feels like my mind has been cleared, and my burden lifted. Even things that bother me about the world, do so in a different way - a way that I can better understand and cope with in a positive way. I feel relieved and better able to do the things I need to do in life.

    -Choronzon333

    -----

    I had to suffer for so many god damn years, and after being days away from suicide I found psychedelics and it changed my life. It took a few doses for it to really take effect, but it's nice to finally have a day where I don't want to die.

    -FutureDoctorMandy

    -----

    I have Seasonal Affective Disorder. Magic mushrooms have played a huge roll in controlling my depression, and I'm the happiest I have ever been. After taking mushrooms for the first time, the world changed drastically and I saw the beauty in everything I once dreaded. I used to be suicidal. Now all I think about is that I will see the sun's beauty tomorrow. The meds never worked. And all it really took was a dose a psilocybin mushrooms.

    -Immortal bliss

    -----

    I first took mushrooms after a death in the family when I was at my lowest ebb of despair. They had a fantastic effect and saved my life. Just one use helps, you take it whenever you feel down. Once a month or so should see you right.

    -Ismene

    -----

    I was depressed for ten years. I took a low dose of mushrooms, and I felt I had been given a new beginning. I had immense motivation, and a thirst for knowledge which had long since passed. This beautiful mindset lasted for close to 6 months.

    -Changed


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    Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study

    Dr Robin L Carhart-Harris, Dr Mark Bolstridge, Dr James Rucker, Dr Camilla M J Day, Dr David Erritzoe, Mendel Kaelen, BSc

    Introduction

    Psilocybin is a naturally occurring plant alkaloid found in the Psilocybe genus of mushrooms. Psilocybe mushrooms have been used for millennia for healing purposes, but were only discovered by modern science in the late 1950s. Psilocybin is a prodrug of psilocin, a serotonin receptor agonist and classic psychedelic drug whose principal psychoactive effects are mediated by serotonin 2A (5-HT2A) receptor agonism. Psilocybin therefore has a novel pharmacology in the context of currently available antidepressant medications, because selective serotonin-reuptake inhibitors are not direct 5-HT2A receptor agonists.

    Enhanced cognitive flexibility, and antidepressant responses have been reported with 5-HT2A receptor agonism in animals, and increased and sustained improvements in wellbeing and optimism have been observed after psychedelic experiences in human beings. Findings from human imaging studies with psilocybin have supplemented these discoveries, showing changes in brain activity suggestive of antidepressant potential; for example, a range of effective antidepressant treatments have been found to normalise hyperactivity in the medial prefrontal cortex and we found reduced blood flow in this region with intravenous psilocybin. Moreover, data obtained from large-scale population studies have recently challenged the view that psychedelics negatively affect mental health, with one study's findings showing lower rates of psychological distress and suicidality among people who had used psychedelics within their lifetime than among those who used no psychedelics. In modern trials, psychedelics have been found to reduce anxious, depressive, and obsessive-compulsive symptoms, as well as addictive behaviours, often for several months after just one or two exposures. Extensive historical and modern evidence now supports the view that, administered in a controlled environment with appropriate support, psychedelics have a favorable safety profile.

    Discussion

    In this open-label, single-arm pilot study, we sought to examine the feasibility of administering psilocybin to patients with treatment-resistant depression as a prelude to a larger randomised controlled trial. Our results support the view that, done with appropriate safeguards, psilocybin can be safely administered to this patient group.

    Because this was a small-scale feasibility study with an open-label design, strong inferences cannot be made about the treatment's therapeutic efficacy. However, the data do suggest that further research is warranted. The response rate to psilocybin was 67% at 1 week after treatment, and seven of these eight patients also met criteria for remission. Moreover, 58% of the patients maintained their response for 3 months, and 42% remained in remission. It is also worth noting that psilocybin has a favorable toxicity profile and is not associated with compulsive drug-seeking behaviors in animals or human beings. The side-effects that we noted were minor, and expected in light of previous studies of psilocybin.

    Spontaneous recovery in refractory depression is rare, and many of the patients in the present study reported having depression for much of their adult lives. Key questions for future research therefore should address why the therapeutic effect observed in the present study is so large, and if it can be replicated when tighter experimental controls are introduced. Because the treatment in our study consisted of not just two psilocybin administrations but also psychological support before, during, and after these sessions, as well as a positive therapeutic environment for the sessions, the relative effects of these factors need to be determined, which can only be done by conducting further trials with appropriate control conditions.

    A logical next step would be to carry out a placebo-controlled randomised trial in which the level of therapist contact is consistent between conditions. This would enable any between-group differences in clinical outcomes to be attributed to psilocybin rather than the psychological support provided. However, a positive interaction between these variables seems likely, and inert placebo-based blinds are known to be ineffective in studies involving conspicuous experimental interventions, because patients can easily discern whether they are in the active condition or not. Use of an active placebo for the control condition might therefore be worth considering. Additionally, randomised comparative efficacy trials incorporating another treatment for refractory depression could also be explored.

    The magnitude and persistence of the antidepressant effects observed are consistent with those observed with psilocybin in chronic psychiatric conditions. For example, 80% of long-term heavy tobacco smokers demonstrated abstinence from smoking 6 months after two treatment sessions with psilocybin. Alcohol-dependent patients demonstrated significantly reduced drinking behaviours over 8 months after one or two psilocybin sessions. Significantly decreased anxiety and depression scores were observed 3 and 6 months after a single dose of psilocybin in patients with anxiety related to end-stage cancer, and improvements in wellbeing lasting for more than 1 year were observed in healthy individuals given a single dose of psilocybin. Rapid and enduring decreases in depressive symptoms were also recently found in a small-scale feasibility trial involving the psychedelic brew, ayahuasca.

    It is important to consider the limitations of this pilot study; for example, although all patients showed some clinical improvements for at least 3 weeks after treatment, and no serious or unexpected adverse reactions were observed, enduring improvements beyond 3 weeks were not observed universally, and five of the 12 patients showed a degree of relapse at 3 months.

    One should be cautious of the potential for inflated effect sizes in early trials, particularly when the sample size is small. That all patients showed some improvement in their depressive symptoms for up to 3 weeks after treatment could be suggestive of an expectancy bias. It may also be relevant that most patients in this trial were self-referring and, thus, actively sought this treatment. Psychedelics are known to promote suggestibility, which might have further enhanced positive outcomes. Future double-blind randomised controlled trials could address the role of expectancy and suggestibility by measuring and controlling these variables. For example, patients could be asked about their pre-treatment expectations, suggestions could be controlled between conditions, and outcomes from self-referred patients could be compared with those from patients referred via clinicians. From a more pragmatic perspective, if expectancy or suggestibility are found to be influential in the context of psychedelic therapy, they could be treated as exploitable components of the treatment model rather than confounding variables.

    Serotonergic antidepressants have been found to down-regulate the primary receptor target of psilocybin (5-HT2A) and attenuated subjective responses to psychedelics have previously been reported in individuals chronically medicated with serotonergic antidepressants. Thus, patients may be required to withdraw from antidepressant medication before receiving psilocybin and this should only ever be done with care.

    In conclusion, we sought to assess the safety and tolerability of psilocybin plus psychological support in patients with unipolar treatment-resistant depression. Our findings support the feasibility of this approach and the magnitude of the post-treatment reductions in symptom severity motivate further controlled research. Psilocybin has a novel pharmacological action in comparison with currently available treatments for depression and thus could constitute a useful addition to available therapies for the treatment of depression.

    https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366%2816%2930065-7/fulltext



    Last edited by mr peabody; 27-12-2018 at 09:39.
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    New clues in the psychedelic treatment of depression

    Depression, despite affecting millions worldwide, is still a condition we don't fully understand.

    In fact, we understand it so poorly that typical pharmaceutical treatments indiscriminately target whole neurochemical systems, resulting in unstable effectiveness and a host of side-effects.

    Up to 44% of people suffering from depression have not found relief from typical antidepressant therapies. Even patients who find some form of relief from the usual prescribed antidepressants need frequent doses, sometimes causing unpleasant side-effects, and these drugs often lose their effectiveness after several years of treatment.

    But where pharmaceuticals are failing, psychedelics could be a new hope.

    Recent large studies using psychedelics such as psilocybin have shown that a single moderate dose of these substances can significantly reduce depression scores in patients with treatment-resistant depression. The antidepressant effect of psychedelics also last much longer than typical treatments, with reduced depression scores maintained for several months after treatment.

