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mr peabody

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Prof. Stephen Hawking

Ayahuasca and ALS

Male, 65, UK, diagnosed with ALS (not Prof. Hawking)

What can you tell us in general about your medical condition, and to what degree has it affected you? (Prior to treatment using ayahuasca)

My prognosis as of March 2013 was that of a one-year life expectancy, I did get a specific MND diagnosis confirmed by a consultant neurologist, on the back of which an insurance company paid up on my critical illness cover, there being a clear understanding that I would probably not last the year. I was very weak and trembly, had lost over 20 pounds in muscle mass, my knees were prone to swelling and I was racked by cramps and muscle twitching. I could barely manage stairs, and couldn't get out of the bath unassisted. I remember being a little challenged by a four inch step across the end of the room, choosing my best leg to step down.

Describe a typical experience with ayahuasca. What is it like during the immediate time the medicine is active in the body? What has been experienced afterwards?

Initially a fair amount of retching, although I didn't actually vomit much. Then some spastic activity, after which a warmth spread throughout my chest cavity, and sensations from the connection between muscle tissue and skeletal bone. It left me exhausted, but it mellowed out? after a while into a contemplation state of mind where the concept of fear had a major part. Stressful emotions such as fear and anxiety seems to be a major vexation (in relation to neurological diseases), and the ayahuasca seemed to soothe that too. I didn't feel that much different immediately afterwards, I suppose I felt a little more relaxed, but the following weeks (after sessions) my massage therapist said the muscle twitching was much improved, and I continued to recover steadily.

Has this treatment relieved or improved your condition in any way so far?

I have made essentially a full recovery, slow but persistent, and NHS consultants involved are mystified. Ayahuasca seems to me to have been instrumental in my recovery, which is fully documented. I am now fully healthy, I cycle to work. Now, after today doing a nine mile coastal walk for the pleasure it, I feel pretty much up to snuff, for a man of my age. A year after my diagnosis I held a party to express my gratitude to all the people who had helped me through, including T.H., the consultant neurologist (he didn't actually come). I was by that time much better, not up to full strength, but could party on and play the saxophone. I told my doctors about ayahuasca in August of 2013 I think, it was for a six monthly reassessment of my condition. T.H was frankly astonished, and when challenged said that the diagnosis was absolutely sound adding that the nerve conductivity tests were particularly unequivocal. It was then that I told him about the ayahuasca, and rather sheepishly, and mistakenly, he asked me if I had had a good trip? I replied that it had been unpleasant and that it was not a therapy for the faint-hearted. Since then T.H. has presented my case to some regional peer group, and a professor K.T. Their response was that perhaps 'I had a mimi', which seems to be exactly the same as the disease except for the outcome; or that the condition 'might have been brought upon me by the cocktail of therapies' I was taking at the time. I have yet to make a measured response to this, but it was not until I had serious symptoms that were initially interpreted as Lyme disease or an atypical sero-negative rheumatoid arthritic condition, that I embarked on any kind of medical therapy at all. The history presents a persuasive argument. My family, friends and some of my patients are aware of my ayahuasca treatment and are generally supportive. My wife plays tennis with a number of retired GPs, and their general opinion is that whatever I did cant be too bad. Hell, I am still walking about and they were initially supporting my wife and family on the clear expectation of my imminent demise.

Will you continue this treatment? If so, will you make any changes to your current regimen?

I don't see any necessity to carry on being treated. I might do the ayahuasca again but that would really be just out of curiosity.

Have you been following any particular diet prior to, or during your treatment?

Lots of organic fruit and vegetables, and I have a small holding so we have organic lamb and chicken too. I haven't eaten dairy for the past two years, and I seldom drink alcohol though I had a glass of cider the other day.

What made you try this alternative treatment?

It was an inspired patient who in doing an art degree in Plymouth came across the (ayahuasca) visionary art, and drew my attention to its source. Curiously some members of the church group with whom I sit proved an unexpected source of interest and loaned me various books on the topic, including those of the late Alexander Shulgin.

-----

Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis, also called ALS or Lou Gehrig’s Disease, is a progressive, degenerative neuromuscular disease that affects the nerve cells in the brain and spinal cord. These motor neurons carry messages from the brain to the spinal cord and, ultimately, to the muscles that are necessary for voluntary and involuntary movement and function.

In people living with ALS, motor neurons progressively die and the brain can no longer communicate with the muscles through the spinal cord. As muscles are used less and less frequently, they can atrophy, causing people with ALS to lose the ability to perform everyday activities, such as walking, speaking, and eating. ALS also affects the diaphragm, an essential muscle responsible for breathing, so people with ALS eventually lose their ability to breathe on their own. The average life expectancy for ALS patients is three to five years after diagnosis and death is generally caused by respiratory failure. There is no known cause or cure for ALS.

Cytokinetics is driven to improve the lives of people fighting ALS by applying our understanding of the mechanics of muscle function and contractility to the discovery and development of novel potential treatments that may directly improve muscle function, potentially delaying disease progression and preserving independence.

 
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mr peabody

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Ibogaine and neurodegenerative disorders

This is a summary on existing research looking at the influence of Ibogaine on glial cell line-derived neurotrophic factor (GDNF) levels in the brain, and the beneficial impact that an increase in this protein can have. While existing studies have examined these areas, few have identified a possible link between Ibogaine, GDNF expression and neurodegenerative diseases.

Parkinson's Disease and ALS are chronic disorders with no known cure, and require management with drugs that can have considerable side effects, causing a very poor quality of life for terminal stage sufferers of these diseases. By contrast, a low dose regime of Ibogaine or Iboga alkaloid extract would be of low toxicity and free of serious side effects.

GDNF has been shown to have potent neurotrophic factor in both rodent and primate models of Parkinson's. Direct brain infusion of GDNF into the brains of five Parkinson sufferers resulted in a 39% improvement in the off-medication motor sub-score of the Unite Parkinsons Disease Rating Scale, and a 61% improvement in the activities of daily living sub score.

Positron emission tomography (PET) scans of dopamine uptake showed a significant 28% increase in putamen dopamine storage after 18 months, indicating a direct effect of GDNF on dopamine function. Furthermore, after one year, no serious clinical side effects were observed. The use of Iboga alkaloid extract or Ibogaine would provide a longer term and much less invasive method of GDNF administration than direct brain infusion. Thus, further research on Ibogaine and GDNF is certainly warranted.

Regarding motor neuron disease, the little research that has occurred in this area, such as gene transfer of neurotrophic factors, suggests potential in the treatment of motor neuron disease. Again, Ibogaine therapy may offer a straightforward, non-invasive, cheap, low-toxicity method of treatment for sufferers of this disease.

@Bancopuma
 
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mr peabody

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Endocannabinoids in MS and ALS

There are numerous reports that people with multiple sclerosis (MS) have for many years been self-medicating with illegal street cannabis or more recently medicinal cannabis to alleviate the symptoms associated with MS and also amyotrophic lateral sclerosis (ALS). These anecdotal reports have been confirmed by data from animal models and more recently clinical trials on the ability of cannabinoids to alleviate limb spasticity, a common feature of progressive MS (and also ALS) and neurodegeneration. Experimental studies into the biology of the endocannabinoid system have revealed that cannabinoids have efficacy, not only in symptom relief but also as neuroprotective agents which may slow disease progression and thus delay the onset of symptoms. This review discusses what we now know about the endocannabinoid system as it relates to MS and ALS and also the therapeutic potential of cannabinoid therapeutics as disease-modifying or symptom control agents, as well as future therapeutic strategies including the potential for slowing disease progression in MS and ALS.

https://www.ncbi.nlm.nih.gov/pubmed/26408162
 
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mr peabody

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Low dose ibogaine

by Dr. Tom Grodski

Parkinson’s disease, ALS and Alzheimer’s are chronic disorders with no known cure. Most neurodegenerative diseases require management with prescription medications that can have considerable side effects, which may cause a very poor quality of life for terminal sufferers. In turn, Ibogaine may be very beneficial to those with degenerative neurological diseases.

Ibogaine is a naturally occurring psychoactive indole alkaloid derived from the roots of the African rain forest shrub Tabernanthe iboga. Ibogaine is part of the Apocynaceae family and traditionally used by the Bwiti, indigenous peoples of Western Africa; in low doses to combat fatigue, hunger and thirst.

Ibogaine increases levels of glial cell line-derived neurotrophic factor (GDNF) in the brain, and this appears to have neuroprotective properties that promote the survival of both dopaminergic and motor neurons. GDNF can also cause sprouting of dopaminergic fibers and clinical improvement in experimental animal and human studies in which the test subjects had Parkinson’s Disease, with the resultant clinical improvement in symptoms. GDNF has been shown to have potent neurotrophic factor in both rodent and primate models of Parkinson’s disease.

Direct brain infusion of GDNF into the brains of five Parkinson sufferers resulted in a 39% improvement in the off-medication motor sub-score of the Unite Parkinson’s Disease Rating Scale (UPDRS) and a 61% improvement in the activities of daily living sub score. Positron emission tomography (PET) scans of dopamine uptake showed a significant 28% increase in putamen dopamine storage after 18 months, indicating a direct effect of GDNF on dopamine function. Further, after one year, no serious clinical side effects were observed.

The use of Iboga alkaloid extract or Ibogaine would provide a longer term and much less invasive method of GDNF administration than direct brain infusion. Thus, further research on Ibogaine and GDNF is certainly warranted. Ibogaine therapy may offer a non-invasive and low-toxicity method of treatment for sufferers of these disorders.​
 
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mr peabody

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Ibogaine and neurodegenerative diseases

Following is a summary on existing research looking at the influence of Ibogaine on glial cell line-derived neurotrophic factor (GDNF) levels in the brain, and the beneficial impact that an increase in this protein can have. While existing studies have examined these areas, few have identified a possible link between Ibogaine, GDNF expression and neurodegenerative diseases.

Both Parkinson's disease and Motor Neuron Disease (ALS) are chronic disorders with no known cure, and require management with drugs that can have considerable side effects, causing a very poor quality of life for terminal stage sufferers of these diseases. By contrast, a low dose regime of Ibogaine or Iboga alkaloid extract would be of low toxicity and free of serious side effects.

GDNF has been shown to have potent neurotrophic factor in both rodent and primate models of Parkinson's disease. Direct brain infusion of GDNF into the brains of five Parkinson's sufferers resulted in a 39% improvement in the off-medication motor sub-score of the Unite Parkinson's Disease Rating Scale (UPDRS) and a 61% improvement in the activities of daily living sub score. Positron emission tomography (PET) scans of dopamine uptake showed a significant 28% increase in putamen dopamine storage after 18 months, indicating a direct effect of GDNF on dopamine function. Furthermore, after one year, no serious clinical side effects were observed. The use of Iboga alkaloid extract or Ibogaine would provide a longer term and much less invasive method of GDNF administration than direct brain infusion. Thus, further research on Ibogaine and GDNF is certainly warranted.

Regarding Motor Neuron Disease (ALS), the research that has occurred in this area, such as gene transfer of neurotrophic factors, suggests its potential as a treatment for this disorder. Again, Ibogaine therapy may offer a straightforward, non-invasive, inexpensive, low-toxicity method of treatment for sufferers of this disease.

@Bancopuma
 
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mr peabody

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Wireless 'pacemaker for the brain' could offer new treatment for neurological disorders

University of California - Berkeley | Science Daily | 1 Jan 2019

Device fine-tunes treatment by stimulating and and recording electric current in the brain at the same time.

A new neurostimulator developed by engineers at the University of California, Berkeley, can listen to and stimulate electric current in the brain at the same time, potentially delivering fine-tuned treatments to patients with diseases like epilepsy and Parkinson's.

The device, named the WAND, works like a "pacemaker for the brain," monitoring the brain's electrical activity and delivering electrical stimulation if it detects something amiss.

These devices can be extremely effective at preventing debilitating tremors or seizures in patients with a variety of neurological conditions. But the electrical signatures that precede a seizure or tremor can be extremely subtle, and the frequency and strength of electrical stimulation required to prevent them is equally touchy. It can take years of small adjustments by doctors before the devices provide optimal treatment.

WAND, which stands for wireless artifact-free neuromodulation device, is both wireless and autonomous, meaning that once it learns to recognize the signs of tremor or seizure, it can adjust the stimulation parameters on its own to prevent the unwanted movements. And because it is closed-loop -- meaning it can stimulate and record simultaneously -- it can adjust these parameters in real-time.

"The process of finding the right therapy for a patient is extremely costly and can take years. Significant reduction in both cost and duration can potentially lead to greatly improved outcomes and accessibility," said Rikky Muller assistant professor of electrical engineering and computer sciences at Berkeley. "We want to enable the device to figure out what is the best way to stimulate for a given patient to give the best outcomes. And you can only do that by listening and recording the neural signatures."

WAND can record electrical activity over 128 channels, or from 128 points in the brain, compared to eight channels in other closed-loop systems. To demonstrate the device, the team used WAND to recognize and delay specific arm movements in rhesus macaques. The device is described in a study that appeared today (Dec. 31) in Nature Biomedical Engineering.

Ripples in a pond

Simultaneously stimulating and recording electrical signals in the brain is much like trying to see small ripples in a pond while also splashing your feet -- the electrical signals from the brain are overwhelmed by the large pulses of electricity delivered by the stimulation.

Currently, deep brain stimulators either stop recording while delivering the electrical stimulation, or record at a different part of the brain from where the stimulation is applied -- essentially measuring the small ripples at a different point in the pond from the splashing.

"In order to deliver closed-loop stimulation-based therapies, which is a big goal for people treating Parkinson's and epilepsy and a variety of neurological disorders, it is very important to both perform neural recordings and stimulation simultaneously, which currently no single commercial device does," said former UC Berkeley postdoctoral associate Samantha Santacruz, who is now an assistant professor at the University of Texas in Austin.

Researchers at Cortera Neurotechnologies, Inc., led by Rikky Muller, designed the WAND custom integrated circuits that can record the full signal from both the subtle brain waves and the strong electrical pulses. This chip design allows WAND to subtract the signal from the electrical pulses, resulting in a clean signal from the brain waves.

Existing devices are tuned to record signals only from the smaller brain waves and are overwhelmed by the large stimulation pulses, making this type of signal reconstruction impossible.

"Because we can actually stimulate and record in the same brain region, we know exactly what is happening when we are providing a therapy," Muller said.

In collaboration with the lab of electrical engineering and computer science professor Jan Rabaey, the team built a platform device with wireless and closed-loop computational capabilities that can be programmed for use in a variety of research and clinical applications.

In experiments lead by Santacruz while a postdoc at UC Berkeley, and by and electrical engineering and computer science professor Jose Carmena, subjects were taught to use a joystick to move a cursor to a specific location. After a training period, the WAND device was capable of detecting the neural signatures that arose as the subjects prepared to perform the motion, and then deliver electrical stimulation that delayed the motion.

"While delaying reaction time is something that has been demonstrated before, this is, to our knowledge, the first time that it has been demonstrated in a closed-loop system based on a neurological recording only," Muller said.

"In the future we aim to incorporate learning into our closed-loop platform to build intelligent devices that can figure out how to best treat you, and remove the doctor from having to constantly intervene in this process," said Muller said.

https://www.sciencedaily.com/release...0101094517.htm
 
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mr peabody

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Taking Psychedelics Seriously

Ira Byock, MD, FAAHPM

Recently published studies in peer-reviewed journals and high-profile articles in the New Yorker, New York Times, and Wall Street Journal, have rekindled professional and public interest in the therapeutic use of psychedelic drugs. It is easy to understand the enthusiasm. The magazine and newspaper articles include accounts of patients with profound depression, demoralization associated with terminal illness, and anxiety related to post-traumatic stress disorder (PTSD), who experienced remarkable improvements, including some who had previously considered suicide.

Nevertheless, psychiatric and palliative care clinicians who care for profoundly depressed, anxious, and seriously ill patients have every reason to be skeptical. As people become more mentally or physically ill and established treatments remain insufficiently effective, patients' susceptibility increases. Physicians play an important role in protecting vulnerable patients from spurious, nonevidence-based miracle cures, as well as from scientifically grounded, but overly zealous burdensome treatments that are certain to do more harm than good.

An abundance of caution should be accorded psychedelics, which carry real risks and are formally designated Schedule I drugs, signifying that they are dangerous, without therapeutic value, and illegal. Older clinicians remember news stories of deaths of individuals high on hallucinogens who thought they could fly, those with bad trips and flashbacks, and studies that purported to show chromosome damage associated with use of LSD.

However, given the extent of persistent emotional and existential suffering that palliative care clinicians encounter in the patients we serve, these medications deserve serious consideration by our field.

Background

Psychedelic properties of mushrooms and cactuses have been used for centuries by indigenous cultures to induce expanded states of consciousness and spiritual experiences. During the 1950s and early 1960s, research sponsored by the National Institute of Mental Health demonstrated potential for drugs of this class to markedly alleviate depression and existential suffering among people with cancer.11–13 Subsequently, non-medical use of these drugs and associated political and cultural upheavals resulted in the Schedule I classification, abruptly banning psychedelics from further clinical research and medical use. Although many of the mid-twentieth century clinical trials involved people with terminal conditions, few references to these published studies can be found in the literature of palliative medicine, a young specialty that developed after this period. Over the past 20 years, a few small clinical studies were conducted abroad, mostly in Europe and the United Kingdom. In the United States, over the past decade, with support from the Multidisciplinary Association for Psychedelic Studies and private funders, a few tenacious researchers earned governmental permission to carry out carefully designed trials of pharmaco-assisted therapy with psilocybin and MDMA.

The recently published research strengthens findings of earlier studies, showing significant efficacy and few adverse effects when these medications are administered as adjuncts to psychotherapy to carefully screened patients, under medical supervision. Three drugs, psilocybin, ketamine, and MDMA, have attracted most of the recent attention. Psilocybin, a naturally occurring drug found in psilocybe mushrooms, has strong and durable benefits for some patients with treatment-resistant depression, and for those with demoralization, anxiety, and depression associated with terminal illness. Ketamine, a Federal Drug Administration (FDA)-approved anesthetic with analgesic and psychedelic properties, has been used off-label in patients with treatment-resistant depression. In case studies and small clinical series, ketamine has shown notably positive effects. MDMA, a drug synthesized in 1912 as a potential anticoagulant, was later found to have strong psychoactive properties. In the 1970s and early 1980s, psychiatrists who administered MDMA in the context of psychotherapy observed sometimes dramatic improvements in patients suffering from severe, treatment-resistant PTSD.

In deciding how to think about these drugs, the distinction between skepticism and cynicism bears examining. Skepticism is warranted, but cynical nonscientific bias can result in therapeutic nihilism. The history of medicine is studded with occasional leaps in progress—consider small pox vaccination, penicillin, and computed tomography scans—that, shortly before they occurred, might have seemed too good to be true. When I graduated from medical school, the idea that duodenal ulcers were caused by bacteria would have been risible; stem cell transplants and gene-editing therapies were the stuff of science fiction. Surprising medical advances humbly remind us to suspend cynicism and that honest inquiry is warranted.

The need is great

While not only for people who are dying, specialty palliative care teams serve the sickest patients in our health systems and communities. It is, therefore, not surprising that we occasionally encounter incurably ill people whose suffering persists despite all available evidence-based treatments.

In treating pain and other physical distress, established treatment protocols guide escalations of doses and combinations of analgesics and co-analgesic medications. When a patient is dying and physical pain, dyspnea, seizures, or agitated delirium persists and causes intolerable suffering, as a last resort, comfort can reliably be achieved with proportionate sedation.

However, not all suffering is based solely in physical distress. Palliative care clinicians and teams also encounter patients whose misery is rooted in emotional, social, existential, or spiritual distress. Cancer, heart failure, liver failure, and amyotrophic lateral sclerosis (ALS) or motor neuron disease are among the diseases that can result in a progression of personal losses: Of feeling in control. Of taking care of one's self. Of contributing to others. Of enjoyment. Of meaning and purpose. Ultimately, some ill people say they have lost any reason to go on living.

People who are incurably ill and living with progressive disease-related disabilities can experience anxiety, depression, and demoralization. Psychotherapy alone and drug treatments for such syndromes are often insufficient. Medications for depression may take weeks to become effective or prove ineffective. Antidepressants and anxiolytics carry side effects that can include mental slowing and confusion. These adverse effects are particularly common and hazardous in patients with advanced physical illness, who are also at risk of polypharmacy, multidrug interactions, and concomitant disequilibrium and falls. When nonphysical suffering persists despite prudent approaches, published, evidence-based guidelines are limited.

Severe psychological and existential suffering can rob people of feeling that life is worth living. A sense of unending helplessness and hopelessness compels some to consider ending their lives. Suicide rates have risen 24% over the past two decades and are highest among middle-aged and elderly adults, particularly men who may suffer most from feelings of dependency. Public health data from Oregon show that since implementation of the Death with Dignity Act, the large majority of patients who received prescriptions for lethal drugs were motivated by nonphysical suffering. Current or fear of future pain contributed in just 26% of cases, while loss of autonomy, decreased ability to enjoy life, and loss of dignity most often brought these people to contemplate hastening their deaths.

Exercising an abundance of caution: screening, supervision, set and setting

Prescribed to carefully screened patients, in recommended doses, in the context of professional counseling and supervision, psilocybin and MDMA have proven to be notably safe. They have no tissue toxicity, do not interfere with liver function, have scant drug–drug interactions, and carry no long-term physical effects.

These drugs are not intoxicants in the usual sense. They do not dull the senses or induce sleepiness. On the contrary, sensory perception is intensified and attention is aroused. Although abuse syndromes have been reported, few people become habituated to these drugs.

Adverse physiological effects are few and of short duration, but can be substantial. During the onset of psychedelic experiences nausea and vomiting are not unusual. In this first hour or more, visual and spatial orientation are commonly disrupted, which can give rise to anxiety. Sympathetic nervous system arousal may occur both because of fear, and from direct effects of the drugs. Particularly during the initial phase of sessions, psychedelics dissolve barriers between physical senses resulting in synesthesia; touches, smells, and tastes can take on sounds, shapes and colors. Similarly, emotions and thoughts may evoke visual images and sounds. These phenomena explain why the term hallucinogen is often used synonymously with psychedelics to refer to this class of drugs.

Clinicians and researchers familiar with this class of pharmaceuticals emphasize the importance of screening, supervision, and “set and setting.”

Screening

Not every suffering patient is a candidate for therapy involving psychedelic drugs. As a general guideline, people who have cognitive and emotional conditions associated with disorganized or diminished ego strength are not good candidates for pharmaco-assisted therapy with psychedelics. MDMA may represent a partial exception to this exclusion, because it has fewer cognitive and sensory effects and more salutary emotional and interpersonal properties. Contraindications include people with borderline personality disorders or schizophrenic tendencies.

Supervision

Supervision is necessary for ensuring safety of psychedelic experiences. Short-term psychological effects are profound. If used in unsupervised fashion by unselected and unprepared people, these drugs can be highly dangerous and, in extreme cases, cause death. The sensory effects described above interfere with hand-eye coordination and fine motor function, making operating a vehicle or machinery or even walking in public potentially dangerous. These effects are sufficient to emphasize that professionals who are skilled in managing adverse effects must be present. Most research into pharmaco-assisted therapy with psychedelics has by protocol required subjects to remain in a single comfortable room throughout the sessions. In addition to safety, the supervising therapists are able to guide patients through their experiences to optimize the drug's beneficial potential.

Set and setting

Anthropologists studying traditional use of psychedelics by shamans and indigenous people recognized the influence of expectations and motivation on subjective experience. Since the earliest psychological research into pharmaco-assisted therapy with psychedelics, clinicians have emphasized the importance of “set and setting.”

The dissolution of assumptions and diminution of barriers caused by these drugs extend to psychological and interpersonal realms of experience. An enhanced sense of connection to others not only underpins some of the therapeutic effects, but also results in vulnerability to emotional contagion. When taken without adequate preparation and when surroundings are anxiety-provoking—either physically uncomfortable or emotionally intimidating—the psychedelic experience predictably results in fear, a prolonged sense of dread, or full panic. Conversely, in controlled settings with elements of soft light, art, and appropriate music, or nature, and gentle, compassionate people, such adverse reactions are rare.

With adequate counseling and preparation, and when psychedelic experiences unfold in calm, aesthetically pleasing environments, they prove beneficial in a high proportion of cases. In these situations, the healing motivations of both therapists and patients may contribute to therapeutic outcomes.

Therapeutic effects

Clinical case studies and research trials describe common patterns of subjective experiences that are associated with therapeutic benefits for people with severe anxiety and depression. As the initial phase of psychedelic experience wanes and people regain familiar barriers between visual, auditory, tactile, olfactory senses, people typically report heightened cognitive clarity and expanded emotional receptivity. Previously unrecognized or unquestioned assumptions related to one's place in the world and relationships to nature, one's physical and social environments become available to being considered anew.

While psychedelic experiences vary significantly from one individual to another, research subjects and people interviewed for journalistic articles commonly express attributes, which include heightened clarity and confidence about their personal values and priorities, and a renewed or enhanced recognition of intrinsic meaning and value of life. People often voice a sense of exhilaration, insight, and strengthened connection to others, as well as a richer sense of relationship with nature or God. People who take psychedelics with an intention of spiritual introspection often report that the drugs opened windows into deeper realms of existential experience. In safe and supportive environments, these effects typically induce a state of wonder, conceptual frame shift, expanded capacity for love, and an intensified sense of connection. Patients living with medical conditions that had robbed them of hope or reason to live may experience a transformative shift in perspective and experience of inherent meaning, value, and worth.

Not all psychedelics drugs are alike and subcategories have been described. Drugs, such as psilocybin and LSD, classified as entheogens, are associated with introspection and new insights, shifts of perspective, and reframing of experience and relationship to others and the world. MDMA is characterized as an empathogen, referring to prominent emotional effects of interpersonal warmth, empathy, and openness. These properties may underlie the benefits of MDMA in the context of therapy for those suffering from severe PTSD.

For most of these drugs, a single six to eight-hour session or short series of sessions suffices for therapeutic benefit. Alleviation of anxiety and depression may persist for weeks to months and, for some, proves permanent. Exceptions to this treatment pattern include protocols of daily low-dose ketamine for depression and recent nonmedical reports of daily or every third day microdosing of LSD.

Political and regulatory considerations

Psychedelic drugs were closely associated with the cultural wars of the 1960s and 1970s when strong political undercurrents contributed to this class of drugs being classified Schedule I. Similarly, MDMA became well known as Ecstasy or Molly, a popular, illicit rave and party drug. In the mid-1980s, despite evidence of MDMA's striking efficacy and relative safety when used therapeutically, the FDA declared MDMA a Schedule I agent. Court rulings challenged that classification; however, in 1998 the FDA reaffirmed and made the Schedule I classification permanent.

The process of renewing clinical research of psychedelics has been long and painstaking. Future efforts to reclassify selected psychedelics, such as psilocybin, as Schedule II drugs, enabling both research and clinical administration will likely meet predictable political resistance. There are compelling reasons, however, to address the expected concerns of opponents and proceed with efforts to reclassify these drugs.

Treatment-resistant depression and anxiety associated with PTSD causes untold suffering and contributes to thousands of deaths each year. A few population health studies suggest that rising suicide rates may in part be due to suicide becoming less shameful and more socially acceptable, lowering barriers for people who feel hopeless. A person with severe depression, who has a coexisting serious, life-threatening physical condition, may feel that his or her quality of life is not worth living and may forgo arduous, but potentially life-saving treatments. Additionally, nearly one sixth of Americans live in states where physician-hastened death is legal and those with terminal illness may choose this option in absence of alternative sources of relief.

There may be higher ground on which political conservatives and progressives—as well as those on opposing sides of the issue of legalizing physician-hastened death—might build consensus. Given the life-threatening nature of persistent, treatment-resistant depression and PTSD, including among veterans of America's wars, and the rising incidence of suicide, the reclassification of psilocybin and MDMA can be legitimately cast as a right-to-try issue. Right-to-try legislation has been used to provide terminally ill patients access to potentially life-extending medications that have been tested in Phase I trials but are of uncertain benefit. Similarly, the FDA's expanded access or compassionate use provisions may make use of drugs that have not been approved available to patients who are otherwise facing death. By diminishing a desire to die among people with severe depression, anxiety, PTSD, and those with terminal cancers, genetic and neurodegenerative diseases, psychedelics may have greater life-saving effects than other drugs that have earned right-to-try and expanded access status.

Final thoughts

Faced with novel therapies with reported clinical benefits that seem too good to be true, skepticism is warranted to protect vulnerable patients from harm. Cynicism, however, may prove more dangerous still. Unscientific bias and nihilistic assumptions can keep effective treatments from people who desperately need them.

Despite the controversial history of psychedelic medications, palliative specialists who care for patients with serious medical conditions and common, difficult-to-treat nonphysical suffering have a duty to explore these hopeful, potentially life-preserving treatments. Against the backdrop of physician-hastened death becoming legal in five states, expanded research of clinical psychedelics must proceed.

In reexamining the use of psychedelics in pharmaco-assisted therapy, we must not allow preconceptions, politics, or puritanism to prevent suffering people, who are now considered helpless and hopeless, from receiving promising, at times life-saving, treatments.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867510/
 
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mr peabody

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'Patients say ayahuasca is like a reboot for the brain'

by Ayelett Shani Aug 30, 2018

The reason psychoactive drugs are banned is strictly cultural, says neurobiologist Dr. Ido Magen from the Weizmann Institute of Science. We need to free ourselves from the dichotomy between drugs and medications

What is it with you and drugs?