    A big part of the reason that psychedelics appear to be so effective at treating depression is due to their ability to induce a mystical experience. Participants who describe a highly spiritual or personally meaningful experience with psilocybin were more likely to have reductions in depression scores, according to one study, and the strength of the mystical experience has also been directly linked to psychedelics' anti-addiction effects.

    It appears that there's something special about having a transcendental encounter during treatment. Linking this powerful effect of psychedelics to their mechanisms of action in the brain is helping scientists start to piece together the way that depression works, and potentially the best ways of treating it.

    A recent review from Dr Robin Carhart-Harris and Professor David Nutt presents a new, all-encompassing model of depression that explains how both typical antidepressants and psychedelic therapies could help treat depression in different way.

    Their bipartite model of serotonin signalling proposes that depression can be most effectively treated through two receptor systems - the 5-HT1A and the 5-HT2A receptors.

    The author's theory is that the 5-HT1A system of the brain is generally in charge of regulating anxiety during normal consciousness. This is the receptor system that typical SSRI medications work through, reducing levels of anxiety directly. This is the system that deals with passive coping.

    However, when people start to experience abnormally high levels of stress (such as in cases of severe depression), the brain's 5-HT2A system takes over, and starts to change the receptivity of the brain. In other words, it makes the brain more flexible to change, and makes us more sensitive to the environment.

    This is the system that deals with active coping. It's the receptor system that psychedelics activate, and this explains a lot about their effects.

    The activation of the 5-HT2A system can backfire if we're in a dangerous or stressful environment. While suffering the stress-inducing effects of severe depression, activation of the 5-HT2A system can amplify our anxiety and make things worse. This explains why people can have traumatic psychedelic experiences if they're not in the right setting, or receiving the proper guidance.

    Activation of 5-HT2A receptors can also produce significant changes in people's cognition, helping them address serious problems in their life in a unique form of self-therapy. This has been observed in participants of clinical trials into the effectiveness of psychedelic therapy, who report the most significant benefits after experiencing major personality changes.

    The theory is that the brain has two mechanisms in reacting to depression. Firstly, the brain's 5-HT1A system tries to address feelings of anxiety. When this becomes too much, and the brain faces too much stress, the 5-HT2A system takes over, and tries to change the way the brain responds to the world in a more dramatic way.

    Therefore, the ideal therapy for depression could be a combination of 5-HT1A activation (to help people cope with anxiety as a first defence), followed by 5-HT2A activation (to help people adapt and heal).

    It's important to know that this is still just a theory. The authors acknowledge that this is an oversimplification of one of the most complicated neurotransmitter systems in the brain, and that the evidence isn't yet complete. But this is arguably the most coherent model of depression that has been put forward so far.

    We're living in a special time, science is starting to provide us with evidence that an holistic approach to mental health is within our grasp. We're starting to understand the power of mystical and transformative personal experiences, and scientific advancements will help us marry the worlds of transpersonal psychology and modern psychiatry.

    Psychedelics could be the catalyst for a theory of depression that treats patients as minds rather than objects; as people rather than malfunctioning machines.

    Here's to a humane, holistic, psychedelic future.

    https://thepsychedelicscientist.com/...ion/#more-1271


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    Ketamine shows potential in anxious treatment-resistant depression

    Salloum NC, et al. - January 4, 2019

    IV ketamine demonstrated similar efficacy in patients with anxious and nonanxious treatment-resistant depression, according to findings from a pilot study.

    Though these exploratory results suggest that ketamine has potential for the treatment of patients with or without anxious treatment-resistant depression, future research is needed, according to researchers.

    “Several controlled trials have now established the rapid and robust antidepressant effect of ketamine in patients with [treatment-resistant depression]. However, evidence for its efficacy in anxious depression remains scarce,” Naji C. Salloum, MD, from the department of psychiatry, Massachusetts General Hospital and Harvard Medical School, and colleagues, wrote in Depression & Anxiety.

    Salloum and colleagues conducted secondary analyses of data from a recent randomized, active placebo-controlled trial of IV ketamine in patients with unipolar treatment-resistant depression that found response to ketamine-combined treatment was superior to midazolam. The researchers compared treatment response to ketamine vs. midazolam in patients with and without anxious depression.

    In total, 99 participants with treatment-resistant depression were randomized to receive either a single dose of IV ketamine, or active placebo. Researchers measured change on the Hamilton Rating Scale for Depression (HAMD-6), as well as change on the Montgomery–Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression-Severity scale (CGI-S). At 1- and 3-days post-treatment, they assessed the effect of anxious depression baseline status on response to ketamine compared with midazolam.

    Overall, 45 patients had anxious treatment-resistant depression. Analysis revealed non-significant interaction effect between treatment group assignment and anxious/nonanxious status as measured by the HAMD-6 post-infusion on the first day. The investigators found similar results on the CGI-S and MADRS on both day 1 and day 3.

    In addition, participants with anxious depression had a lower level of dissociative symptoms at 40 minutes after infusion initiation than those without anxious depression as measured by the Clinician-Administered Dissociative States Scale, according to the results.

    “In contrast to reports from monoaminergic antidepressants, our data suggest that patients with anxious depression respond equally as well to ketamine compared to those with nonanxious depression,” Salloum and colleagues wrote. “The exact mechanism behind the differential response to ketamine versus other conventional antidepressants in anxious depression remains unclear. These results are still exploratory and future larger and adequately powered studies designed to specifically test this aim are warranted.” – Savannah Demko

    https://www.healio.com/psychiatry/mo...ant-depression
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    The case for Ketamine in treating Suicidal Ideation

    Eugene Rubin M.D., Ph.D., Charles Zorumski M.D.

    Should ketamine be used in the emergency room to treat suicidal patients?

    In an article published recently in the American Journal of Psychiatry, Samuel Wilkinson and colleagues examined the effect of ketamine in reducing suicidal ideations. They utilized a technique called meta-analysis to combine data from ten clinical studies that fulfilled specific rigorous criteria. They found that a single intravenous infusion of ketamine, at doses akin to those used in other studies to treat major depression, led to a rapid decrease in suicidal ideations. Within a day, about 55 percent of individuals who received ketamine no longer had suicidal ideations, compared to 20 percent who received a placebo. This reduction in suicidal ideations lasted for at least seven days.

    Does this mean that emergency room physicians should routinely administer infusions of ketamine to patients who voice suicidal ideations? Should ketamine be used as an anti-suicide medication regardless of the patient’s diagnosis or the circumstances associated with the suicidal ideations?

    At least for now, our opinion is an emphatic “no.” Let us explain.

    Several disorders are associated with suicidal ideation and completed suicide, including depressive disorders, substance use disorders, and certain personality disorders. Short-term and long-term treatments differ for these illnesses. Suicidal ideation associated with a major depressive episode substantially increases the risk for medically or psychologically significant suicide attempts. The degree of risk varies as a function of age and gender. For example, elderly men with depression and suicidal ideations are at high risk for killing themselves. Although administering ketamine in the emergency room might lower suicidal ideations and decrease depressive symptoms, would it be safe to discharge such an individual without observing them on a psychiatric inpatient unit first and seeing how they do over several days?

    Suicidal ideations are a common reason why some individuals with personality disorders (for example, borderline personality disorder) seek treatment in the emergency room. Most research investigating the influence of ketamine on suicidal ideations has involved patients with major depression. Data do not exist about the effectiveness of ketamine in patients suffering from a personality disorder in the absence or presence of major depression. These individuals frequently benefit from counseling that helps to alleviate current stressors. With appropriate support and follow-up arrangements, the individual often can be discharged from the emergency room. It is unknown what a ketamine infusion would do in these circumstances. Would it alleviate the suicidal ideation? Would it give the treatment team the sense that they could substitute an infusion of ketamine for a careful diagnostic interview and counseling?

    There is also no information available about the use of ketamine for suicidal ideation in patients with substance-use disorders. These disorders are major contributors to completed suicides, and ketamine itself is an abused drug. It also remains unclear what to do for patients who have recurrent suicidal ideation. Should they be exposed to repeated infusions of ketamine? At what interval can they be treated safely, and what are the risks of repeated ketamine infusions?