I did my doctorate under Prof. Raphael Meshulam on the subject of cannabis. The truth is that it’s not something that I was aiming for. It turned out that I got to a lab that happened to be doing a study with Meshulam, who is the high priest of cannabis worldwide. The idea was to use substances that he synthesizes from cannabis to treat a liver disease. We used CBD, which is the non-psychoactive element in cannabis, and saw that it actually worked.

Back when I was working on my Ph.D., I asked myself how it was possible that alcohol is legal and cannabis isn’t. That really bugged me. I knew from the research that it’s not a dangerous substance. As I extended my knowledge on the subject, I saw that the source of the ban on cannabis is actually cultural: racism toward Hispanics who immigrated to the United States in the 1930s. My interest only deepened. I began to collect material systematically, and at some point I started to lecture on drugs and to write articles. Somehow it gathered momentum.

Today, in my day-to-day work I am investigating the disease ALS [Lou Gehrig’s Disease] from completely different directions, but I continue to take an interest in psychoactive drugs and to lecture and write on the subject.

You are also active publicly on the subject. I saw an extremely sharp letter that you sent to the Israel Anti-Drug Authority.

As someone who deals with the subject from the scientific angle, I consider it absolutely a mission to illuminate the issue from that perspective and perhaps also to uproot the ignorance that characterizes the authorities’ entire attitude toward drugs. I really don’t like the messages that the IADA transmits to the broad public. I don’t like the fact that the state authorities are lying, simply disseminating fake news – or presenting alternative facts, to put it more mildly.

You are critical of the “gateway theory” – cannabis serving as the entryway to hard drugs, the joint that morphs into a syringe, etc.

The IADA claims that there is scientific proof that cannabis leads to the use of hard drugs down the line. That is a total lie. Even the authority itself makes opposite claims on its web page. It presents many figures as being factual, even though they have no empirical basis. For example, that a chronic use of cannabis leads to addiction and that the attempt to stop smoking it involves rehab with harsh physical symptoms; or data about the physical damage that smoking weed entails, among them a heightened risk of fatal diseases, damage to the respiratory system and so forth – whereas there are conflicting and not unequivocal findings about all those effects.

I think that the messages should be accurate and based on facts. In this era, in which people are exposed to a great deal of information, it’s anachronistic, not to say ridiculous, to continue to disseminate messages that are clearly far from the truth.

Many influential people are meddling in the legalization issue.

I think that certain enforcement agencies have an interest in continuing this line, because it’s easier to deal with people who smoke joints than with real criminals. They get very big budgets – the police, after all, are even against decriminalization, although they have no grounds for this other than the excuse that “this is how we catch dealers.” Do people who smoke have to be hostages of the police in order to catch drug dealers? Is the arrest of drug dealers useful in reducing the dimensions of the phenomenon?

What about the pharmaceutical companies?

I don’t have a smoking gun, of course, but there are hypotheses that the pharma companies are behind the super-slow progress being made in regard to medical cannabis. Its export has been bogged down for a few years [in Israel], and the prevailing conjecture, which to me sounds logical, is that the pharmaceutical corporations are behind this. Their interest is clear: They don’t want people to start using cannabis and then reduce or stop taking medications. So I see it as a mission: to free the public of its ignorance and to apprise it of the true facts.

There’s a petition to the court now, submitted by Green Leaf [a political party that advocates the legalization of cannabis] against the criminalization of marijuana, on the grounds that it violates the Basic Law on Human Dignity and Freedom. I was asked to write a professional opinion, and am doing so. It will be part of the petition.

What do you plan to say?

Naturally, I can’t reveal too much, but overall it’s about refuting mini-myths related to cannabis in order to persuade the justices that it’s not some monstrous substance that will lead to a disaster if the ban on its use is lifted.

Drugs and immigrants

Let’s talk about the process, which you address in your talks: namely, the gradual use of recreational drugs in medical treatment. You have a certain perspective on this, because the research you conducted ended a decade ago.

At that time people didn’t talk about cannabis like they do today. There were occasional experiments. Attempts were made to use cannabis in treating anorexia, for example, but it didn’t gain momentum. Today, drugs like these are used to treat a great many diseases and phenomena, after many years during which drugs were considered anathema. In the United States, the process of outlawing drugs began during Prohibition. Alcohol, after all, is a psychoactive drug in every respect, and that law was a reaction to massive immigration from Europe to the United States and to the culture of drinking in Europe, which the authorities very much did not like.

It’s interesting, by the way, that precisely at the stage when the prohibition on alcohol was lifted, the ban on cannabis began. The hypothesis is that the personnel who were in charge of enforcing the alcohol ban were left with no work to do, so they were sent to persecute cannabis users. Until the early 20th century, cannabis was legal and was even sold in drugstores. But when it arrived in the United States together with a wave of immigration from Mexico, it was outlawed. And it’s clear that economic interests were involved then, too.

What about psychedelic drugs?

Psychedelic drugs were very popular in South America and gradually penetrated the United States and the Western world overall. Aldous Huxley tried mescaline, and Timothy Leary, a professor [of psychology] at Harvard, conducted his famous experiment and aroused the fear and suspicion of the establishment. Leary’s experiment was halted and he became the darling of the hippies and of various proponents of the counterculture, who used LSD and mushrooms to the point where they became the very trademarks of the counterculture. Finally, LSD and the mushrooms were outlawed, which didn’t, of course, stop people from continuing to use them.

In our time we’re seeing the opposite trend: recognition of their medical qualities. Why is this so? Why now? Is the approach “Let’s try all existing substances until we find something”?

I can’t pinpoint the exact turning point when this trend started, but it certainly has to do with the discovery of the mechanisms of these drugs and their modes of operation. With cannabis, for example, until Prof. Meshulam discovered its active substances, no one knew what that it did, and that opened a window to a whole world.

In other words, the new conception derives from progress in brain research.

When it was discovered that psychedelic drugs work by activating serotonin, it was already known that illnesses such as depression are related to serotonin. So someone did the calculation that they might be useful for depression, too, but that really is progress made in the past few years. The psychedelic drugs specifically were like outcasts. They were feared because they generate hallucinations, and because most of them are synthetic. The objections to them were greater than for cannabis.

Let’s talk a bit about neural conduction. Roughly and simplistically, information in the brain is transmitted when one cell fires a chemical substance – a neurotransmitter – at another cell. It’s in that encounter, in the space between the cells in which the substance exists, that the influence of drugs occurs.

I like the analogy by which the chemical substance, the neurotransmitter, is like a key, and the receptor to which it attaches is a lock. Each key actually fits one specific lock, with the exception of a few substances that can attach to a number of receptors. Opening the lock causes electrical changes in the door that’s being opened. The drug can work on a particular neurotransmitter, it can inhibit the process of reabsorption into the cell that fired it, as in psychiatric medications; and cocaine and Ecstasy actually reverse the direction of the carrier, the substance that is responsible for returning the neurotransmitter to the cell that released it, so that instead of returning to the cell from which it was fired, it flows to the receiving cell, and thus its effect is prolonged.

The psychoactive drugs intervene in the process of neural conduction in the brain. They can alter it, intensify it or weaken it, extend or abbreviate its duration. Because neural conduction has a direct connection to our feelings, our consciousness, our cognitive functioning, it influences us, as well.

Reward and addiction

What about the reward system in the brain?

The reward system in the brain is actually intended to strengthen natural behaviors that are beneficial to our survival, such as sexual relations, which are critical for the species’ survival, or [a craving for] sweet foods that supply calories. All psychoactive drugs affect the brain’s reward system to one degree or another. Effectively, they deceive the system: We feel that we have done something that benefits us, even though in practice, of course, that’s not true. People use drugs to activate the mechanism by force, simply because that activation gives us pleasure even though it doesn’t serve any survival goal. The drugs trigger the reward mechanism – it signals us that we feel pleasure in the wake of the use of a drug, so we want to repeat the action over and over. That’s addiction.

So the question is not why to use drugs to try to gain relief or to cure mental problems, but why it took so long to arrive at this solution.

The answer is: cultural obstacles and vested interests. Conservatism. Across history, strange as it may sound, psychoactive drugs were not reviled. The ban is relatively new. The length of time in which cannabis, for example, has been prohibited is a tiny dot in our history, because there is evidence of its use going back thousands of years. All told, we’re talking about a hundred years, even less, since it’s been outlawed, but we’re brainwashed into thinking that this is natural.

And in contrast, psychiatric medications are considered totally legitimate and normative, even though in many ways their effect and the way they work are similar.

It’s only a matter of labeling. What’s the difference? A psychiatric medication is a chemical substance that affects the nervous system, and cannabis is a natural substance that affects the nervous system. In English the word “drug” also means medication – there’s no difference in the terminology. In Hebrew there’s a clear distinction [between sahm (drug) and terufah (medication)].

One of things I try to emphasize in my talks is that we need to free ourselves from the dichotomous division between drug and medication and from the mistaken working assumption that a medication is something good and a drug is something bad. All these substances affect our body in one form or another, they affect our functioning and our consciousness.

And in both cases we don’t know the full scope and consequences.

Correct. Opiod medications in the United States are simply killing thousands of people today. It’s ridiculous to think that they should be legal while cannabis isn’t. It’s really only a matter of convention.

Let’s turn to the use of psychedelic drugs for treatment of psychiatric problems. For example, ayahuasca, which has been found effective in the treatment of depression.

Ayahuasca is a herbal brew that was used by Native Americans for ritual purposes. It contains two relevant active substances. One works on serotonin receptors, the second effectively inhibits the breaking-down, thanks to which it’s possible to achieve a prolonged effect of the substance, after we drink it.

We should explain that the drinking of ayahuasca is a ceremony performed under the guidance of a shaman. I know a few people who have tried it. They described a psychedelic experience, hallucinations.

Yes. Obviously, the well-known ceremony was not performed as part of the clinical experiment that was done in a Brazilian university. The subjects, all of whom were suffering from depression and had not been helped by conventional medication, received either ayahuasca or a placebo under the supervision of the researchers. The experiment found that ayahuasca reduced the depressive symptoms, whereas the patients who received the placebo didn’t report any improvement – in fact, in some patients the depressive symptoms became even more acute.

But what was really interesting in that study was that a correlation was found between the intensity of the mystical experience, which was quantified through all kinds of questionnaires, and the improvement in the patients’ condition. The more powerful their experience, the more the depressive symptoms were weakened. That’s interesting, because in another study too, one that used psilocybin, which is produced by magic mushrooms, a connection was found between the intensity of the mystical experience and the level in the blood of a substance that is a product of the breakup of nicotine. In other words, the stronger the mystical experience, the less people smoked.

So there is a correlation between the intensity of the mystical experience and the therapeutic effect.

The conjecture is that the mechanism that causes the mystical sensations is also responsible for relief in the depressive symptoms. Of course, it’s impossible to prove the existence of a causal relationship.

Yes, but it can be assumed that there’s a connection to the release from the shackles of consciousness. The question arises of the degree to which consciousness creates the pathology.

These substances cause a blurring of the senses, liberation. They open the doors of perception, in the words of Aldous Huxley, and that allows us to be exposed to things and content that had been simply hidden from us. Brain scans done on people under the influence of LSD show that their whole brain lights up. There is very powerful activity, a great many regions in the brain are communicating with one another, the sensory experience changes.

Studies on LSD found that one of its effects is to dissolve the sense of the self – a Buddhist truth for liberation from suffering.

It’s not by chance that psychedelic drugs help in the treatment of mental illnesses more than other drugs. Cannabis also affects the physiological system, but with psychedelic drugs the effect on the body is minor; their primary influence is on the brain and on consciousness. Psychedelic drugs will not be used to relieve heart disease, say.

On the other hand, the description of heightened brain activity and a change in the sensory experience sounds similar to what happens in a psychotic attack.

I suppose that’s true – people undergoing a psychotic attack have powerful experiences, hear voices, see colors. That raises the question of whether psychedelic drugs are likely to aggravate schizophrenia or ease it. In any event, they are not used in cases of psychoses. Depression, in contrast, is not a psychosis, and psychedelic drugs can be used in an attempt to treat it. A study conducted in England tried to treat people suffering from depression that is immune to medications by means of psilocybin. The subjects underwent three brain scans in the experiment and immediately after the mushroom treatment. All of them reported a relief of the depression. The scans showed a change in brain activity.

That experiment examined long-term influences. How is it possible that it relieved the symptoms over time? After all, psychiatric drugs need to be taken daily.

That’s an interesting question, to which I don’t think they have an answer. We can only surmise. I find it hard to believe that the use of a drug caused a change in the brain chemistry, in the neurotransmitters. Possibly it’s a matter of dosage. The patients reported that it worked on them like a reboot of the brain. Despite the positive results, it was a preliminary study with a small number of patients, and we have to remember that this substance has side effects, so I wouldn’t recommend taking it just for the fun of it, and certainly if anyone wants to use it to relieve depression, that has to be done under medical supervision.

It’s interesting whether the patients themselves were able to overcome their prejudices about psychedelic drugs. It seems to me that when they’re used, the expectations shape the experience.

In indigenous cultures the psychedelic drugs are perceived as legitimate and are used in ceremonies and so forth. Western culture views them as something foreign, because they come from a foreign culture, and Western culture is not tolerant of anything that is “other.” Consider cannabis, for example, which was in widespread use in pre-Mandate Palestine, but under the British was added to the Dangerous Drugs Ordinance. Why? In my opinion, because they wanted to make it clear that they intended to impose a different culture here.

And the natives here are “drinking hashish” [reference to a line from the 1978 film “Lemon Popsicle”].

Yes. When the Spaniards arrived in South America they also banned the use of psychedelic substances, and for the very same reason. It’s something deeper and bigger than the approach to drugs as such – it’s an approach to what is different from you, something that doesn’t exist in your culture. The very definition of certain substances as “drugs” is a matter of culture. What is alcohol? Isn’t it a drug? Isn’t nicotine a drug? The word “drug” is used to indicate something that is foreign, not to say threatening, to our culture.

https://www.haaretz.com/israel-news...asca-is-like-a-reboot-for-the-brain-1.6431971
 
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mr peabody

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Endocannabinoids in MS and ALS

Pryce, Baker

There are numerous reports that people with multiple sclerosis (MS) have for many years been self-medicating with illegal street cannabis or more recently medicinal cannabis to alleviate the symptoms associated with MS and also amyotrophic lateral sclerosis (ALS). These anecdotal reports have been confirmed by data from animal models and more recently clinical trials on the ability of cannabinoids to alleviate limb spasticity, a common feature of progressive MS (and also ALS) and neurodegeneration. Experimental studies into the biology of the endocannabinoid system have revealed that cannabinoids have efficacy, not only in symptom relief but also as neuroprotective agents which may slow disease progression and thus delay the onset of symptoms. This review discusses what we now know about the endocannabinoid system as it relates to MS and ALS and also the therapeutic potential of cannabinoid therapeutics as disease-modifying or symptom control agents, as well as future therapeutic strategies including the potential for slowing disease progression in MS and ALS.

https://www.ncbi.nlm.nih.gov/pubmed/26408162
 
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HERVs: Can viruses in the genome cause disease?

by Katarina Zimmer | The Scientist | 31 Dec 2018

Clinical trials that target human endogenous retroviruses to treat MS and ALS, but many questions remain about how these sequences may disrupt our biology.

In 2005, an HIV patient in an unusually difficult situation walked into a neuroimmunology clinic at Johns Hopkins University, where he was seen by the specialist Avindra Nath. The patient had not only immune deficiency resulting from HIV infection, but amyotrophic lateral sclerosis (ALS) as well, and the neurodegenerative disease was causing his condition to deteriorate rapidly. For several months, the patient had noticed his hands and feet becoming increasingly sore and weak, making tasks such as eating with utensils or opening a window all but impossible. When Nath saw him, the 29-year-old had difficulty climbing stairs and couldn’t get up from a seated position on the floor without assistance.

The patient was initially reluctant to take a combination of anti-retroviral drugs to treat his HIV due to his rapidly progressing ALS symptoms, Nath recalls. “He said he would likely die from ALS before he died from HIV infection, so why take the anti-retrovirals?” But the doctor had read some clinical reports about other HIV-ALS patients’ ALS symptoms improving after a course of antiretrovirals, and Nath suggested he take them. The patient agreed and, like the other patients Nath had read about previously, rapidly began to feel better. When Nath saw him a year later, the patient no longer complained of weakness or muscle twitching, and his gait was normal. “This patient’s symptoms had totally reverted,” Nath tells The Scientist. “It’s one thing seeing it in the literature, but another thing to witness it yourself.”

The experience piqued Nath’s interest in the potential role of viruses in ALS. Digging further into published research on the disease, he also found a handful of blood analyses indicating the activity of reverse transcriptase, an enzyme that converts the RNA genome of a retrovirus into DNA. But when scientists had looked for infectious retroviruses in those blood samples, they hadn’t found any. Nath reasoned that if the culprit wasn’t an exogenous virus, it could be one that’s already present in the human genome.

Human endogenous retroviruses (HERVs) through the ages

Over the course of evolution, several groups of ancient viruses colonized our ancestors’ genomes, leaving thousands of fragments of viral code in modern-day human DNA. The bulk of HERVs integrated during primate evolution. Subsequent mutations in these sequences have rendered older insertions nonfunctional, but some of the younger and more intact sequences from HERVs have been linked to disease.



Around 8 percent of our genetic code stems from HERVs, the bulk of which integrated during primate evolution.

- HERV-K viruses colonized the genomes of ancient primates as early as 55 million years ago (mya). Many of the youngest and most preserved elements, such as those in the HERV-K (HML-2) group, can produce viral proteins and have been linked to ALS.

- The HERV-W group, which invaded the genome starting around 25 mya, was first detected in Multiple Sclerosis patients and named MS-associated retrovirus (MSRV) for its connection to the myelin-degenerating condition.

- HERV-Fc, the youngest member of the HERV-F viruses, integrated into the genome more than 20 mya and has also been linked with Multiple Sclerosis.

- HERV-L elements have been detected in all placental mammals, and are thought to have integrated between 100 million and 150 mya. They represent the oldest HERVs in the human genome, are not known to produce any proteins, and so far have not been linked to disease.

Like many other animal species, humans carry viral remnants in genomes, left behind from the integration of retrovirus sequences into the germline DNA of our ancestors over the course of millions of years. Today, these human endogenous retroviruses (HERVs) exist as 450,000 fragments of biological code, representing 39 major viral groups, broken up and scattered throughout the genome. Nath asked his colleague Jeffrey Rothstein, now the director of Johns Hopkins’s Robert Packard Center for ALS Research, for some samples of postmortem brain tissue of ALS patients, and began to search them for RNA transcripts of HERV sequences.

The work yielded one match: HERV-K, the youngest group of viral insertions in humans. The transcripts were specifically associated with ALS, Nath and his colleagues found; they were not present in the brains of healthy individuals who died in accidents or in the brains of Parkinson’s patients. Since then, Nath, who now heads the Section of Infections of the Nervous System at the National Institutes of Health in Bethesda, Maryland, and others have been steadily accumulating evidence that these viral sequences are expressed in a subset—about 30 percent—of ALS patients.

The vast majority of the HERV protein-coding sequences scattered across the genome have over time accumulated many mutations that render them inactive. That HERVs can cause damage to their hosts in modern times has long been dismissed as a fringe idea. Over the past three decades, however, research has implicated several of the younger, more intact HERV insertions in a range of diseases, including ALS, Multiple Sclerosis (MS), cancer, and schizophrenia.

“Though they’ve mostly been ignored by the medical research community for quite a long time, they can actually have a large effect on the human body in more than one disease setting,” says Molly Hammell, a geneticist who studies HERVs at Cold Spring Harbor Laboratory in New York. Since this idea has come to light, some researchers have launched clinical studies to evaluate HERVs’ roles in diseases.

Skeptics are still wary of the evidence that HERVs are involved in pathogenesis at all. Although there is a correlation, few studies address a possible causative role. “We know that they’re expressed,” says virologist George Kassiotis of the Francis Crick Institute in London, “but whether that expression really causes or really contributes todisease, that remains to be proven.”

Rise of the Phoenix proteins

In 1967, University College London virologist Robin Weiss noticed a viral envelope protein emerging not just from chicken cells that he had infected with a Rous sarcoma virus, which is known to cause cancer in poultry, but also in control cells that had not been exposed to the virus. Together with geneticist Jim Payne, the former director of the now-defunct Houghton Poultry Research Station in the UK, he conducted classical Mendelian cross-breeding experiments that pointed to the protein’s heritability, identifying the virus as avian leukosis sarcoma virus, an endogenous retrovirus in chicken genomes. “These things are inherited, just like Mendel’s peas,” says Weiss, noting that Peter Vogt of the Scripps Research Institute came to this conclusion around the same time.

Initially, journals were reluctant to publish the result, says Weiss, who recently retired. At the time, reverse transcriptase—which made the concept of a retrovirus integrating into the genome plausible—wasn’t even known to exist yet. After the enzyme’s discovery in 1970, the idea that viral protein-coding genes could live in host DNA gained traction as additional endogenous retroviruses were found in mice and other animals. Many of these viruses proved to be active, giving rise to infectious viral particles capable of inserting new pieces of DNA into the animals’ genomes—and causing diseases, including cancer and autoimmune disorders.

Since discovery of endogenous retroviruses in humans in the 1980s, there has been a contentious debate as to whether HERVs behave like endogenous retroviruses in animals. While scientists have established that most HERVs are dormant, some researchers believe that the youngest insertions of a HERV-K virus called the HML-2 virus, which invaded our lineage as recently as 670,000 years ago, can produce retroviral particles that infect other cells. In 2006, a group of French researchers succeeded in reconstructing the ancestral HML-2 virus in the lab based on a consensus sequence from all its snippets in the human genome. The resulting “Phoenix” element, as they called it, was capable of infecting other mammalian cells in culture. And in 2015, a team of Stanford University biologists captured electron micrographs of HML-2 viral particles—containing proteins and nucleic acids—budding off cultured human blastocysts,4 a phenomenon that researchers now think occurs naturally during development.

To date, however, there is no in vivo evidence that such particles can infect other cells or result in new HERV-K insertions in the human genome. "In fact, Ralf Toenjes of Germany’s Paul Ehrlich Institute discovered in 1999 that two nearly intact insertions of HERV-K viruses have inactivating mutations, leading to a nonfunctional retrovirus,” he explains.

Even if HERVs can’t assemble into infectious particles, they can still have a significant influence on human biology. For instance, many HERV sequences can be transcribed and even translated in human cells, with hundreds of HERV genes likely having the capacity to yield viral proteins, says Cornell University geneticist Cedric Feschotte. Some of these proteins may have taken on beneficial roles in humans. For instance, HERV-encoded syncytin 1 is produced in early development, and is thought by some researchers to function in the formation of the placenta. Moreover, humans appear to have co-opted many viral promoters to help drive the expression of our own genes.

While Kassiotis doesn’t believe that HERV particles trigger disease, "in rare cases, the mere presence of HERVs in the genome can cause problems," he says. "For example, when normally silenced viral promoters lie upstream of an oncogene, and happen to be activated during cancer, they can sometimes contribute to accelerating the disease," explains Kassiotis.

But other researchers are steadily accumulating evidence that our viral hitchhikers may be involved in much more than that—perhaps playing a direct role in the pathology of other ailments, in particular, ALS and MS.

HERVs and neurological disease

In 1985, Herve Perron, then a doctoral student at the University Hospital of Grenoble, France, came across a Nature paper that postulated a retroviral cause of MS. He decided to look for evidence of retroviruses in tissue samples from MS patients as part of his thesis. Sure enough, he found fragments of viral proteins in cultures grown from cells inside donors’ cerebrospinal fluid. In further experiments, he and others found the same viral particles in macrophages isolated from the blood of MS patients, but not in cells taken from control samples. Together with University College London’s Jeremy Garson, who had developed a technique to detect the RNA of unknown retroviruses, and other colleagues, Perron characterized the viral particle for the first time in 1997 and showed that the viral genetic code closely matched an endogenous family of retroviruses—the first hint that the element was endogenous. Perron called it the MS-associated retrovirus (MSRV), and it was later found to belong to a larger group named HERV-W.

Parsing the HERV-disease link

Current research suggests that viral hitchhikers in human DNA may play roles in cancer, inflammation, and neurodegenerative disorders. The mechanisms that underpin these connections between human endogenous retroviruses (HERVs) and disease are just beginning to emerge. Transcription of viral RNA can signal the presence of foreign DNA in cells, triggering defensive immune reactions. Scientists have also proposed that synthesis of the HERV envelope protein—which once enclosed the viral capsid of its retroviral ancestors—exerts pathogenic effects. In other contexts, such as certain cancers, researchers think that the disease state activates HERVs, rather than the other way around.



(1) Activation of viral promoters: Ancient retroviral infections have left viral promoters throughout the human genome. Although our bodies have coopted many of them to drive the expression of our own genes, a lot of those promoters are kept silenced through epigenetic repression. Reactivation of these elements can result in abnormal expression of nearby oncogenes or tumor-suppressor genes.

(2) Expression of viral genes: Under some circumstances, such as cancer, many regions of the genome that are normally silenced can awaken. This can activate the transcription of HERVs, causing viral RNA to accumulate in the cytoplasm. According to the “viral mimicry” theory, these molecules alert cellular RNA-sensing pathways to the viral material, triggering an immune response.

(3) Translation of viral proteins: Some viral RNAs are translated into proteins, which can be secreted and travel to other cells. It’s unclear what effects these proteins have, but some researchers hypothesize they activate surface receptors and ultimately initiate immune reactions.

Just as Weiss’s results had experienced 16 years earlier, these findings were met with a chilly reception. “People had the dogma that in humans, there are very few of such elements in the genome, and they are all junk DNA that is completely inactivated by mutations,” Perron recalls.

But a series of studies has uncovered more associations between MS and HERV-W sequences as well as those of another viral group known as HERV-F. In the brains of deceased MS patients, for instance, researchers discovered fragments of viral proteins within the lesions that form in the central nervous system due to a loss of axonal myelin sheaths. And virologist Antonina Dolei of the University of Sassari in Italy and other researchers have uncovered a strong correlation between the blood levels of HERV-W RNA and the severity of MS symptoms: levels increase around the onset of the disease and as symptoms get worse, but decrease during remissions and under effective therapies. “The virus is present in the right place at the right times,” she says.

"By now, researchers have a very well-argued case for an association,” says MS researcher Tove Christensen of Aarhus University in Denmark, “but we haven’t yet come to the point of showing that it’s actually causative.” Weiss is particularly skeptical of the idea of a cause-effect relationship. “I would say that maybe it’s the autoimmune activation that’s activating the virus, and not the virus that’s causing the autoimmune disease,” he says, though he adds that “the virus in turn may exacerbate the disease.”

The idea that HERVs might play a role in MS was supported by the detection of a HERV-K virus in pathological tissue in ALS, as shown by Nath and others. "But a lot more work is needed to establish causation," Nath cautions. "Understanding the mechanisms at play is key not only for establishing its role in ALS,” he says, “but also for developing targeted therapy.”

Mechanistic insights into HERVs

In figuring out the possible mechanisms underlying HERV-disease connections, Nath says he thinks one of the most pressing questions is whether they’re capable of forming infectious retroviral particles. An infectious retrovirus would help explain the progressive nature of ALS symptoms, from motor extremities to the central nervous system. “If it’s not HERV-K being transmitted [from cell to cell], then there’s got to be some other factor that’s being transmitted to activate it,” he says.

So far, there’s no evidence for this type of viral behavior in ALS or in MS. Rather, researchers have focused on HERV envelope proteins, because the homologous proteins in HIV are known to have neurotoxic effects. In 2015, Nath’s team created a transgenic mouse line in which the animals produced the envelope protein of HERV-K. The mice subsequently developed ALS-like symptoms, including spasticity, weakness, and muscle atrophy.

How this occurred is a mystery. Nath hypothesizes that the HERV-K envelope protein can cause dysfunction in the nucleolus, the membraneless structure within the nucleus that hosts ribosome biogenesis. “And this messes up the entire protein synthesis machinery in the cell itself . . . that eventually leads to toxicity,” Nath speculates.

MS researchers similarly suspect that the HERV-W envelope protein, which activates the immune-linked toll-like receptor 4 on microglia and macrophage cells, could drive the disease’s pathology. In fact, Perron is so convinced of its role that in 2006 he and others launched the Geneva-based biotech company GeNeuro to develop novel therapies based on antibodies that specifically target HERV envelope proteins. In a mouse model, Perron’s team found in 2013 that injecting the animals with the HERV-W envelope protein contributed to the development of motor defects and inflammation of the nervous system. "While not providing evidence of causation, the experiments showed that the protein is capable of initiating an autoimmune process that results in inflammation and tissue destruction in the central nervous system,” writes Robert Glanzman, the company’s chief medical officer, in an email.

In subsequent experiments in murine and human cell cultures conducted by German researchers, the protein appeared to stifle the maturation process of oligodendroglial precursor cells, which would normally help repair degraded myelin sheaths. And in other research from the same group that has yet to be published, the envelope protein also inhibited microglia cells from scavenging myelin debris—another process critical to myelin repair—and stimulated them to secrete proinflammatory cytokines, Glanzman adds.

HERV proteins in neurodegenerative disease

The discovery of viral proteins in the eroded brains of MS and ALS patients has prompted researchers to investigate the role of HERVs in these diseases. Although this research is becoming more widespread, the mechanisms are still unclear and remain hypothetical.