    As more is learned about the effects of ketamine, it may become appropriate to utilize this medication in individuals with suicidal ideation who are suffering from severe depression and are admitted to an inpatient psychiatric unit. The medication might rapidly help with depressive symptoms, including suicidal thoughts, and allow the inpatient treatment team to more effectively work with these individuals. It is conceivable that such a treatment might allow for more rapid improvement, leading to a shortened hospital stay. In any event, even a short hospitalization allows for careful monitoring of the patient and more time to confirm the diagnosis and institute appropriate follow-up plans.

    In our opinion, administering an infusion of ketamine to a suicidal patient in an emergency room and then discharging the patient a few hours later isn’t, in general, a good therapeutic approach. More research is needed to determine the influence of ketamine in individuals with and without major depression, as well as its influence on the prognosis of a person presenting to the emergency room with depression and suicidal thoughts.

    https://www.psychologytoday.com/us/b...cidal-ideation

    -----

    Use of Ketamine in acute cases of suicidality

    Jae Lee, DO, Puneet Narang, MD, Manasa Enja, MD, Steven Lippmann, MD

    Ketamine is an N-methyl-D- aspartate antagonist with rapid antidepressant effects. Research shows that ketamine has a fast onset of reduction in depressive symptoms and shows sustained remission of suicidal ideation in some patients. This article provides a brief review of the literature on the use of ketamine for depression and in acute cases of suicidality. The authors conclude that, while further investigation is needed, ketamine may be a useful treatment option for acute suicidality in emergency room settings.

    Major depressive disorder (MDD) is a common psychiatric illness in the United States, with a lifetime prevalence of 17 percent. Bipolar disorder (BD) has a prevalence of 1 to 4 percent in the United States. Suicide occurs in up to 1,500 cases of MDD and BD each year, and even hospitalization for suicidal ideation or behavior does not prevent all suicides; in fact, the risk for suicide is high immediately following hospital discharge among patients who have been hospitalized for suicidal behavior.

    While there are many treatment options for depression, none rapidly diminish symptoms (i.e., within hours). Ketamine, an N-methyl -D- aspartate (NMDA) antagonist, has been shown to have rapid onset of antidepressant effects, which might be useful in acute cases of suicidalality in the emergency room setting.

    USE IN SUICIDALITY

    Noting the rapid antidepressive effects of ketamine, research has demonstrated its effectiveness in emergency room settings. In a study involving 14 subjects who presented to the emergency room for depression with suicidality, a single intravenous ketamine bolus was prescribed.16 These patients, whether discharged or hospitalized, were monitored for four hours and were followed up daily for 10 days. After 4 hours, the mean MADRS score decreased from 40.4 at baseline to 11.5 and the MADRS suicide score decreased from 3.9 to 0.6. Furthermore, diminished suicidal ideation was sustained over 10 days, maintaining a greater than 50-percent reduction in MADRS at Day 10 post-infusion for all patients.

    A single-blind clinical trial involving 49 subjects who presented to the emergency room with suicidal ideation or behaviors received a single bolus of 0.2mg/kg ketamine and were rated at baseline, 40, 80, and 120 minutes. After 40 minutes, the SSI score dropped from 23 at baseline to 16.2 and the MADRS score dropped from 38.2 to 25.6. The greatest reduction in SSI and MADRS scores was at 40 minutes. Ten days after the ED visit, only 6.1 percent of the enrollees expressed suicidal ideations.

    One patient with chronic suicidality had a decrease in MADRS score from 4 to 2 within 24 hours following a single oral dose of ketamine. In a double-blind, randomized, crossover, placebo-controlled trial, 15 subjects with bipolar I or II maintained on lithium or valproate received IV infusions of ketamine.7 Using a 50-percent change in MADRS as response criteria, 64 percent of the ketamine-infused subjects responded within 40 minutes after its infusion with reduced suicidal thinking.

    CONCLUSION

    Ketamine can induce fast onset antidepressant effects in patients with depression. It also may rapidly decrease suicidal thinking within 40 minutes. Sustained decrease in suicidal ideations at 10 days post-infusion has also been reported.

    Until further investigation on ketamine’s clinical use, safety, duration, and dosing is completed, ketamine treatment is not recommended for routine clinical applications or for use in place of psychiatric hospitalization during acute episodes of suicidality. Despite evidence of rapid improvement within 40 minutes, response times to ketamine may be slower in some subjects.

    Clinicians should also be mindful of dissociative effects and abuse potential. Nevertheless, given its rapid onset of antidepressive effects, ketamine could be useful in times of suicidal crises in emergency room settings, and its use warrants further investigation.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382138/

    -----

    A possible role for Ketamine in suicide prevention in emergency and mainstream psychiatry

    T. S. Sathyanarayana Rao, Chittaranjan Andrade

    There is a growing body of evidence that indicates that, in subanesthetic doses, ketamine has rapid antidepressant and anti-suicidal action. In fact, suicide risk is one context within a major depressive episode in which the use of ketamine has been specifically suggested. Small studies conducted in emergency department settings have demonstrated that the anti-suicidal effect of ketamine may even be apparent within 40 min of treatment.

    Many studies have assessed the antisuicidal effect of ketamine. These studies were examined in a systematic review and meta-analysis by Bartoli et al. These authors searched electronic databases and other sources and identified five clinical trials that assessed outcomes at or within 4 h after a single session of IV ketamine in patients with current suicidal ideation. Two of these trials were conducted in emergency room settings. Two trials administered ketamine as an IV bolus and the other three administered ketamine as an IV infusion. In summary, a single session of IV ketamine was found to be associated with a substantial reduction in suicidal ideation in patients with current suicidal ideation. The effect was seen within 4 h of treatment, and the effect size was large.

    Whereas open studies and randomized controlled trials of single and repeated doses of iv ketamine have demonstrated that ketamine attenuates measures of suicidality even in patients with treatment-refractory depression, the benefits have been observed to wear off within days to a week, along with the wearing off of the other antidepressant benefits of ketamine. In some patients, anti-suicidal benefits may persist for as long as 10 days. Repeated dosing with ketamine may then be necessary to maintain antisuicidal action if the risk of suicide reemerges after initial attenuation with ketamine.

    Suicidal behavior does not occur only in the context of a major depressive episode. It may also occur in patients with personality disorder, those exposed to sudden, serious stress, and other conditions/situations. Research is necessary to determine whether subanesthetic dosing with ketamine has anti-suicidal benefits in patients with diagnoses beyond major depressive disorder or bipolar depression.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5659073/

    -----

    My son tried to commit suicide, and was placed in a psych ward for a week. But about six to eight months after this attempt, he tried again-this time the emergency room doctors gave him ketamine-in an IV-and a very small amount over a few hours time. My son said with in just a few minutes of starting the IV, something clicked over-he said it was amazing! He said it felt like it went in his head and literally swept it-like a broom-clean?! I was of course surprised and concerned-but after I saw him and it was physically obvious that he felt a lot better, I relaxed a little. I am a skeptic by nature. But, he told me that the ER doctor told him he could come in every three months and they would hook him up and give him a dose of ketamine - if he wanted to be part of the study, and his insurance would cover it. He hasn't gone back, but he hasn't had another "suicide spell" either in almost a year?! He still takes a serotonin reuptake-and counseling. But, even I, the skeptic am amazed! Astonished! And feel like yes, they should be using this in the ER. Ketamine will save lives!

    https://www.psychologytoday.com/us/b...cidal-ideation
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    I am someone who has suffered from severe depression since childhood. I've tried prescription anti-depressants, therapy, exercise and sleep. I'm a pro-active and intelligent person who has never taken recreational drugs and tries not to abuse alcohol. A very good friend told me about psilocybin and said it might help, and although deeply skeptical, I felt like it was worth a shot and took them in a safe, controlled environment.

    The difference has been enormous. It's not permanent (I have to repeat it every 4-6 months), but it's like having the volume turned down on part of my brain that seizes onto negativity or procrastinates, and it's like waking up the next day and feeling optimistic about the future for the first time. If nothing else it's given me the opportunity, and relief to be able to put in place the structures that will hopefully help me maintain a drug-free long-term mental health that would otherwise be impossible.

    -FreshFlesh

    -----

    I had depression / anxiety / whatever for about 11 years. I booked a hotel room in Amsterdam this year, took some mushrooms and found some revelations. You realise that the mind is conditioned, and that the capacity for imagination is infinite. The personal revelations made me realise the importance of making certain changes in my life, which I did when I got back.
    I feel happier, and I'm on a more meaningful path, or rather the only real path for me.