Multiple Sclerosis

The HERV-W envelope protein binds toll-like receptor 4 on microglia, triggering the cells to secrete proinflammatory cytokines (1). At the same time, the protein also inhibits these cells from scavenging myelin debris (2), a mechanism important for rebuilding myelin sheaths that are damaged in MS, and prevents oligodendrocyte precursor cells (OPCs)—which normally help remyelinate damaged axons—from maturing (3). Combined, these two pathways create an inflammatory environment that contributes to the development of lesions in the brain, while also impairing the ability of local cells to repair the damage. Researchers haven’t yet discovered what triggers the production of HERV-W in the first place.



ALS

Experiments in mice have shown that activation of the most recently integrated HERV in the human genome, known as HERV-K, in specific regions of the nervous system causes motor neuron deterioration. This could explain the neurodegeneration seen in ALS, although it is still unclear exactly how HERV-K is involved. Researchers speculate that the envelope protein of HERV-K causes disruption of the machinery in the nucleolus responsible for producing ribosomes, and this in turn results in cell death (1). This process is thought to spread from cell to cell—in accordance with the progressive deterioration seen in ALS—through factors that stimulate the production of the viral envelope protein, through the secretion of the protein (2), or possibly through the spread of HERV-K itself, though there is no evidence that the endogenous virus can behave in this way.



"The envelope protein is not the only way that HERVs can mess with the immune system. Even in the protein’s absence, excess HERV RNA and other HERV-derived nucleic acids can trigger the body’s immune response, alerting cellular sensors that detect cytoplasmic DNA," explains Feschotte, who receives funding from GeNeuro. And “when these sensors get overwhelmed, it triggers autoimmune reactions,” he says. “That’s very well characterized.”

A key question that remains unanswered is why these disease processes would occur in only some people. The vast majority of HERV sequences are present in everyone. But people can carry variable numbers of particular HERV fragments, and a few HERV snippets are found only in some human genomes—both factors that can in theory contribute to individual susceptibility to HERV-driven pathologies.

In addition, work by Christensen’s team at Aarhus University suggests that the host’s individual genetic makeup may come into play. In 2011, the researchers demonstrated a preponderance of certain single-nucleotide polymorphisms around a particular locus of HERV-Fc1, a member of the HERV-F group, on the X chromosome in MS patients, compared with healthy individuals. And other research suggests that environmental factors—such as Epstein-Barr virus, a common infection thought to play a role in MS—can activate the expression of HERV-W. Hammell and colleagues have found that the aggregation of the TDP-43 protein, an RNA- and DNA-binding protein known to accumulate in the vast majority of ALS patients, induces the expression of an endogenous retrovirus in Drosophila.

Rush to the clinic

Although the mechanisms remain murky, researchers are already eyeing HERVs as possible therapeutic targets for several diseases. Some researchers are now conducting trials with ALS and MS patients testing the antiretrovirals that have proven effective in preventing HIV’s reproduction and entry into the genome.

The ALS patient Nath treated in 2005 inspired him to launch a small pilot study in which five individuals with both HIV and ALS each received a different combination of up to 16 antiretrovirals. Similar to his earlier observations, Nath noted that three patients experienced a reversal of motor symptoms associated with ALS, and the other two experienced a notable slowing of their ALS progression. "However," Nath says, “it is quite possible that the antiretroviral had an effect on the ALS only because of downregulation of HIV.” He is now planning another study to investigate whether a combination retroviral therapy can affect the levels of HERV-K in the blood and cerebrospinal fluid of 20 ALS patients without HIV.

Other diseases associated with HERVs

There is copious research on the involvement of HERVs in ALS, MS, and cancer. But researchers have also identified tenuous links between the endogenous viruses and a handful of other conditions.

1. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), a neurological disorder characterized by progressive weakness and sensory disturbances in the legs and arms:

- HERV-W envelope protein is found in the serum of some CIDP patients, and viral RNA is present in peripheral blood mono-nuclear cells.

- The protein is also found in peripheral nerve lesions. In Schwann cells and immune cells of blood serum, the protein induces the secretion of proinflammatory factors.

2. Schizophrenia and bipolar disorder

- HERV-W RNA is present in the cerebrospinal fluid and brains of some deceased schizophrenia patients.

- One particular HERV-K insertion serves as a genetic enhancer for the schizophrenia-linked gene PRODH.

- Transcription of the HERV-W envelope (env) gene is elevated in bipolar disorder and schizophrenia compared with healthy controls.

3. Type 1 diabetes

- HERV-W envelope protein is detected in the blood serum of some type 1 diabetes patients, and its corresponding RNA is found in peripheral blood mononuclear cells.

- Transgenic mice expressing the HERV-W env gene display hyperglycemia and decreased levels of insulin.

4. Addiction

- One specific variant of HERV-K, which is in close proximity to a gene involved in dopaminergic activity in the brain, is more common in drug addicts than in controls.

Julian Gold, a virologist at Queen Mary University of London, is interested in using antiretrovirals to treat MS, but a 2014 pilot study of 20 MS patients proved disappointing: the antiretroviral drug Raltegravir didn’t help reduce the number of new lesions, the most visible sign of myelin loss, that appeared in MRI scans of the patients’ brains.13 Gold thinks this is because he used a single drug, and not a combination therapy that is typically effective in HIV. In March, he concluded a separate trial in 40 ALS patients, this time using a combination therapy known as Triumeq. “The trial clearly shows that it’s safe and well tolerated,” says Gold, who is also director of Albion Centre, a public health-care facility in Sydney, Australia. The efficacy results are not yet published, but Gold says "the initial data make him optimistic about this approach in ameliorating symptoms in some MS patients."

But Glanzman is skeptical, as he posits another reason for Gold’s disappointing MS trial—the use of an antiretroviral drug to target what Glanzman thinks is an inactive virus. "If the HERVs that have been linked to these diseases are incapable of replicating, trying to approach them with an antiviral treatment is not going to be effective,” says Glanzman. Instead, he and his GeNeuro colleagues are developing an envelope-targeting antibody called GnbAC1 that binds to a surface subunit of the envelope protein to block its interactions with toll-like receptor 4 carried by microglia and macrophage cells and has been recently shown to promote myelination in rat nerve cell cultures. Last March, the company concluded a Phase 2b trial with 270 MS patients in Europe that showed preliminary evidence of the drug’s effectiveness in treating the disease. In results that were presented at a conference on MS research in Berlin last fall, patients who got the antibody at the highest dose experienced 31 percent less shrinkage of cortical tissue, a hallmark of MS, compared with patients treated with placebo for six months. Treated patients also experienced a 63 percent reduction in the formation of “T1 black holes,” the brain lesions associated with the most severe damage to the central nervous system.

"It’s early days," Glanzman says, "but so far the results look promising. Now we have the clinical data to support that if you block the protein, you have beneficial effects.” The company is now following some of these patients to see if the changes observed in their brains translate to a clinical benefit; results are expected later this year.

The company recently made an agreement to work together with Nath on treatments for ALS with a similar antibody approach, and is starting to work on other diseases that have been linked to HERVs. For instance, "unpublished research from GeNeuro suggests that HERV-derived proteins are toxic to the pancreases of mice," Glanzman says. After a study finding that 70 of 100 patients with type 1 diabetes had evidence of a HERV-W envelope protein in the pancreas, they initiated a one-year trial to see if an antibody against the HERV-W envelope protein is safe in type 1 diabetes patients. The company also plans to test HERV-targeting therapies to treat a condition known as chronic inflammatory demyelinating polyneuropathy as well as inflammatory psychosis, which encompasses some forms of schizophrenia and bipolar disorder.

Other researchers have begun cancer trials that aim to improve immunotherapy treatments by epigenetically boosting the expression of HERVs to coax the immune system into killing the tumor cells. For example, George Washington University’s Katherine Chiappinelli recently showed that administering compounds that remove the methylation around HERV genes triggered the immune system to attack tumor cells in a mouse model of ovarian cancer. “The cancer cell thinks it has a virus, because it sees the viral RNA,” she explains, "triggering an immune response that helped the mice survive much longer than controls."

"Despite the growing link between HERVs and disease, and the positive results from early-stage trials, the idea that the viruses of the human genome can become destructive is still not widely accepted,"
Nath notes. “The way most of these things work is some people think it’s great science, some people are going to be skeptics, so it takes some time before other labs can reproduce your results,” he says. “Publishing one or two papers, it gets people excited about the field, but it takes much, much longer for people to accept the concept.”

https://www.the-scientist.com/featur...104.1546301593
 
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Ayahuasca – Ethnobotanical medicine for treatment of ALS

by Daniel Gustafsson

This article is the culmination of six years work, having studied ethnobotanical natural medicine and the field of motor neuron disease, making connections between the two in the search for viable treatment option for ALS, and similar neurodegenerative conditions.

In south and central america, native people of many tribes living within the Amazon rainforest have a long historical tradition of preparing and consuming a natural medicinal tea called ayahuasca. It is harvested and made mainly from a wild growing vine, its latin name being Banisteriopsis Caapi. Often, but not always, leaves from trees named Chacruna or Chaliponga (Psychotria Viridis and Diplopterys Cabrerana) are added to the tea, or in some regions Jurema tree bark (of the Leguminosae family and Mimosa species).


Banisteriopsis Caapi

The rainforests of the earth are known to be enormously resourceful and a necessity in upholding the ecosystem of the planet. An estimated abundance of undiscovered medicinally valuable plants remain to be explored within these forests. Many conventional pharmaceuticals originate from substances found in rain forest plants, or from their synthesized variants. Ethnopharmacologists are long since aware of vast support for the medicinal value of ayahuasca and its use in treatment of a wide variety of diseases, but until recently evidence has been limited. This however has changed in the 21st century, as interest and studies in ayahuasca have increased.

Natural substances extracted from ayahuasca plants have been found to possess unique restorative and strongly antioxidative properties on specific nerve cells in the brain and central nervous system, controlling neurotransmission, muscle and motor activity, memory and coordination. This gives probable cause to the theory that ayahuasca could be an effective treatment for neurodegenerative diseases such as ALS, Alzheimer’s, and Parkinson’s disease. Promising results as of date have also been obtained from studying the substance psilocybin, remarkably closely related from a molecular view to the substances found in ayahuasca, naturally occurring in certain species of medicinal mushrooms consumed by the indigenous people where ayahuasca is also used.

According to Dr. Juan Ramos, head of the neurological disease department at the South Florida university, USA, initial studies show that mushroom tryptamine substances semi-identical to the ones contained in ayahuasca stimulate the development of new cells in the areas of the brain controlling the above mentioned functions. If this could prove to become an eventual cure through complete restoration of damaged and already lost nerve cells remains to be seen, but initial results indicate this could potentially be the case. Other studies led by Dr. Jordi Riba at the spanish university of Sant Pau, Barcelona, show connections between ayahuasca and neural pathway redevelopment in the neocortex. Cancer researchers have also shown interest in B. Caapi, as its alkaloids have shown to be effective against the growth of cancer cells, and are believed to be able to stabilize and balance mitochondrial function. This relates also to ALS research in that mitochondrial dysfunction is nominated one of the main causes of cell damage in ALS, and that the normalization of mitochondrial metabolism through modulation of calcium influx from beneficial alkaloids contained in ayahuasca could prevent motor neuron damage and increase nerve cell survival rate. Mitochondrial function is directly related to neuronal survival, and unregulated levels of intracellular calcium are thought to initiate motor neuron dysfunction, or amplify other mechanisms prone to injure motor neurons.

Eduardo E. Schenberg, Federal University of Sao Paulo:

“There are enough available evidence that the active substances in ayahuasca, especially DMT and harmine, have the positive effect of preventing cancer cells in cultures used for cancer research, and that these substances affect the biochemical processes that are crucial to the treatment of cancer in-vitro as well as in-vivo. The reports available about people with experience from ayahuasca in the treatment of cancer should be taken seriously. The hypothesis is that the combination of (beta-carboline) alkaloids and DMT present in ayahuasca blocks the transportation of nutrients to tumors, lessens the dividing process of cancer cells, and changes the unbalanced mutation-causing metabolism in cancer cells.”



A recent study by Icahn School of Medicine, New York, singled out harmine (from the ayahuasca Caapi plant) among 100.000 substances, as the only one able to cause beta cells in the pancreas (the internal organ that produces insulin) to regenerate, a discovery of great interest to diabetes researchers. Other evidence suggest that ayahuasca may have the potential to regenerate several different types of cells, in many places in the body where needed, the specifics of which calls for medical research in many areas – especially neurodegenerative diseases without a known cure to this date. There is also a growing interest in exploring the cell regenerative properties of these plants in spinal cord injury research. Harmine in ayahuasca has also been found to regulate glutamate pump expression in the central nervous system, thereby reducing glutamate toxicity – one of the causes believed to trigger and aggravate ALS through excitotoxic reactions occuring through excessive receptor stimulation by neurotransmitters.

What was previously controversial about ayahuasca, was that the plants in question used to be thought of simply as so called hallucinogens by western science. In other words, these medicinal plants of great importance, were neglected by the scientific community and thought of simply as if they were natural drugs. A more accurate term for these plants, in respect to the indigenous culture in which ayahuasca is a part, would be “entheogens” – meaning plants used in a context sacred to the native people, inducing spiritually oriented experiences (explained from their own perspective and worldview). In several countries, such as Peru, ayahuasca is fully legal and accepted as a complement to conventional medicine, and during recent decade, western countries have to an increasing degree changed a former unfounded and faulty attitude towards entheogens such as ayahuasca, as more studies of entheogenic plants have been completed with positive outcome.

Along several other similar harmala-alkaloids found in B. Caapi, harmaline is a monoamine oxidase inhibitor. Monoamine oxidase (MAO) is an enzyme in the body that breaks down signal substances (such as serotonin). The inhibition of MAO allows the signal substance to remain in the synapse for a longer period of time. Many anti-depressants work in a similar manner, as they stimulate receptors in a targeted area. However, the alkaloids present in ayahuasca should not be compared to antidepressants, as they are not exactly comparable though they both have the ability to affect the same receptors. A comparison is that Caapi alkaloids and antidepressants have the same type of delivery system, but different contents. The biochemical properties of plants used in ayahuasca, and the effects they cause on a multitude of bodily functions remain unique to these plants alone. Various types of harmala alkaloids exert suppression of neurotoxic metabolites, such as quinolinic acid and kynurenine – metabolites correlating with ALS, Alzheimer’s disease, Parkinson’s disease and Huntington’s disease, all in which elevated levels of given metabolites are found and thought to contribute to onset of disease through interaction with spinal motor neurons.


Harmaline, harmine and tetrahydroharmine are the main
components in the medicinal plant Banisteriopsis Caapi.




Comparison between DMT, Psilocin- and Serotonin-molecules

Ayahuasca in itself is proven unharmful, its compounds being non-toxic, although temporary side effects such as nausea and vertigo are common when used in amounts above medicinal purposes. However, combining certain medical drugs with MAO-inhibitors (such as the ones found in ayahuasca) can be dangerous, even lethal in some cases. This means that in order to safely consume ayahuasca, it must not be combined with any counterindicated pharmaceutical drugs, and those suffering from certain health conditions such as epilepsy or high blood pressure are advised to either refrain from use or to proceed only with caution and supervision. Uncomfortable side effects from ayahuasca are greatly dose dependent, and a smaller amount consumed for medicinal purpose can thus easily equal few if any side effects experienced.