    -ID7034232

    -----

    I had bipolar disorder throughout my teens and 20s. I started regularly using LSD, mushrooms and MDMA in my 30s. That helped me enormously, and for the first time in my life, I really came to terms with who I am and my place in the world. I am in my 40s now, and I only indulge occasionally. I've had very good mental health for the last decade, a happy state that I honestly attribute to psychedelics.

    -campesque

    -----

    Iboga is an amazing substance. I had some emotional issues that I was able to manage with few drinks. But after some time I was drinking a lot, and I ended up with depression in really bad shape, not only emotionally, but physically as well. I got really scared and tried to get back to normal, but it's not so easy when you're tired all time and don't have the energy to do anything. Someone told me about Iboga and after some research I did my first flood dose. It was a really intense experience, but after 1-1/2 days of proper cleansing of my mind and body, I was reborn. Iboga gave me full access to understanding myself, to my own mind programs and behavior patterns.

    -Mike M



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    Teaching an old drug new tricks: Ketamine and Depression

    by Nancy Brier | January 29, 2019

    “No fresh flowers,” my doctor said. “Avoid salad. No uncooked food. And don’t bring visitors home.”

    Treatment for breast cancer took the better part of a year, and a lot of that time, I spent alone. No wonder cancer sometimes comes with depression.

    I had chemotherapy for 16 weeks, and after each session, my white blood cell count dropped dangerously low. It’s a side effect called neutropenic fever, and it nearly took my life. Chemo saved me, but it almost killed me in the process.

    During those bouts of fever, my doctor told me to quarantine myself. I couldn’t risk exposure to germs that might weasel into my system. Being around my husband and our daughter was OK because our bodies have built up resistance to each other. Everyone else was off limits.

    The only upside was that my sisters cleaned my house. While I was getting infused with life-saving meds, Peg and Jane boiled every surface in our home. They scrubbed trashcans, bleached countertops, and scoured corners. Sometimes I wish I could fake neutropenic fever just to get my house that clean again.

    After chemo and surgery, I had a five-minute blast of X-rays every day for six weeks. My hospital was hours from home, and I thought my heart would break when Gary and Lauren waved goodbye in front of our house.

    Months later, Gary told my doctor I was depressed.

    For as long as I can remember, I’ve battled depression. Childhood trauma left a gash on my soul I’ve tried to patch, and I guess cancer added another layer to that wound.

    My oncologist put me on an antidepressant, which helped, but other people haven’t been so lucky. When depression goes untreated, it can be more dangerous than any disease I know. Lots of people haven’t survived it, and studies suggest that breast cancer can increase the risk.

    That’s why I attended a lecture in Palm Desert, California, about the link between depression and cancer.

    Dr. Samuel Ko, the guest speaker, is a soft-spoken emergency room specialist and a pioneer in treating depression using a drug with a complicated history.

    In 1970, the FDA approved ketamine as a dissociative anesthetic used by ER doctors and anesthesiologists for sedation during painful procedures. It’s also been used during wartime as a battlefield anesthetic, in veterinary medicine, and even recreationally as a hallucinogenic drug akin to LSD, MDMA, and mushrooms.

    Under the careful supervision of a medical doctor, the off-label use of ketamine can also provide immediate relief to people at risk for suicide due to depression and for others frustrated with attempts to combat depression.

    Dr. Ko’s first experience with using ketamine on a depressed patient was in the ER. He said in the speaking session, “The problem with antidepressants is that they take a long time. Sometimes they don’t work at all. Or they have intolerable side effects. Since I’d used ketamine for procedural sedation and done a deep dive into the evidence behind ketamine, I suggested we try it on a patient who’d run out of options.”

    Using ketamine to treat depression in the emergency room was — and still is — out-of-the-box thinking. But after an explanation of the latest research, Dr. Ko convinced the charge nurse and staff to try it. Serendipitously, the nurse had a brother with depression and PTSD, and she’d heard about the benefits of ketamine.

    “The patient, who was suicidal when she arrived, experienced immediate relief. Although she faced hard work in the future, the agony she presented with was lifted, and I decided I’d create a clinic focused on providing ketamine infusions.”

    Although every case is different, most ketamine patients get an infusion three times a week throughout two weeks, for six initial infusions. Then, they get booster infusions until treatment is no longer needed.

    Before each treatment, Dr. Ko asks patients to set an intention. He wants them to think about an objective for that session and concentrate on it throughout the infusion. This mind-body connection, he says, is integral to healing.

    After talking with Dr. Ko, I visited his infusion room. It has soft colors, an overstuffed recliner, and a view of palm fronds against a blue sky. The patient’s blood pressure, cardiac rhythm, oxygen saturation, and respiratory rate are monitored throughout the process, and a doctor or nurse stays in the room the entire time.

    Dr. Ko’s emphasizes that as soon as they’re able, patients need to adopt lifestyle changes to keep depression at bay. Physical exercise, artistic expression, healthy relationships, restful sleep, clean diet, and spirituality are all part of the healing process he advocates.

    “Sometimes,” Dr. Ko says, “having depression is like being in quicksand. Ketamine can be the catalyst that helps people get unstuck so they can better help themselves.”

    https://breastcancer-news.com/2019/0...cer-treatment/


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    Psychedelics and depression: My experience

    by Tim Williams

    I suffer from PTSD, and quite a severe level. I have severe depression with suicidal ideation, short term memory issues, anticipative anhedonia, and aversion to interacting with other members of the public. There ARE some things you can look at that may be of considerable help. I have extensive, personal experience with each, and they've all helped me to great degrees.

    The curative abilities of psychedelics are well-documented and have been noted since the 1960s. Specifically, low-dose psilocybin provokes neurogenesis (neuron birth) in the hippocampus. This is significant since the hippocampus shrinks in profoundly depressed and anxious people. Short term low-dose psilocybin has been shown to cause fear extinguishment, i.e. cessation of the nervous response when exposed to a trauma trigger. I can vouch for this being of considerable benefit for me right now. MDMA and LSD also have effects, though slightly different. LSD is known to weaken depression and addictive/compulsive behaviours, and MDMA was one of the most effective tools in psychoanalysis until it was banned as a party drug. Single or intermittent use of DMT is also known to be of benefit - this one, personally, completely cured fear of dying on my first go.

    Ibogaine is a psychedelic but a very unusual and interesting one. It has a number of effects on a number of receptors, with stunning and profound results. One of its uses is in drug addiction, where it is up to 20x more effective than traditional detox programs. The OTHER use, which is intertwined with the anti-addictive effects, is in non-psychotic depressive disorders.

    Its multi-pronged action simultaneously resets opiate receptor tolerance; floods the brain with dopamine, leading to re-regulation of disturbed dopaminergic effects such as anhedonia; has profound NMDA inhibitory effect (which is a whole new area of anti-depressive research right now, and also allows you to re-process traumatic memories); is a stimulant (cures brain fog and lethargy); is an SSRI (cures depressive behaviours); and last but not least, it up-regulates production of BDNF. BDNF is a growth factor which causes neurons to re-sprout and repair - think a bare tree growing new leaves. Further, taking the full flood dose of 25mg/kg gives you a fascinating 20 hour trip in which you have unparalleled access to all your memories (thanks, NMDA inhibition) and can literally re-visit and gain insight into any part of your life. This has been called "2 years of intensive therapy in a single day."

    Ibogaine can be dosed as the psychedelic flood dose, but that requires medical preparation, a minder, and is quite rough as a trip - expect nausea and ataxia. However it's rewarding enough that many people do it once a year just for the incredible insight into one's self that it brings.

    The way I tend to use it is microdose. This is a 50mg dose per day, in a 7 days on, 3 days off pattern. The dose is not psychedelic at this point. You don't notice it affecting you at all, but it IS there doing its work... and by the second week you will definitely start to notice significant improvements in many areas.
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    Ketamine for Treatment-Resistant Depression
    *

    Lee C. Chang , Suman Rajagopalan , and Sanjay J. Mathew, Carlos A. Zarate Jr.

    First conceptualized by Hippocrates, depression and mania are mankind’s oldest known brain disorders. These illnesses are common, often disabling, and associated with a significantly elevated risk of suicide. Indeed, major depressive disorder (MDD) is the most common psychiatric disorder in developed countries, with a prevalence of approximately 17 %. In 2004, the World Health Organization (WHO) ranked MDD third among the leading causes of global disease burden.

    Today, available medications for MDD act almost exclusively on monoamine neurotransmitter systems (dopamine, norepinephrine, and/or serotonin). Unfortunately, conventional antidepressants have low rates of treatment response; one-third of patients with MDD will respond to their first antidepressant, but approximately two-thirds will achieve an initial response only after trying several classes of antidepressants and augmentation strategies. Even when these agents are effective, they are associated with a delayed onset of action of several weeks. This latency period significantly increases risk of suicide and self-harm and is a key public health issue.

    The situation for bipolar disorder (BD) is perhaps even bleaker. Lithium, discovered in the late 1940s, remains the only drug specifically indicated for BD; BD is otherwise managed in clinical practice with a wide array of drugs, including anticonvulsants, antidepressants, and antipsychotics. Thus, there is a strong need to identify and rapidly test novel antidepressants with different biological targets beyond the classic monoaminergic receptors and their downstream targets; these agents would also be expected to act faster and more effectively.

    The chapters in this study chart the rapid and remarkable field of research into ketamine and other glutamatergic modulators. In the early 1990s, a seminal rodent behavioral despair model study of depression first demonstrated that the NMDA receptor complex played a major role in antidepressant action. A decade later, the first report was published of rapid antidepressant effects associated with ketamine in patients with MDD. Since 2006, when ketamine began to be systematically studied particularly in treatment-resistant depression—the number of studies investigating ketamine as well as other glutamatergic modulators in MDD has multiplied exponentially.

    This study is the first-ever scholarly compendium of scientific information about the use of ketamine in treatment-resistant depression and related conditions, an area in which there is surging worldwide interest. It is worth noting that one author recently observed that the discovery of subanesthetic NMDA receptor antagonists as rapid and robust antidepressants revolutionized the field of mood disorders research, noting that their discovery was “arguably the most important discovery in psychiatric research in half a century.” In this study, we have brought together an international group of clinicians and researchers from a broad swath of interrelated disciplines to offer the most up-to-date information about clinical and preclinical findings in ketamine research.

    The discovery of ketamine’s rapid and robust antidepressant efficacy has provided hope for patients with treatment-resistant depression as well as the health professionals who work in this field. Ketamine is a paradigm-shifting agent for several reasons. First, its use as a proof-of-concept agent has led to the identification of novel glutamate-based mechanisms of disease and treatment response in depressive disorders. Second, it may hold promise as a first-in-class rapid-acting antidepressant medication. Indeed, the initial clinical studies with ketamine bolstered the view that rapid antidepressant effects are achievable in humans. These findings facilitated the development of new treatments for depression that target alternative neurobiological systems. New therapeutics could significantly lower morbidity and mortality for both MDD and BD and commensurately minimize or prevent disruption to personal, family, and occupational life and functioning as well as lower risk of suicide.

    An additional area of considerable importance is that ketamine appears to have significant anti-suicidal effects. This is an area of public health where swift onset and significant response are absolutely vital and where ketamine may have an immediate impact. Notably, ketamine has also shown preliminary efficacy in other disorders such as obsessive-compulsive disorder, post-traumatic stress disorder, and alcohol/ substance abuse, which may ultimately extend its utility in clinical practice. Synergistically, ketamine has also been used in conjunction with electroconvulsive therapy (ECT) to increase its effectiveness.

    Research over the past decade—and particularly over the last five years—has made great advances toward improving our understanding of ketamine’s underlying mechanisms of action as well as compiling mounting evidence of its superior antidepressant efficacy. Importantly, this work has provided a sort of scaffolding on which our knowledge has grown exponentially with every preclinical and clinical study. This burgeoning evidence is essential for the future development of targeted therapies that are more effective, act more rapidly, and are better tolerated than currently available treatments.

    Historical Perspective

    Ketamine is an old drug that has been reborn as a potential treatment for one of the most serious of all diseases: treatment-resistant depression. Ketamine was synthesized by Calvin Lee Stevens, professor of organic chemistry at Wayne State University and a chemical consultant to Parke Davis. Early preclinical pharmacological testing at Parke Davis was done by Graham Chen and Duncan McCarthy. Ketamine was found to produce excellent anesthesia and was short-acting. Its safety profile in animals was evaluated by Alex Lane, head of clinical pharmacology at Parke Davis.

    The initial ketamine studies in humans were led by Edward F. Domino, M.D., from the University of Michigan, with the first human receiving ketamine in an intravenous subanesthetic dose on August 3, 1964. Domino recounts, with a hint of regret, that many years ago while working part-time as a clinical pharmacologist at the Lafayette Clinic in Detroit, he would be referred patients who were abusing ketamine, a number of whom were depressed.

    “I remember one young lady, in particular, who was a chronic phencyclidine and later ketamine abuser. She had serious bouts of mental depression. I asked her why she took these illicit drugs rather than her usual antidepressant medications. Her answer was ‘Oh, doctor, my antidepressants don’t work as well’. She stated that ketamine and phencyclidine worked quickly and were much better antidepressants, but they didn’t last as long so she took them again and again. I promptly recommended that she stop this bizarre practice because it would only harm her. I never pursued the possible antidepressant actions of ketamine.”


    Ketamine emerges as an antidepressant

    The possibility that glutamate could be involved in depression and that N-methyl-D-aspartate (NMDA) antagonists such as ketamine could possess antidepressant-like actions can be traced to studies conducted in the early 1990s, particularly those by Phil Skolnick and colleagues.

    Building on the observation that inescapable stress exposure in animals disrupted hippocampal long-term potentiation, an NMDA receptor-dependent process, Skolnick and his associates found that many types of drugs that reduce NMDA receptor function had antidepressant-like effects in several animal models. Reduced NMDA receptor function emerged as a correlate of long-term antidepressant administration. Thus, by the mid-1990s, there was a compelling preclinical literature that supported the notion that ketamine might have antidepressant properties, but this hypothesis had not yet had an unambiguous test in humans.

    In the early 1990s, John Krystal and I, when we were together at Yale, led a research group that began to focus on the role of glutamate in a number of psychiatric disorders. We were aware of the literature just cited when we initiated our first study of ketamine in depressed patients. However, we were not expecting the rapid and robust antidepressant effects of ketamine that we observed in our patients. But we thought we might be onto something important and decided to publish our findings.

    To our surprise, the initial report had very little impact on the field. Perhaps it was just not believed that an antidepressant effect within hours was possible. Also, there was likely concern about the abuse potential and psychotomimetic effects of ketamine. For years, there was no attempt to replicate the antidepressant effects of ketamine. Consequently, when I was leading the Mood and Anxiety Disorders Program at the National Institute of Mental Health (NIMH), I suggested to Carlos Zarate and Husseini Manji that we should attempt to replicate the original findings of the study by Berman and colleagues.

    Our NIMH research team was able to successfully replicate the findings, which were subsequently reported by Zarate and colleagues. It is noteworthy that the initial paper by Berman and colleagues was cited only about 20 times/year between 2000 and 2005, but after the paper by Zarate and colleagues was published, it was cited an average of 68 times/year between 2006 and 2011 and 179 times/year between 2012 and 2015. This reflects the explosion of research on the efficacy and antidepressant mechanism of action of ketamine.

    Following publication of the paper by Zarate and colleagues, subsequent published clinical data on ketamine has consistently indicated very strong efficacy of single doses and short-term repeated doses along with a good safety profile. There is also anecdotal information from practitioners using ketamine off-label that repeated doses of ketamine over longer periods of time may be effective in maintaining antidepressant response.

    It is also noteworthy that ketamine may have anti-suicidal effects and may be effective for treating PTSD. Recently, provocative preclinical investigations indicate that ketamine may have preventative effects on the ability of stress to cause depression and anxiety. This needs to be tested in clinical populations.

    The path forward

    Much work remains to be done. The antidepressant effects of ketamine need to be evaluated in larger-scale clinical trials to determine the optimal dose, best route of administration, and durability and safety of long-term ketamine treatment.

    Elucidation of ketamine’s mechanism of antidepressant, putative anti-anxiety, and preventative actions could prove extremely valuable in helping not only guide the development of novel pharmaceutical interventions but also in advancing the basic understanding of the pathophysiology of mood disorders. Presently, most studies have focused on ketamine’s action on the NMDA receptor, where it functions as a noncompetitive antagonist. A growing number of preclinical studies provide strong evidence that this action, and an ensuing cascade of effects involving increased neurotrophic factor activity and changes in synaptic plasticity, may be critical in generating an antidepressant-like response in rodent models.