When searching for information about ayahuasca, a few negative articles can be found, emotionally angled (understandably so), since they tell stories of unfortunate tourists who on their own, or having been duped into doing so, drink something entirely else than ayahuasca – for instance the toxic plant datura, or liquid made from tobacco plant – with serious outcome to their health (including death in a few known cases, from apparent nicotine poisoning). This leads to fear and misinformation, and is not only tragic for the diseased and their families, but also for the natural medicine community trying to promote safe and responsible use of natural medicine for health benefits, and treatment of diseases that regular medical care have failed providing options for. Sensationalistic headlines making unfounded claims, written by people without any knowledge about ethnobotanical medicine, will definitely not help neither ALS patients or people searching for information, and only makes medicinal plant research more difficult. In several countries, including Peru, Brazil and Costa Rica, established retreats offer ayahuasca treatment where the correct plants are harvested (and sometimes organically grown on the property) and prepared by experienced botanists.



One of the earliest studies on B. Caapi were done in the 1920’s, and involved patients with Parkinson’s disease. The patients experienced great symptom relief in early trials, but unfortunately the research was prematurely discontinued due to lack of profit potential – as substances already present in natural plants could not be applicable for patents useful to pharmaceutical companies.

Ayahuasca therapy is likely to gain further attention in coming years, but is already well established in some places. Should discoveries eventually lead to production of a therapeutic pharmaceutical drug derived from these plants, it would take many years until a final widespread and established product reaches and helps actual patients. The process from studies, through trials, to eventual launch of an approved pharmaceutical made for use in the medical care system, is slow due to obvious reasons. The real and interesting fact is that ayahuasca in its natural form is something already available to people with diagnoses lacking other treatment options. For those who can and want to use ayahuasca, there is, while not in any way guaranteed, a possibility for improvement that is still real. As in many other cases, individual results vary, and there should be an emphasis on not overly promoting this medicine (and thereby people’s hope) while questions and work remain. There is also the importance of emphasizing and thereby minimizing the risks involved concerning contraindications with other medications and conditions. Awaiting further studies, this information should still be worth the attention of those suffering from a debilitating progressive disease such as ALS, and researchers in medical science.

My personal connection to this topic and project, was the passing of a close friends’ mother in ALS which occurred in 2012. The course of her disease was rapid and aggressive, and unfortunately several of the now available studies referred to in this article, were not yet published at the time. This led me into investigating biochemical aspects of entheogenic plant medicine in search for treatment of neurological disease, and making information on the topic publicly available, while connecting it to a study currently in progress.

B. Caapi is legally obtainable in most countries and states much in the same way as other known herbal remedies, such as Echinacea and Ginseng. However, as with any other potent natural supplement, it is up to the consumer to use and combine supplements and herbal remedies in an informed and responsible way. In the same way as conventional pharmaceuticals, natural medicines should always be treated with proper respect. One commonly known species that actually contains small amounts of harmala alkaloids is passion flower, or passion fruit tree, although the concentrations in its leaf foliage and flowers are far too low (and the fruit contains none) to be used effectively for monoamine oxidase inhibition and ayahuasca purposes. Also, while similar to some degree, the alkaloid profile in terms of proportions and molecular structural deviations between distinct alkaloids does not match up exactly with that of B. Caapi, making the two species related from a certain aspect, but far from equal regarding their medicinal properties. Extracts from various passiflora species are however produced and sold worldwide as mild herbal relaxants and sleeping aids, and as an antispasmodic for treating Parkinson’s.

The substance known as DMT, found in plants traditionally added to ayahuasca, is regulated by law in a number of countries classified as a scheduled substance. This particular substance contained in the additional aforementioned plants induces the altered state of consciousness, a many times misunderstood and stigmatized phenomenon. A description of this altered state is that it is dreamlike, that it stimulates memory and the ability to think abstract, and has self-therapeutic qualities. Even though DMT is naturally occurring in the human body, thought to be produced in small amounts by the pineal gland in the brain during sleep, it remains an illegal substance in a number of western countries since the 1960’s and 70’s, when lawmakers prematurely criminalized almost any substances suspected of having any effect on the mind, including natural ones, due to the widespread moral panic at the time – regardless of the fact that many of them, including DMT, were never proven unhealthy, having in fact been used by indigenous people, in the form extracted from plants, to successfully treat diseases and health problems for centuries. Leaf juice from Chacruna has been used traditionally as a remedy for migraines and ant bites, and Jurema bark for treating burn wounds – significantly quickening regeneration of skin and scar tissue. DMT also targets chaperone sigma 1, a receptor subtype expressed in both neurons and glia of multiple regions within the central nervous system, with capacity to modulate biological mechanisms implicated with neurodegeneration. Sigma 1-receptors present compelling targets for pharmacologically treating neurodegenerative disorders, and DMT acts as an endogenous Sigma-1 receptor regulator, but interactions between the two in association with motor neuron disease is not understood.

Although, several European countries have redefined their policy regarding many formerly frowned upon medicinal plants in recent years, much due to an increasing awareness and access to new and unbiased information and up-to-date research regarding these plants. In Scandinavia, Sami natives from Sapmi, Sweden, were recently acquitted from all charges in the court of law, for having brought Peruvian medicinal cactus into the country. The court established that natural plant material alone cannot be defined as a scheduled substance, and that the therapeutic work involved people were doing, which included Echinopsis Pachanoi cactus, was indeed not a criminal act, but served the purpose to help and heal people. Another similar case with the same outcome involved ayahuasca additive plants. Cacti from the Echinopsis and Lophophora species are known for their restorative and cleansing effects on the body, and are used as such in ethnobotanical medicine.

To be precise, the definition of Ayahuasca is any tea made from either the plant Banisteriopsis Caapi alone, or from B. Caapi and additional plants containing DMT. A tea made from B. Caapi alone does not have what is sometimes referred to as “visionary” qualities, as only the addition of DMT from additive plants, or actually the combination of mao-inhibiting alkaloids in B. Caapi together with DMT content induces a state of mind formerly mislabeled “hallucinogenic”. It needs to be clarified that this word brings up negative associations in many people, and is thus feared and misunderstood. Unlike what some people tend to think, one does not hallucinate things appearing out of thin air after having consumed ayahuasca, but rather there are sequences of inner dreamlike visions taking place while resting, while still awake and fully conscious, provided a significant amount of tea has been consumed. It is actually quite undramatic, aside from the unpleasant vomiting which does affect some people (which is entirely intentional in traditional in cleansing rituals).

And herein lies the essence many times misunderstood: It does not take a great amount of ayahuasca to experience strictly its medicinal effects – without abstractions and visionary effects, or nausea/vomiting which naturally people want to avoid. Several medicinal health benefits can be obtained even by using B. Caapi alone – without additive plants, thereby ensuring no visual effects experienced at all, should this be desired. It should be noted though, that the synergistic effect between the two plants used simultaneously will bring the best medicinal and bodily response. Exaggerations regarding ayahuasca made these medicinal plants overlooked for many years in the west, but the reputation has been revised as more people with experience in a medicinal context have made statements, claiming the medicinal value of ayahuasca relevant to medical conditions of different types – the field of neurological disease being the latest. Ayahuasca has already been effectively used for symptom relief from Multiple Sclerosis and rheumatoid arthritis, by a growing number of people in Europe since at least 2006. ALS, MS, Alzheimer’s and Parkinson’s all share a lot of common ground, being that they all involve varieties of nerve cell degeneration. Thus it is likely that any type of natural broad spectrum medicine able to affect the process of nerve cell regeneration, and that also has substantially antioxidative and cell protective properties, could prevent and slow the progression of neurological disease in general.

Whatever wild or strange stories about ayahuasca that may occasionally be found circulating, they stem mostly from people who went to live with native tribes during the late 80’s and early 90’s, taking part in traditional ceremonial use of ayahuasca – consuming exceptionally generous or concentrated amounts of the medicine, enfolding themselves in deep cleansing experiences not necessarily easily endured. This medicine, like all others, should definitely be well respected, but not subject to exaggeration or downright misrepresentation – causing people to dismiss what they are simply uneducated about, which in turn may lead to people never getting treatment that could slow the progression of their terminal health condition, or in some cases even reverse it. The vivid and fascinating visions induced by strong tea often seem to have a theme rooted in nature, perhaps tied into the underlying psychological expectations associated with the revered history of ayahuasca itself, as depicted quite beautifully in colorful paintings by Peruvian artist Pablo Amaringo (1938-2009). The visions arise from the simple fact that the alkaloids and tryptamines dissolved in the tea, combine to affect receptors that in turn stimulate the processing of memory relating to images and words – noticeably of relevance to Alzheimer’s research.

Ayahuasca is proven non-addictive, and is even used to aid people in breaking their drug dependencies, as ayahuasca has a detoxifying and documented effect of ridding the user of drug related abstinence issues.

MAO-inhibition makes uptake of DMT in the body possible, unable to occur otherwise as DMT without MAO-inhibition is rapidly broken down by enzymes in the stomach, unable to cause effect. DMT is almost molecularly identical to the above mentioned psilocybin from Dr. Ramos research. Researchers think that psilocybin and DMT binds to brain receptors that stimulate growth and healing, acting on the hippocampus, a part of the brain that is essential to learning and forming memories, receiving sensory impulses and that has target cells and receptors for important signal substances. Hippocampus atrophy occurs when nerve cells die, or when abnormal levels of stress hormones prevent neurogenesis, and is a known sign in Parkinson’s disease. It is theorized that the unique combination of a variety of harmala-alkaloids from B. Caapi, and DMT from additional plant sources used in ayahuasca, work on cellular level to repair and restore nerve cells, stimulate and enhance motor neuron transmission, and to protect remaining nerve cells from degeneration. This is without doubt valuable from a neuromedical perspective.


Ayahuasca plants as packaged and sold in health food stores, Peru. Various strains of this particular
vine are available, each having a slightly different, but similar alkaloid profile.


As the non regulated B. Caapi alone has proven positive abilities, potentially effective against neurological and cancer diseases, it is thus something real and available that may be a valid treatment option. For anyone who experience positive results to any degree, but does not live in a state or country where the use of plants containing DMT is permitted, there is the possibility to travel to one of the many countries (or states) which by law allows the use of added secondary plants with their combined medicinal properties for evalution of full-spectrum ayahuasca treatment. In Europe, Spain is one of several countries where ayahuasca is becoming an established therapy, and Spain is also the chosen location for an international conference 2014, where ethnopharmacologists, psychologists and researchers from all over the world gather around the topics of ayahuasca and medicinal entheogens.

Among others, Ede Frecska, M.D., Ph.D, University of Debrecen, lectures on the possibilities of recreating braincells and regulating the immune defense system through this plant-based medicine and others. This event is held by ICEERS – International Center for Ethnobotanical Education Research and Service, and can be followed at: http://www.aya2014.com/en/confirmed-speakers-2/


Caapi medicinal vine specimen

Furthermore, besides ability to aid and enhance the process of nerve cellular repair and protection against cell oxidation, several entheogenic plants (and fungi), including ayahuasca, do possess psychotherapeutical qualities as well. Coping with degenerative illness is obviously stressful to patients, and a great deal of emotional relief, personal insight, and ability to better cope with personal situation is achievable through the single or repeated experience of entheogenic medicinal plants/mushrooms in a comfortable and supportive environment, according to renowned Johns Hopkins medical university.

The fact that many of these medicinal plants are becoming revived as they receive scientific approval, is great news in several ways. Sustainability and environmental issues comes to mind, and so far the outlook remains positive. Many organic farms have developed in south and central america, cultivating ayahuasca plants for both local use and for export, providing work and income for people in rural areas otherwise stricken with poverty. This also serves as a way for numerous local people to reconnect with their cultural past, as ayahuasca is declared a national heritage in Peru among other places.


Sustainable ayahuasca plantation, Brazil. These Chacruna trees take several years
before reaching their mature height of 2-3 meters.





Dennis Mckenna, PH.D, one of the world’s most renowned ethnopharmacology researchers speaks on the importance of sustainability, regarding cultivation of ayahuasca and the preservation of rainforests. This should concern all people who benefit from treatment using ayahuasca medicinal plants. Dr. Mckenna is co-founder and director of ethnopharmachology at Heffter Research Institute, New Mexico. He is also a faculty member of the Academic Health Center at the University of Minnesota, and was key organizer in the Hoasca Project, an international biomedical study of ayahuasca, funded by the Stanley Medical Research Institute. While ayahuasca plants take years to mature for harvest, they can actually be grown at home in gardens anywhere in the world where the climate allows, or indoors or in heated greenhouses elsewhere, and the seeds are both cheap and abundant – available from numerous online ethnobotanical vendors worldwide, ensuring the survival of these medicinal plant species and their sustained availability for future generations.

Formerly unknown to science, we are beginning to understand the potential and medicinal aspects of this particular plant, replacing neglect of entheogens with knowledge as scientific groundwork in this matter becomes firm.

People should not be led into thinking this is some kind of natural miracle cure, but used the right way it could provide longterm aid in the restorement of body and mind function in certain neurological conditions. Together we can all inform people in an unbiased, ethical and safe way about any and all viable treatment options, and about the medicinal and therapeutical value of entheogens in general.

Common sense should be applied to determine dosage in order to ensure a sufficient degree of medicinal activity, while not being harmful or overwhelming. Specific diet is essential in conjunction with ayahuasca, in order to minimize side effects and to maximize utilization of medicinal compounds, and basic knowledge on the process of preparation of the medicine is helpful in order for the plants to synergize correctly. The help and information needed for these purposes, along with protocols for detoxification are individually provided to participants in the below pilot study.

There is currently an ongoing international non-clinical Pilot study involving people diagnosed with ALS, documenting use of this plant medicine, the gathering and evaluation of results being processed.

To follow this project, or if you are interested in joining the study, click on the following link: https://ayahuascatreatment.wordpress.com/2014/09/22/natural-als-treatment-pilot-project/

Ayahuasca has been used for a very long time historically, and only recently for treatment of the conditions brought up in this article. Any substantial health improvement from this natural medicine in cases of motor neuron disease would be likely to reveal itself long-term at first. Initial updates from people participating in the ayahuasca ALS treatment pilot study report a few things in common; wider range of movement, weight gain in muscle mass, muscle tension relief, reduced spasticity and improved strength in affected limbs, though it should be noted that none of the participants had lost all muscle control prior to treatment, and that whether or not this effect turns out to be persistent or permanent is not known at the moment.