    In summary, the discovery that ketamine has rapid antidepressant qualities has been hailed, in some quarters, as the most significant advance in the treatment of depression in decades.

    From the study here: https://www.academia.edu/30709950/Ke...ant_Depression
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    Ketamine could be the key to reversing America’s rising suicide rate

    By Cynthia Koons and Robert Langreth

    Joe Wright has no doubt that ketamine saved his life. A 34-year-old high school teacher who writes poetry every day on a typewriter, Wright was plagued by suicidal impulses for years. The thoughts started coming on when he was a high schooler himself, on Staten Island, N.Y., and intensified during his first year of college. “It was an internal monologue, emphatic on how pointless it is to exist,” he says. “It’s like being ambushed by your own brain.”

    He first tried to kill himself by swallowing a bottle of sleeping pills the summer after his sophomore year. Years of treatment with Prozac, Zoloft, Wellbutrin, and other antidepressants followed, but the desire for an end was never fully resolved. He started cutting himself on his arms and legs with a pencil-sharpener blade. Sometimes he’d burn himself with cigarettes. He remembers few details about his second and third suicide attempts. They were halfhearted; he drank himself into a stupor and once added Xanax into the mix.

    Wright decided to try again in 2016, this time using a cocktail of drugs he’d ground into a powder. As he tells the story now, he was preparing to mix the powder into water and drink it when his dog jumped onto his lap. Suddenly he had a moment of clarity that shocked him into action. He started doing research and came upon a Columbia University study of a pharmaceutical treatment for severe depression and suicidality. It involved an infusion of ketamine, a decades-old anesthetic that’s also an infamous party drug. He immediately volunteered.

    His first—and only—ketamine infusion made him feel dreamlike, goofy, and euphoric. He almost immediately started feeling more hopeful about life. He was more receptive to therapy. Less than a year later, he married. Today he says his dark moods are remote and manageable. Suicidal thoughts are largely gone. “If they had told me how much it would affect me, I wouldn’t have believed it,” Wright says. “It is unconscionable that it is not already approved for suicidal patients.”

    The reasons it isn’t aren’t strictly medical. Over the past three decades, pharmaceutical companies have conducted hundreds of trials for at least 10 antidepressants to treat severe PMS, social anxiety disorder, and any number of conditions. What they’ve almost never done is test their drugs on the sickest people, those on the verge of suicide. There are ethical considerations: Doctors don’t want to give a placebo to a person who’s about to kill himself. And reputational concerns: A suicide in a drug trial could hurt a medication’s sales prospects.

    The risk-benefit calculation has changed amid the suicide epidemic in the U.S. From 1999 to 2016, the rate of suicides increased by 30 percent. It’s now the second-leading cause of death for 10- to 34-year-olds, behind accidents. (Globally the opposite is true: Suicide is decreasing.) Growing economic disparity, returning veterans traumatized by war, the opioid crisis, easy access to guns—these have all been cited as reasons for the rise in America. There’s been no breakthrough in easing any of these circumstances.

    But there is, finally, a serious quest for a suicide cure. Ketamine is at the center, and crucially the pharmaceutical industry now sees a path. The first ketamine-based drug, from Johnson & Johnson, could be approved for treatment-resistant depression by March and suicidal thinking within two years. Allergan Plc is not far behind in developing its own fast-acting antidepressant that could help suicidal patients. How this happened is one of the most hopeful tales of scientific research in recent memory.

    Dennis Charney, dean of the Icahn School of Medicine at Mount Sinai in New York, works from an office filled with family pictures, diplomas, and awards from a long career in research. One thing on the wall is different from the rest: a patent for the use of a nasal-spray form of ketamine as a treatment for suicidal patients. The story of the drug is in some ways the story of Charney’s career.

    In the 1990s he was a psychiatry professor, mentoring then associate professor John Krystal at Yale and trying to figure out how a deficit of serotonin played into depression. Back then, depression research was all about serotonin. The 1987 approval of Prozac, the first selective serotonin reuptake inhibitor, or SSRI, ushered in an era of what people in the industry call me-too drug development, research that seeks to improve on existing medicines rather than exploring new approaches. Within this narrow range, pharmaceutical companies churned out blockbuster after blockbuster. One in eight Americans age 12 and older reported using antidepressants within the past month, according to a survey conducted from 2011 to 2014 by the U.S. Centers for Disease Control and Prevention.

    Charney was a depression guy; Krystal was interested in schizophrenia. Their curiosity led them to the same place: the glutamate system, what Krystal calls the “main information highway of the higher brain.” (Glutamate is an excitatory neurotransmitter, which helps brain cells communicate. It’s considered crucial in learning and memory formation.) They had already used ketamine to temporarily produce schizophrenia-like symptoms, to better understand glutamate’s role in that condition. In the mid-1990s they decided to conduct a single-dose study of ketamine on nine patients (two ultimately dropped out) at the Yale-affiliated VA Connecticut Healthcare System in West Haven to see how depressed people would react to the drug.

    Outside the field of anesthesiology, ketamine is known, if it’s known at all, for its abuse potential. Street users sometimes take doses large enough to enter what’s known as a “K hole,” a state in which they’re unable to interact with the world around them. Over the course of a day, those recreational doses can be as much as 100 times greater than the tiny amount Charney and Krystal were planning to give to patients. Nonetheless, they decided to monitor patients for 72 hours—well beyond the two hours that ketamine produces obvious behavioral effects—just to be careful not to miss any negative effects that might crop up. “If we had done the typical thing that we do with these drug tests,” Krystal says, “we would have completely missed the antidepressant effect of ketamine.”

    Checking on patients four hours after the drug had been administered, the researchers saw something unexpected. “To our surprise,” Charney says, “the patients started saying they were better, they were better in a few hours.” This was unheard of. Antidepressants are known for taking weeks or months to work, and about a third of patients aren’t sufficiently helped by the drugs. “We were shocked,” says Krystal, who now chairs the Yale psychiatry department. “We didn’t submit the results for publication for several years.”

    When Charney and Krystal did publish their findings, in 2000, they attracted almost no notice. Perhaps that was because the trial was so small and the results were almost too good to be true. Or maybe it was ketamine’s reputation as an illicit drug. Or the side effects, which have always been problematic: Ketamine can cause patients to disassociate, meaning they enter a state in which they feel as if their mind and body aren’t connected.

    But probably none of these factors mattered as much as the bald economic reality. The pharmaceutical industry is not in the business of spending hundreds of millions of dollars to do large-scale studies of an old, cheap drug like ketamine. Originally developed as a safer alternative to the anesthetic phencyclidine, better known as PCP or angel dust, ketamine has been approved since 1970. There’s rarely profit in developing a medication that’s been off patent a long time, even if scientists find an entirely new use for it.

    Somehow, even with all of this baggage, research into ketamine inched forward. The small study that almost wasn’t published has now been cited more than 2,000 times.

    Suicide is described in medicine as resulting from a range of mental disorders and hardships—a tragedy with many possible roots. Conditions such as severe depression, bipolar disorder, and schizophrenia are known risk factors. Childhood trauma or abuse may also be a contributor, and there may be genetic risk factors as well.

    From these facts, John Mann, an Australian-born psychiatrist with a doctorate in neurochemistry, made a leap. If suicide has many causes, he hypothesized, then all suicidal brains might have certain characteristics in common. He’s since done some of the most high-profile work to illuminate what researchers call the biology of suicide. The phrase itself represents a bold idea—that there’s an underlying physiological susceptibility to suicide, apart from depression or another psychiatric disorder.

    Mann moved to New York in 1978, and in 1982, at Cornell University, he started collecting the brains of people who’d killed themselves. He recruited Victoria Arango, now a leading expert in the field of suicide biology. The practice of studying postmortem brain tissue had largely fallen out of favor, and Mann wanted to reboot it. “He was very proud to take me to the freezer,” Arango says of the day Mann introduced her to the brain collection, which then numbered about 15. “I said, ‘What am I supposed to do with this?’ ”

    They took the work, and the brains, first to the University of Pittsburgh, and then, in 1994, to Columbia. They’ve now amassed a collection of some 1,000 human brains—some from suicide victims, the others, control brains—filed neatly in freezers kept at –112F. The small Balkan country of Macedonia contributes the newest brains, thanks to a Columbia faculty member from there who helped arrange it. The Macedonian brains are frozen immediately after being removed and flown in trunks, chaperoned, some 4,700 miles to end up in shoe-box-size, QR-coded black boxes. Inside are dissected sections of pink tissue in plastic bags notated with markers: right side, left side, date of collection.

    In the early 1990s, Mann and Arango discovered that depressed patients who killed themselves have subtle alterations in serotonin in certain regions of the brain. Mann remembers sitting with Arango and neurophysiologist Mark Underwood, her husband and longtime research partner, and analyzing the parts of the brain affected by the deficit. They struggled to make sense of it, until it dawned on them that these were the same brain regions described in a famous psychiatric case study. In 1848, Phineas Gage, an American railroad worker, was impaled through the skull by a 43-inch-long tamping iron when the explosives he was working with went off prematurely. He survived, but his personality was permanently altered. In a paper titled “Recovery From the Passage of an Iron Bar Through the Head,” his doctor wrote that Gage’s “animal propensities” had emerged and described him as using the “grossest profanity.” Modern research has shown that the tamping iron destroyed key areas of the brain involved in inhibition—the same areas that were altered in the depressed patients who’d committed suicide. For the group, this was a clue that the differences in the brain of suicidal patients were anatomically important.

    “Most people inhibit suicide. They find a reason not to do it,” Underwood says. Thanks to subtle changes in the part of the brain that might normally control inhibition and top-down control, people who kill themselves “don’t find a reason not to do it,” he says.

    About eight years ago, Mann saw ketamine research taking off in other corners of the scientific world and added the drug to his own work. In one trial, his group found that ketamine treatment could ease suicidal thoughts in 24 hours more effectively than a control drug. Crucially, they found that the antisuicidal effects of ketamine were to some extent independent of the antidepressant effect of the drug, which helped support their thesis that suicidal impulses aren’t necessarily just a byproduct of depression. It was this study, led by Michael Grunebaum, a colleague of Mann’s, that made a believer of Joe Wright.

    In 2000, the National Institutes of Health hired Charney to run both mood disorder and experimental drug research. It was the perfect place for him to forge ahead with ketamine. There he did the work to replicate what he and his colleagues at Yale had discovered. In a study published in 2006, led by researcher Carlos Zarate Jr., who now oversees NIH studies of ketamine and suicidality, an NIH team found that patients had “robust and rapid antidepressant effects” from a single dose of the drug within two hours. “We could not believe it. In the first few subjects we were like, ‘Oh, you can always find one patient or two who gets better,’ ” Zarate recalls.

    In a 2009 study done at Mount Sinai, patients suffering from treatment-resistant depression showed rapid improvement in suicidal thinking within 24 hours. The next year, Zarate’s group demonstrated antisuicidal effects within 40 minutes. “That you could replicate the findings, the rapid findings, was quite eerie,” Zarate says.

    Finally ketamine crossed back into commercial drug development. In 2009, Johnson & Johnson lured away Husseini Manji, a prominent NIH researcher who’d worked on the drug, to run its neuroscience division. J&J didn’t hire him explicitly to develop ketamine into a new pharmaceutical, but a few years into his tenure, Manji decided to look into it. This time it would come in a nasal-spray form of esketamine, a close chemical cousin. That would allow for patent protection. Further, the nasal spray removes some of the challenges that an IV form of the drug would present. Psychiatrists, for one thing, aren’t typically equipped to administer IV drugs in their offices.

    While these wheels were slowly turning, some doctors—mostly psychiatrists and anesthesiologists—took action. Around 2012 they started opening ketamine clinics. Dozens have now popped up in major metropolitan areas. Insurance typically won’t touch it, but at these centers people can pay about $500 for an infusion of the drug. It was at one time a cultural phenomenon—a 2015 Bloomberg Businessweek story called it “the club drug cure.” Since then, the sense of novelty has dissipated. In September the American Society of Ketamine Physicians convened its first medical meeting about the unconventional use of the drug.

    “You are literally saving lives,” Steven Mandel, an anesthesiologist-turned-ketamine provider, told a room of about 100 people, mostly doctors and nurse practitioners, who gathered in Austin to hear him and other early adopters talk about how they use the drug. Sporadic cheers interrupted the speakers as they presented anecdotes about its effectiveness.

    There were also issues to address. A consensus statement in JAMA Psychiatry published in 2017 said there was an “urgent need for some guidance” on ketamine use. The authors were particularly concerned with the lack of data about the safety of prolonged use of the drug in people with mood disorders, citing “major gaps” in the medical community’s knowledge about its long-term impact.

    The context for the off-label use of ketamine is a shrinking landscape for psychiatry treatment. An effort to deinstitutionalize the U.S. mental health system, which took hold in the 1960s, has almost resulted in the disappearance of psychiatric hospitals and even psychiatric beds within general hospitals. There were 37,679 psychiatric beds in state hospitals in 2016, down from 558,922 in 1955, according to the Treatment Advocacy Center. Today a person is often discharged from a hospital within days of a suicide attempt, setting up a risky situation in which someone who may not have fully recovered ends up at home with a bunch of antidepressants that could take weeks to lift his mood, if they work at all.

    A ketamine clinic can be the way out of this scenario—for people with access and means. For Dana Manning, a 53-year-old Maine resident who suffers from bipolar disorder, $500 is out of reach. “I want to die every day,” she says.

    After trying to end her life in 2003 by overdosing on a cocktail of drugs including Xanax and Percocet, Manning tried virtually every drug approved for bipolar disorder. None stopped the mood swings. In 2010 the depression came back so intensely that she could barely get out of bed and had to quit her job as a medical records specialist. Electroconvulsive therapy, the last-ditch treatment for depressed patients who don’t respond to drugs, didn’t help.

    Her psychiatrist went deep into the medical literature to find options and finally suggested ketamine. He was even able to get the state Medicaid program to cover it, she says. She received a total of four weekly infusions before she moved to Pennsylvania, where there were more family members nearby to care for her.

    The first several weeks following her ketamine regimen were “the only time I can say I have felt normal” in 15 years, she says. “It’s like you have 50 pounds on your shoulders, and the ketamine takes 40 pounds off.”

    She’s now back in Maine, and the depression has returned. Her current Medicare insurance won’t cover ketamine. She lives on $1,300 a month in disability income. “Knowing it is there and I can’t have it is beyond frustrating,” she says.

    Ketamine is considered a “dirty” drug by scientists—it affects so many pathways and systems in the brain at the same time that it’s hard to single out the exact reason it works in the patients it does help. That’s one reason researchers continue to look for better versions of the drug. Another, of course, is that new versions are patentable. Should Johnson & Johnson’s esketamine hit the market, the ketamine pioneers and their research institutions stand to benefit. Yale’s Krystal, NIH’s Zarate, and Sinai’s Charney, all of whom are on the patent on Charney’s wall, will collect royalties based on the drug’s sales. J&J hasn’t said anything about potential pricing, but there’s every reason to believe the biggest breakthrough in depression treatment since Prozac will be expensive.

    The company’s initial esketamine study in suicidal patients involved 68 people at high risk. To avoid concerns about using placebos on actively suicidal subjects, everyone received antidepressants and other standard treatments. About 40 percent of those who received esketamine were deemed no longer at risk of killing themselves within 24 hours. Two much larger trials are under way.

    When Johnson & Johnson unveiled data from its esketamine study in treatment-resistant depression at the American Psychiatric Association meeting in May, the presentation was jammed. Esketamine could become the first-ever rapid-acting antidepressant, and physicians and investors are clamoring for any information about how it works. The results in suicidal patients should come later this year and could pave the way for a Food and Drug Administration filing for use in suicidal depressed patients in 2020. Allergan expects to have results from its suicide study next year, too.

    “The truth is, what everybody cares about is, do they decrease suicide attempts?” says Gregory Simon, a psychiatrist and mental health researcher at Kaiser Permanente Washington Health Research Institute. “That is an incredibly important question that we hope to be able to answer, and we are planning for when these treatments become available.”

    Exactly how ketamine and its cousin esketamine work is still the subject of intense debate. In essence, the drugs appear to provide a quick molecular reset button for brains impaired by stress or depression. Both ketamine and esketamine release a burst of glutamate. This, in turn, may trigger the growth of synapses, or neural connections, in brain areas that may play a role in mood and the ability to feel pleasure. It’s possible the drug works to prevent suicide by boosting those circuits while also reestablishing some of the inhibition needed to prevent a person from killing himself. “We certainly think that esketamine is working exactly on the circuitry of depression,” Manji says. “Are we homing in exactly on where suicidal ideation resides?” His former colleagues at NIH are trying to find that spot in the brain as well. Using polysomnography—sleep tests in which patients have nodes connected to various parts of their head to monitor brain activity—as well as MRIs and positron emission tomography, or PET scans, researchers can see how a patient’s brain responds to ketamine, to better understand exactly what it’s doing to quash suicidal thinking.