Summary of key points

Ayahuasca could effectively be used in treatment of ALS and other motor neuron diseases based on the fact that studies suggest uniquely antioxidative effects that seem to protect brain/nerve cells, targeting motor neurons through a unique biochemical transport system, and that it and other moleculary similar substances, also naturally occurring, stimulate neurogenesis – the development of new brain/nerve cells, and improved neural connectivity. In studies it has been found to reduce symptoms in Parkinsons’s patients – all neurodegenerative diseases share common ground, making it likely that something that improves one major neurological condition could also be beneficial to other closely related conditions. Also based on credible personal accounts from people having used ayahuasca for symptom relief from their multiple sclerosis (once again – the common ground of neurodegenerative diseases), documented in books about ayahuasca, and descriptions of early stage minor improvement by Ayahuasca ALS Treatment study participants, already having used the medicine for a period of time. Studies also indicate ability to normalize metabolism in mitochondria crucial to motor neuron survival, and to regulate and decrease levels of excitotoxicity in the central nervous system.

Ayahuasca and other entheogens can and will gain the credibility and amends they truly deserve, and bring new possibilities to many people living with diseases lacking clinical healthcare treatment options. Until then, these medicinal plants remain available for personal evaluation by individuals who choose to explore the option. In relation to the medical conditions brought up in this article, these plants may hold future keys in becoming a powerful tool for reversal of ALS progression and related conditions. Share this important information if you find it valuable.

https://ayahuascatreatment.wordpres...ethnobotanical-medicine-for-treatment-of-als/
 
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Harmine and ALS

Yun Lia, Rita Sattlera, Eun Ju Yang, Alice Nunes, Yoko Ayukawa, Sadia Akhtar, Grace Ji, Ping-Wu Zhang, Jeffrey Rothstein

Recently, the excitatory amino acid neurotransmitter glutamate was implicated in the pathogenesis of various chronic degenerative neurological diseases in humans and animals. This report describes abnormalities in excitatory amino acids in the central nervous system of 18 patients with amyotrophic lateral sclerosis (ALS). We conclude that excitatory amino acid metabolism is altered in patients with ALS. Based on neurodegenerative disease models, these changes may play a role in motor neuron loss in ALS.(1)

Glutamate is the predominant excitatory amino acid neurotransmitter in the mammalian central nervous system (CNS). Glutamate transporter EAAT2/GLT-1 is the dominant astroglial protein that inactivates synaptic glutamate. Previous studies have shown that EAAT2 dysfunction leads to excessive extracellular glutamate and may contribute to various neurological disorders including amyotrophic lateral sclerosis (ALS).

Few compounds have been shown to activate increased glutamate transporter-EAAT2/GLT1 protein expression and function in vivo. Our new cellular screen has provided insight into a class of compounds that could serve as a starting point for new GLT1 activators. Given harmine’s CNS side effects and its multi-target activities, harmine itself is not a suitable candidate for immediate clinical applications. However, it may eventually be possible to separate its effects on GLT-1 upregulation and on CNS pharmacology through optimization of its chemical structure. Medicinal chemistry efforts to do so are ongoing, which will hopefully lead to a more potent and selective drug candidate that can be moved through the drug development process reaching from preclinical studies to clinical trials. These trials may include clinical applications such as ALS, and other neurodegenerative disorders.(2)

(1) https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.410280106
(2) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3220934/

-----

ALS is an exclusion diagnosis. There is for example a published case of a paraplegic patient who was diagnosed with ALS by two independent neurologists who experienced complete remission when it was discovered that he was suffering from gluten intolerance. There is another published example of patient who experienced complete remission (from a wheel chair ALS diagnosis) after treatment with the antibiotic ceftriaxone and an anti-parasitic substance, since he apparently was suffering from several tick-borne infections.

The take home message is that any source or cause of persistent inflammation in the CNS has the potential to perfectly mimic ALS, provided that the inflammation is sufficiently strong and localized to upper- or lower motor neurons. In these very rare cases anti-inflammatory substances - for example including curcumin or Harmine - clearly have the potential to "cure" ALS patients who has been misdiagnosed.

-Nemesis



 
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mr peabody

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A promising new medication for ALS

Experiments conducted on worms, zebrafish, mice and, finally, on human subjects in a limited clinical trial conclude that pimozide may be effective in treating ALS, or “Lou Gehrig’s disease.”

Researchers from the University of Montreal Hospital Research Centre (CRCHUM) and the Cumming School of Medicine (CSM) at the University of Calgary have discovered a medication that could make it possible to treat individuals with amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease.

An article published today in JCI Insight concludes that pimozide was found to be safe and over the short term, preliminary data shows that it could stabilize the progression of ALS. This neurodegenerative disease normally leads to a progressive paralysis of the skeletal muscles and, on average, three years after the onset of symptoms, to death.

“This medication alleviates the symptoms of ALS in animal models,” said Alex Parker, a CRCHUM researcher and professor at University de Montreal. “Riluzole and edaravone, the drugs currently used, have modest effects. Other studies must be conducted to confirm our results, but we believe that we’ve found a medication that may prove to be more effective in improving patients’ quality of life.”

From worm to man

The story behind the discovery began six years ago with a little millimeter-long nematode worm called C. elegans. In his laboratory, Parker genetically modified the worms so that they would exhibit aspects of the human form of ALS. Simultaneously, his colleague Pierre Drapeau did the same thing to another animal, the zebrafish, a tiny tropical fish only 5 centimetres long.

The two scientists obtained funding from the U.S. Department of Defense to test medications on these worms and fish born with ALS. “We sifted through a library of 3,850 molecules approved for the treatment of other diseases, and found a class of antipsychotic drugs that stabilize mobility in worms and fish,” said Drapeau, a CRCHUM researcher, professor at University de Montreal and principal investigator on the study. “Pimozide works especially well in preventing paralysis in fish by preserving the neuromuscular junction.”

Subsequently, University de Montreal Professor Richard Robitaille performed electrophysiological tests on mice in his laboratory and reached the same conclusion. Thus, pimozide was shown to maintain neuromuscular function in three different animal models: worms, fish and mice.

Pimozide: a well-known drug

At the annual ALS Canada Research Forum in 2012, the researchers met Dr. Lawrence Korngut, an Associate Professor at the CSM, member of the Hotchkiss Brain Institute (HBI) and Director of the Calgary ALS/Motor Neuron Disease Clinic. “Pimozide is a drug that has been well-known for 50 years,” the neurologist said. “It was approved for treating certain types of psychiatric conditions, like schizophrenia, and costs only 9 cents per pill. Other recent studies have shown genetic links between schizophrenia and ALS. The next logical step was to test it on human volunteers with ALS.”

In 2015, the first preclinical trial for ALS was launched in Canada with a small group of 25 patients who had ALS. Funding was provided by the Quirk family of Calgary, by the HBI, and the Clinical Research Unit at UCalgary.

“We found the highest dose most likely to be tolerated in individuals with ALS – a lower dose than that used in other conditions – and we have preliminary proof showing that pimozide may be useful,” said Korngut.

The initial clinical trial was modest in scope. But after only six weeks, the researchers had a first indication of the drug’s efficacy. Loss of control of the thenar muscles, located in the palm of the hand between thumb and index finger, is usually one of the first signs of ALS. For patients who took pimozide, this function remained stable. This observation is tempered by the very limited size and length of the clinical trial.

“For us, this is an indication that we found the right therapeutic target,” said Drapeau. “Pimozide acts directly on the neuromuscular junction, as shown in our animal models. We don’t yet know whether pimozide has a curative effect, or whether it only preserves normal neuromuscular function to at least stabilize the disease. This is also the first time that a potential drug for human patients was discovered based on basic research on small organisms such as worms and fish.”

The next step: a phase II clinical trial

Now comes the next step: a phase II clinical trial on 100 volunteers, funded by the “The Ice Bucket Challenge” through a partnership between ALS Canada and Brain Canada to begin in the next few weeks. Headed by Korngut in Calgary and conducted in nine hospital centres across Canada, the study aims to confirm that pimozide is safe and to measure, over a six-month period, its effect on the progression of the disease and its symptoms and on patients’ quality of life.

Daniel Rompre, 47, father of two teenage girls, hopes to participate in the new study. He was diagnosed with ALS in March 2016. The muscles of his upper body are getting weaker, he is beginning to have trouble speaking, and he can no longer use his left arm. “It is hard to maintain a positive outlook,” Rompre said. “You ask yourself: ‘Why me?’ But at least it’s encouraging to see that research is advancing. There has been more progress in the last five years than in 100 years of research on the disease.”

It is too soon to draw firm conclusions about the safety and efficacy of pimozide. “At this stage, people with ALS should not use this medication,” Korngut emphasized. “We must first confirm that it is really useful and safe in the longer term. It is also important to be aware that pimozide is associated with significant side effects. Therefore, it should only be prescribed in the context of a research study.”

About the pimozide clinical trial

The recruitment of patients for the phase II clinical trial, “A Clinical Trial of Pimozide in Patients with Amyotrophic Lateral Sclerosis (ALS) (Pimozide2)” began on October 16, 2017. Funded primarily by ALS Canada and Brain Canada, the study is registered at clinicaltrials.gov (NCT03272503). The trial is headed by Dr. Lawrence Korngut at the University of Calgary, with the collaboration of nine hospital centres in Canada.

http://www.innovationtoronto.com/2017/11/lou-gehrigs-disease-or-als-may-have-a-promising-medication/



 
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mr peabody

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ALS drug shows success in clinical trials

IFLScience | 20-Nov-2018

A drug to treat Motor Neurone Disease (MND) – also known as amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease – appears to have dramatically slowed the diseases' progress in Phase I clinical trials. The scientists responsible are keen to stress the trials' limitations and say they “don't want to add to the hype”, but the work certainly marks one of the most encouraging developments in the fight against the disease that killed Stephen Hawking we have seen.

For people with MND, respiratory failure is the most common cause of death. So the announcement at the 29th International Symposium on ALS/MND that 32 patients given the drug CuATSM showed significantly less decline in lung capacity than beforehand is very important.

The trial's participants had very mixed rates of progression and time since diagnosis, forming a fairly representative sample. Many were also suffering cognitive decline prior to being put on the drug. This also stabilized significantly. A trial like this isn't designed to quantify effects, but disease progression apparently slowed by more than half.

Dr Kevin Barnham of Melbourne's Howard Florey Institute stressed to IFLScience the trial had no control group, so the comparison could only be with the patient's own rate of decline beforehand. It also lasted for just six months, so we don't yet know if the benefits are sustained.

Considering the best existing MND drugs only extend life by 2-3 months, however, these results are easily good for Collaborative Medicinal Development, the company developing CuATSM, to begin enrolling people in a double-blind Phase II trial to start later this year.

The story of CuATSM is an excellent example of the far from linear way science progresses. Fifteen years ago Barnham was part of a group of scientists were toying with the theory that copper had an important part to play in the development of Alzheimer's disease. Barnham told IFLScience they designed a drug that could cross the blood-brain barrier and alter the movement of copper. For a control, they needed a similar drug.

CuATSM was that control. Having used it in an animal trial, the team wondered if they could find any other applications. Drugs that cross the blood-brain barrier are quite rare, and CuATSM has anti-oxidant properties, which raised the possibility it might protect brain cells from damage. Barnham had worked on MND and, going on what he calls “a hunch” tried giving CuATSM to animals with the disease.

When it came to MND, CuATSM's effects in animals were impressive, although Barnham told IFLScience he and his colleagues are still debating the mechanism. The results for Parkinson's models were also sufficiently encouraging that Collaborative Medicinal Development has a second Phase I trial currently underway. However, animal trials showed no benefits for Alzheimer's, the disease against which CuATSM was originally designed.

https://www.iflscience.com/health-a...isease-drug-shows-success-in-clinical-trials/



 
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mr peabody

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Role of the Sigma-1 receptor in ALS

Timur Mavlyutov, Lian-Wang Guo, Miles Epstein, Arnold Ruohoa

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease primarily targeting spinal cord motoneurons (MN). ALS can occur due to genetic mutations or environmental factors. Familial cases represent only about 10 percent of ALS cases and these are linked to mutations in particular proteins that eventually result in dysfunction and death of MN. Usually ALS is diagnosed in humans after the age of 40, but in some cases it can occur in juveniles. There is no cure for ALS and the best known protector, riluzole, which, in part, reduces levels of the excitatory neurotransmitter, glutamate, from neuronal synapses can only extend human life for a few months.

The Sigma-1 Receptor and neurodegenerative diseases

The Sigma-1 Receptor (S1R) chaperone protein has been shown to be a target for the treatment of a variety of chronic neurological diseases including Alzheimers, Parkinsons, and Huntington's Disease. Recently, ALS was added to this list. It is remarkable that MN express S1R at the highest levels in the CNS. Mutations of the S1R have been found to result in the establishment of ALS in humans. In contrast, genetic knockout of the S1R in mice did not produce an ALS phenotype. S1R knockout mice on an ALS background, however, showed a faster onset of disease and decreased longevity while application of S1R ligands significantly extended the lifespan of ALS model mice.

The Sigma-1 Receptor, Indole(ethyl)amine N-MethylTransferase (INMT) and N,N-Dimethyltryptamine (DMT)

Several endogenous compounds have been shown to bind to the S1R and thus may provide regulation of S1R activities. Although the affinity of these compounds for the S1R varies considerably, activation of the S1R may depend on the cellular environments and the local concentrations in various mammalian tissues. We have shown that DMT is an agonist for the S1R. The relationship between DMT and the S1R was further reinforced by the demonstration that the enzyme, Indole(ethyl)amine N-methyltransferase (INMT) that converts the amino acid tryptophan decarboxylation product, tryptamine, into DMT, co-localized with the S1R in C-terminals of the primate MN. This paradigm shifting observation of co-localization of S1R and INMT to produce DMT, may be functionally very important to provide high local concentrations of the agonist due to the close juxtaposition with the S1R.

Studies demonstrate and propose new biological roles for DMT, which may act as a systemic endogenous regulator of inflammation and immune homeostasis. According to these new results, DMT and 5-MeO-DMT possess the capability to inhibit the polarization of human moDC-primed CD4+ T helper cells toward the inflammatory Th1 and Th17 effector subtypes in inflammatory settings. The mobilization of innate immune mechanisms is also well established in many psychiatric and neurological disorders. Thus, as a target for future pharmacological investigations, DMT emerges as a potent and promising candidate in novel therapies of peripheral and CNS autoimmune diseases such as Multiple Sclerosis, Amyotrophic Lateral Sclerosis and cancer.

https://www.sciencedirect.com/science/article/pii/S1347861314000346



Eleusis​
 
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mr peabody

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Potential therapeutic target for ALS identified

Harvard University | January 15, 2019

Discovery opens doors to improving diagnostics and developing new therapy for majority of ALS patients.

New research has revealed that the protein TDP-43 regulates a gene called Stathmin2 (STMN2). STMN2 shows promise as a therapeutic target and could be the first biomarker ALS, which is extremely difficult to diagnose and treat.

Patient specific stem cell-derived motor neurons stained for the neuronal marker III-Tubulin (green) and the ALS-implicated protein TDP-43 (magenta). In this study, the authors determined that TDP-43 sustains normal levels of the microtubule destabilizing protein STMN2, which helps neurons grow and regenerate axons.