    Concerns about the side effects of ketamine-style drugs linger. Some patients taking esketamine have reported experiencing disassociation symptoms. Johnson & Johnson calls the effects manageable and says they cropped up within an hour of the treatment, a period in which a person on the drug would likely be kept in the doctor’s office for monitoring. Some patients also experienced modest spikes in blood pressure within the same timeframe.

    Nasal-spray dosing brings other issues. The Black Dog Institute in Australia and the University of New South Wales in Sydney, which teamed up to study a nasal-spray form of ketamine, published their findings last March in the Journal of Psychopharmacology. The researchers found that absorption rates were variable among patients. J&J says its own studies with esketamine contradict these findings.

    But in the wake of the opioid crisis, perhaps the biggest worry is that loosening the reins too much on the use of ketamine and similar drugs could lead to a new abuse crisis. That’s why Wall Street analysts are particularly excited by Allergan’s rapid-acting antidepressant, rapastinel, which is about a year behind esketamine in testing. Researchers say it likely acts on the same target in the brain as ketamine, the NMDA receptor, but in a more subtle way that may avoid the disassociation side effects and abuse potential. Studies in lab animals show the drug doesn’t lead creatures to seek more of it, as they sometimes do with ketamine, says Allergan Vice President Armin Szegedi. Allergan’s medicine is an IV drug, but the company is developing an oral drug.

    For its suicide study, Allergan is working hard to enroll veterans, one of the populations most affected by the recent spike in suicides, and has included several U.S. Department of Veterans Affairs medical centers as sites in the trial. More than 6,000 veterans died by suicide each year from 2008 to 2016, a rate that’s 50 percent higher than in the general population even after adjusting for demographics, according to VA data.

    “How the brain mediates what makes us who we are is still a mystery, and maybe we will never fully understand it,” Szegedi says. “What really changed the landscape here is you had clinical data showing ‘This really does the trick.’ Once you find something in the darkness, you really have to figure out: Can you do something better, faster, safer?”

    https://www.bloomberg.com/news/featu...cidal-ideation
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    Ayahuasca study shows huge potential as a treatment for severe depression

    by Luis Fernando Tofoli, Draulio Barros de Araujo, and Fernanda Palhano-Fontes | Feb 13, 2019

    “Leon” is a young Brazilian man who has long struggled with depression. He keeps an anonymous blog, in Portuguese, where he describes the challenge of living with a mental illness that affects some 300 million people worldwide, according to the World Health Organization.

    Leon is among the roughly 30 percent of those patients with treatment-resistant depression. Available antidepressant drugs like selective serotonin reuptake inhibitors do not alleviate his depressed mood, fatigue, anxiety, low self-esteem and suicidal thoughts.

    A new study may offer hope for Leon and others like him. Our team of Brazilian scientists has conducted the first randomized, placebo-controlled clinical trial of ayahuasca—a psychedelic drink made of Amazonian plants. The results, recently published in the journal Psychological Medicine, suggest that ayahuasca can work for hard-to-treat depression.

    Ayahuasca, a word from the indigenous Quechua language, means “the vine of the spirits.” People in the Amazonian region of Brazil, Peru, Colombia and Ecuador have for centuries used ayahuasca for therapeutic and spiritual purposes.

    The medicinal beverage’s properties come from two plants. Banisteriopsis caapi, a vine that twists its way up to the treetops and across river banks of the Amazon basin, is boiled together with Psychotria viridis, a shrub whose leaves contain the psychoactive molecule DMT.

    Starting in the 1930s, Brazilian religions were founded around the use of ayahuasca as a sacrament. By the 1980s, the ayahuasca ritual had spread to cities across Brazil and the world.

    Ayahuasca first became legal for religious use in Brazil in 1987, after the country’s federal drug agency concluded that “religious group members” had seen “remarkable” benefits from taking it. Some people who drink ayahuasca describe feeling at peace with themselves, God and the universe.

    For our study, which took place at Brazil’s Federal University of Rio Grande do Norte, researchers recruited 218 patients with depression. Twenty-nine of them were selected to participate because they had treatment-resistant depression and no history of psychotic disorders like schizophrenia, which ayahuasca use may aggravate.

    These 29 people were randomly assigned to undergo a single treatment session, in which they were given either ayahuasca or a placebo substance to drink. The placebo was a brownish liquid, bitter and sour to the taste, made of water, yeast, citric acid and caramel colorant. Zinc sulphate mimicked two well-known side effects of ayahuasca, nausea and vomiting.

    The sessions took place in a hospital, though we designed the space like a quiet and comfortable living room.

    The acute effects of ayahuasca—which include dream-like visions, vomiting and intense introspection—last for about four hours. During this period, participants listened to two curated playlists, one featuring instrumental music and another with songs sung in Portuguese.

    Patients were monitored by two team members, who provided assistance to those experiencing anxiety during this intense emotional and physical experience.

    One day after the treatment session, we observed significant improvements in 50 percent of all patients, including reduced anxiety and improved mood.

    A week later, 64 percent of the patients who had received ayahuasca still felt that their depression had eased. Just 27 percent of those in the placebo group showed such effects.

    Our findings support a 2015 Brazilian clinical trial on the potential of ayahuasca as an antidepressant.

    That study, led by Dr. Jaime Hallak of the University of Sao Paulo, likewise found that a single ayahuasca session had a fast-onset antidepressant effect. All 17 participants reported that depression symptoms diminished in the first hours after ayahuasca ingestion. The effect lasted 21 days.

    This study received significant attention from scientists. Its promising conclusions were limited, however, because there was no control group of patients who received a placebo drug.

    In clinical trials for depression, up to 45 percent of patients who take a placebo may report significant benefits. The placebo effect for depression is so strong that some scientists have questioned whether antidepressants really work.

    Dr. Hallak and other researchers from the 2015 University of Sao Paulo study were part of our follow-up clinical trial.

    These two studies, while preliminary, contribute to a growing body of evidence that psychedelic drugs like ayahuasca, LSD and mushrooms can help people with difficult-to-treat depression.

    But because these substances are illegal in many countries, including the United States, their therapeutic value has been difficult to test. Even in Brazil, using ayahuasca as an antidepressant remains a fringe, informal enterprise.

    Leon, the Brazilian blogger, discovered the drug doing internet research. “Desperate” to find solutions for his intractable condition, Leon decided to take part in an ayahuasca ceremony at a Santo Daime church in Rio de Janeiro, one of several Brazilian religions that use ayahuasca as a sacrament.

    The church does not track its membership, but the Uniao do Vegetal, a similar faith, has approximately 19,000 members worldwide.

    These religious organizations are among many groups across the Americas that harvest indigenous traditions around natural psychedelics. They believe psychoactive plants like ayahuasca, peyote or psilocybin open people’s minds to metaphysical realms and deeply meaningful experiences.

    This spiritual knowledge is now being translated into the language of science, as researchers in Brazil, the United States, Canada and beyond begin rigorous medical evaluations of these substances.

    Leo’s blog provides an excellent description of his ayahuasca experience.

    At times, he conjured visions—dream-like scenarios that offered rare insight into the relationships in his life. At other times, Leon experienced “a feeling of ecstasy and a deep sensation of a manifesting inner spirituality.”

    We believe that these effects are critical to why ayahuasca works.

    Participants in our study responded to the Hallucinogen Rating Scale, which helps translate these ineffable experiences into numbers. Participants who took ayahuasca scored significantly higher on that questionnaire than those who drank a placebo.

    Those who described the most abundant visual, auditory and physical effects during their ayahuasca trip had the most prominent depression reduction benefits seven days later.

    Ayahuasca is not a panacea. Such experiences may prove too physically and emotionally challenging for some people to use it regularly as treatment. We have also observed regular ayahuasca users who still suffer from depression.

    But, as our study demonstrates, this Amazonian sacred plant has the potential to be used safely and effectively to treat even the hardest to treat depression.

    http://reset.me/story/ayahuasca-show...re-depression/

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