Research led by stem cell scientists at Harvard points to a potential new biomarker and drug target for ALS, a neurological disease that is extremely difficult to diagnose and treat. Published in Nature Neuroscience, the study used stem cell models of human motor neurons to reveal the gene STMN2 as a potential therapeutic target, demonstrating the value of this human stem cell model approach in drug discovery.

Diagnosing and treating ALS

Patients with ALS experience the loss of motor neurons and progressive paralysis. Following a long diagnostic journey, they may survive up to five years. Two ALS drugs have been approved by the U.S. Food and Drug Administration (FDA), but they act only to slow the disease.

In addition to a cure -- or even a treatment that is effective for more ALS patients -- a robust test for ALS is sorely needed. For that to happen, scientists need to find a reliable biomarker of the disease.

TDP-43: a hallmark of ALS

Ten years ago, scientists found aggregates of a protein called TDP-43 in post-mortem neurons from ALS patients. This protein should have been in the nucleus of those neurons, but instead it was being flushed out, and building up in the cytoplasm.

Clearly, some of the genes at work in the trash-disposal system of neurons (called the proteasome) were interacting with TDP-43 in a way that led to ALS. But which genes are involved, and what they are doing, has not been known.

The gene that encodes for TDP-43 can be mutated to trigger ALS. It is passed on to future generations, who then develop either ALS or, in some cases, frontotemporal dementia (FTD). Since TDP-43 aggregates were discovered in ALS patients, they have been well known as a hallmark of the disease.

What the researchers did

TDP-43 is one of many proteins that binds to RNA, which is responsible for transmitting genetic information and translating it into a concise recipe for a given protein, for example part of a growing neuron.

The researchers set out to identify, for the first time, all the possible types of RNA that are regulated by the TDP-43 protein in the context of human neurons. Until now, studies like this have only been carried out in mice and cancer cell lines.

Then, they looked at what happened to each gene when they manipulated TDP-43.

What they found

The researchers reduced the levels of TDP-43 protein in human stem cell-derived motor neurons. Then, using RNA-sequencing, they analyzed how gene expression changed in these cells.

Among the thousand or so genes that changed when TDP-43 was manipulated, one stood out: Stathmin2 (STMN2), a gene that is important in neural outgrowth and repair. STMN2 changed consistently in step with TDP-43.

"Once we had a connection between the TDP-43 and the loss of this other critical gene, STMN2, we could see how a motor neuron might begin to fail in ALS," said Joseph Klim, postdoctoral fellow in the Harvard Department of Stem Cell and Regenerative Biology (HSCRB).

"With the discovery that our human stem cell model had predicted exactly what was happening in patients, Joe went on to test in this system whether fixing Stathmin2 could rescue the motor neuron degeneration in our dish caused by disturbing TDP-43. In a beautiful series of experiments that I believe provide great hope for patients, he went on to show this was exactly the case: rescuing expression of Stathmin2 rescued motor neuron growth," said Kevin Eggan, Professor of Stem Cell and Regenerative Biology at Harvard.

The culprit

The researchers observed that without TDP-43, STMN2's perfectly read protein-making instructions turn into nonsense.

"We discovered that when TDP-43 levels are diminished in the nucleus, a cryptic exon is spliced into STMN2 messenger RNA. That basically deletes its instructions for making functional protein," explained Klim. "It becomes impossible for STMN2 to create a vital component for repairing or growing motor neuron axons."

Double- and triple-checking

The next step was to see if their findings reflected the reality of a patient's biology. They obtained data from RNA sequencing studies that used post-mortem samples from ALS patients. Those rare datasets, compared with controls, echoed the team's original findings in human stem cell models. The data from ALS-patient spinal cords mapped to the cryptic exon, but data from the controls did not.

Luis Williams of Q-State Biosciences, whose Ph.D. thesis in HSCRB was the first major step in this study, added, "Because we had pluripotent stem cells of human origin, we could make cells in a dish that are relevant to ALS and investigate this very specific problem in the right context: with a human genome and all of the genetic factors that regulate motor neurons."

Why it matters

"These experiments point towards a clear path for testing whether repairing Stathmin2 in patients can slow or stop their disease," said Professor Eggan. "The discovery we have made suggests a clear approach for developing a potential therapy for ALS -- one that would intervene in all but a very small number of individuals, regardless of the genetic cause of their disease."

https://www.sciencedaily.com/releases/2019/01/190115162311.htm
 
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mr peabody

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Therapy approved for Parkinson’s has potential to treat ALS

by Marta Figueiredo | Aug 31, 2018

Requip (ropinirole), a medication already approved to treat Parkinson’s disease, may be a potential therapeutic agent for amyotrophic lateral sclerosis (ALS), according to a preclinical study.

The study, “Modeling sporadic ALS in iPSC-derived motor neurons identifies a potential therapeutic agent,” was published in the journal Nature Medicine.

Most cases of ALS (90-95 percent) are considered to be sporadic, with only 5-10% of cases inherited, or familial. The sporadic nature of the majority of cases of ALS makes it difficult to create models of the disease, and to identify disease-causing genes and potential therapeutic compounds.

As a result, while a dozen mutations have been shown to cause familial ALS, such as in the SOD1, TDP-43, and FUS genes, the causes of sporadic ALS are largely unknown.

However, increasing evidence has pointed to the existence of several common features between sporadic ALS and non-SOD1 familial ALS — such as those affecting the TDP-43 or FUS genes — suggesting that compounds suppressing these common features may represent new therapeutic agents for a wide range of ALS patients.

Japanese researchers evaluated the therapeutic effects of selected compounds in a variety of ALS cases through the establishment of sporadic ALS models.

They generated motor nerve cells from induced pluripotent stem cells (iPSCs) — stem cells derived from differentiated cells that can virtually generate any cell type in the body — of 32 sporadic ALS patients.

These cells were able to mimic the patients’ genetic and clinical diversity in vitro, making them successful cellular models of sporadic ALS.

“We clearly demonstrated that iPSC technology enabled the generation of elaborate disease models that accurately reflect the clinical features of genetic conditions, even sporadic diseases,” the researchers wrote.

An analysis of the therapeutic effects of more than 1,000 approved medications in non-SOD1 familial ALS models, as well as the compounds’ serious side effects and ability to cross the blood-brain barrier — a protective membrane that restricts the passage of large molecules to the brain — pointed at Requip as the best potential therapeutic agent.

Requip, an anti-Parkinson’s medication, acts as a substitute for dopamine in the brain. Dopamine is an essential chemical messenger between nerve cells that recent studies have suggested is a regulator of motor nerve cell function.

Adding Requip to the sporadic ALS models was found to suppress cell death, abnormal protein aggregation, nerve cell atrophy, and the production of oxygen-related damaging molecules in most of the models.

While the majority of the sporadic models that responded to Requip showed similar features to TDP-43– and FUS-familial ALS models, those that did not respond had a gene expression profile more similar to SOD1-familial ALS models — which were also non-responders.

These findings highlight the potential of Requip to treat a diverse range of ALS cases, both familial and sporadic.

Additional analysis of the changes in gene activity induced by Requip showed the involvement of inflammation — fat degradation — and dopamine-related pathways.

These results support the use of this approach to generate sporadic ALS models, better understand the mechanisms behind specific cases of ALS, and identify new therapy candidates.

The team noted that this approach may be applied to other sporadic neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease.

https://alsnewstoday.com/2018/08/31...pproved-parkinsons-therapy-preclinical-study/



 
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Xorkoth

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It hurts to read some of this stuff because my father was diagnosed with ALS 6 years ago. He's still alive, but for years he's been almost entirely paralyze... now he is like Stephen Hawking basically, and he is absolutely suffering and miserable 100% of the time, it's horrible. Even if he did something now to stop it, when the damage is already done, he would consider that a fate worse than death. Unfortunately my father is really against taking "drugs" (which means recreational drugs, which means to him, not even weed which has been legalized). My brother and I tried really hard to get him to start taking CBD years ago, before it had gotten bad, we even got our mom on our side. He resisted though until it got legalized in their state, and the disease had already progressed substantially. Then he tried it for a week and said it wasn't working and stopped. The idea of using ayahuasca to actually stop or at least help the disease is something he would never do. It's very likely that if this had happened 10 years from now, he would have jumped at the chance. I'm so excited that psychedelic research is finally unfrozen and happening with increasing gusto, because I think there is so much potential for healing there. The decades of research from the 50-70s that got mostly suppressed and buried agrees with that, too.​
 
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Transplanted human bone marrow cells hold promise as ALS therapy

by Jose Marques Lopes | April 5, 2019

With amyotrophic lateral sclerosis (ALS) improved their motor function and preserved motor neurons by repairing the barrier protecting the spinal cord.

The study with that finding, “Human Bone Marrow Endothelial Progenitor Cell Transplantation into Symptomatic ALS Mice Delays Disease Progression and Increases Motor Neuron Survival by Repairing Blood-Spinal Cord Barrier,” was published in the journal Scientific Reports.

The blood-brain and blood-spinal cord barriers (BSCB) are composed of endothelial cells, pericytes, located along the walls of tiny blood vessels called capillaries, and processes derived from astrocytes, a cell type also involved in the response to injury.

Increasing evidence has linked impairments in each of these components to ALS, both in patients and in animal models. Disrupted barriers allow the entry of immune cells and other potentially harmful substances from the blood circulation, which may aggravate degeneration of motor neurons — specialized cells that control muscle contraction — a hallmark of ALS.

In mice with ALS, the team at University of South Florida in Tampa previously showed that human bone marrow cells containing the CD34 marker (hBM34+) may be a therapeutic stray for ALS, as they delayed disease progression, preserved motor neuron survival, lessened a marker of reaction to injury, and maintained barrier integrity. The transplanted cells differentiated into endothelial cells — those that line blood vessels — and nested in capillaries of the spinal cord.

A subsequent study in the same mouse model, G93A, revealed that a high dose of transplanted cells restored the fine structure of capillaries and stabilized their density in the spinal cord, while also improving myelin integrity. (Myelin is the protective layer that insulates the nerves.)

As noted in a press release, although these findings support the use of such cells to repair the BSCB and improve ALS-related alterations, the most significant effect of hBM34+ cells on motor function was determined at four weeks after transplant. Also, a substantial damage in spinal cord capillaries was detected even after high-dose treatment.

This made the team test whether human endothelial progenitor cells (EPCs) — bone marrow-derived, but more similar to endothelial cells than undifferentiated stem cells — would provide superior BSCB restoration in G93A mice.

At two to three weeks after transplant via intravenous infusion, mice given EPCs from adult donors showed significantly higher body weight, improved motor function and slowed disease progression than controls with ALS, as assessed by extension reflex scores, grip strength, and motor coordination.

At four weeks, these mice also demonstrated BSCB repair associated with widespread attachment of EPCs to capillaries in the cervical and lumbar spinal cord and in the brain’s motor cortex and brainstem — two regions known for motor neuron degeneration.

Other improvements in the cervical and lumbar spinal cord included restored capillary and pericytes’ structure, normalized astrocytic processes, less leakage into the spinal cord, and extended survival of spinal cord motor neurons. This was reflected by signs of degeneration in only a small subset of motor neurons and by higher number of these nerve cells than in controls with ALS.

Cautioning that further studies are needed, the team commented that “from a translational viewpoint, the initiation of cell treatment at the symptomatic disease stage offered robust restoration of BSCB integrity and shows promise as a future clinical therapy for ALS.”

 
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Perhaps the ‘Dark Ages’ can enlighten us to think ‘Why Not?’

by Rick Jobus | ALS News Today | Apr 3, 2019

One of the dictionary definitions of karma is an “action, seen as bringing upon oneself inevitable results, good or bad, either in this life or in a reincarnation.”

After my ALS diagnosis was rendered, and then confirmed, I went through the agonizing process of trying to understand why. Given that the causality remains a mystery, one is left with suppositional rabbit holes to explore. I needed something — be it a genetic defect, behavior, lifestyle choice, toxin exposure, or geographic anomaly — to regret. When nothing singularly plausible was forthcoming, I recounted every significant sin I had committed, questioning whether the cumulative tally might justify my newly dispensed punishment.

Eventually my desire for the “why” answer abated. I may never know the reason that ALS chose me. That’s OK. There are bigger fish to fry. By replacing the “why me?” with “why do I still have it?” my Holy Grail-like quest was redirected. On the surface, the lack of a cure appears reasonably obvious.

- The complexity of the disease necessitates an immense research and development effort.
- The anticipated profits don’t attract the required large-scale investment.
- No one is willing to forgo personally profiting from the discovery. The days of a Jonas Salk type of heroically altruistic approach to disease eradication are long gone.
- We are left with a scattered “catch-as-catch-can” approach to thwarting ALS.

But I believe the inherent obstacle to be systemically much simpler to identify, yet paradoxically, far more challenging to overcome. As a society we accept ALS. Just like we do cancer, Parkinson’s, Alzheimer’s, multiple sclerosis, and any other condition that defies arrest. Culturally, we could demand that cures be found. And if we were serious, they would be. Just like we did when we decided to intervene in the wars in Europe, win the arms race, and land men on the moon. When America is truly determined and focused, the daunting is achieved, and even the seemingly impossible is made possible.

Pondering this notion of the collective tolerance made me recall a “Saturday Night Live” episode from 1978 that introduced the character Theodoric of York, played by Steve Martin. The skit was done twice, with the same premise. It was about a man working in a more primitive time, relying on superstitions, but the joke was that it was the most up-to-date technology available. The skits ended with Theodoric wrestling with enlightenment, whereby he would be on the cusp of changing the tack of humanity for the better, only to consider that too far-fetched.

My favorite of the two had Theodoric as a medieval barber. Medieval barbers were also the forerunners of today’s physicians. Liberally employing bloodletting, augmented by elixirs whose constituents might include powder of staghorn, gum arabic, sheep’s urine, and boar’s vomit, Theodoric would “practice” medicine. He would dutifully treat ailments caused by an imbalance of bodily humors, perhaps brought on by a toad or a small dwarf living in the stomach, as indicated by the state-of-the-art diagnostic tool the Caladrius bird. The outcomes, like the age they spoofed, were hilariously dark. As were Theodoric’s aborted attempts at renaissance thinking.

Maybe there is a way to heal the previously unhealable. What if we diverted a tiny portion of the U.S. discretionary spending request for 2020 of $1.4 trillion toward curing a heretofore mysterious neurological disease? What if we reallocated 1 percent of the 2019 military budget of $716 billion toward the effort? That would be $7 billion this year alone, and over $60 billion over 10 years, given our historical spending of $7 trillion from 2007 through 2017.

Then, when we identified the mechanism to restore health, we could export it around the world. Might that gesture serve to reduce tensions with other countries and ideologies, bolster sentiment toward the U.S., and safeguard the world order we attempt to influence? Is it possible to simultaneously lessen human suffering and reduce the need for defense? If so, wouldn’t it be wonderful for us to recapture the mystique and prestige of the Greatest Generation?

 
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