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Science Parkinson's

mr peabody

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Welcome! Following is a DIGEST of articles and reports that is constantly updated. Jump in!




Is ibogaine a promising new treatment for Parkinson's?

by Jonathan Dickinson

There is reason to believe that ibogaine may be beneficial in Parkinson's treatment. Columbia's 2-year animal study represents the first time that researchers will probe for a direct link.

The exact mechanisms of action of ibogaine are still obscure, but the theory for ibogaine's benefit for Parkinson's rests on the fact that along with its other effects, it has been shown to increase the production of a protein called glial cell-derived neurotrophic factor, or GDNF. This and other neurotrophic factors have been shown to stimulate the production of dopaminergic fibers throughout the brain, and some existing research shows that GDNF in particular improves the recovery of dopaminergic neurons and leads to an improvement of Parkinson's symptoms.

Previous methods used to increase the expression of GDNF were limited gene therapy and direct brain infusion, but according the research abstract, the research team, led by Dr. Serge Przedborski, President of the World Parkinson Coalition, is exploring whether ibogaine could provide safer and more convenient means to enhance GDNF production in the brain.

Dr. Jeffrey Kamlet, a Miami medical doctor and board certified addiction specialist has been researching ibogaine for over 20 years, and is a strong advocate for medical supervision. According to Dr. Kamlet, "Ibogaine is the most important discovery in the field of opiate dependency in the history of addiction medicines, and I am confident that it will one day be a main stay treatment for many addictions."

Even with this in mind, some advocates believe that ibogaine application as a treatment for Parkinson's may prove more straightforward for research. In the case of addiction therapy, ibogaine is most often administered in a single large dose, but there is anecdotal evidence that the repeated use of very low sub-perceptual doses, which are generally agreed to be well tolerated in patients, could be sufficient to reverse Parkinson's symptoms over time.

Patient D was 69 years old in 2012 when he was diagnosed with Atypical Parkinson's, a Parkinson's-like syndrome that does not include the characteristic palsy. By last year Patient Ds symptoms had advanced to the point where his facial muscles felt frozen. He had difficulty finding his balance, talking or using his hands. As a writer and artist, he noted that emotionally it was the first time in his life he had lost his desire to do anything creative.

Patient D was treated with CKBR-12, an experimental natural health product and ibogaine-derivative, at a medical center in Rosarito, Mexico. He took a small dosage twice a day for 30 days, and after the first two weeks began to notice that he could use his fingers to pick up objects again. After a month he had seen a gradual improvement in all of his symptoms to the point where he could carry on normal conversation, and coordinate previously impossible tasks such as buttoning his shirt.

In a post-treatment interview that was published on YouTube, Patient D says, "It's difficult to explain what Parkinson's is, but you lose your edge. And I have got my edge back in a few areas. It may be small things to some, but they are big things for me. I am anxious to see what happens next."

When we spoke, to Patient D, he said that he had continued to have improvements with further treatment. His case has been reviewed by several doctors, including Dr. Susanne Cappendijk of Florida State University Medical Center, who relayed some of the results at a conference at the New York Academy of Sciences.

http://www.braintalkcommunities.org/showthread.php/101868-Ibogaine-and-Parkinson’s-Disease
 
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mr peabody

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Is it time to rethink Parkinson’s pathology?

by Ashley Yeager | The Scientist | Oct 1 2019

New evidence points to a waste-clearing problem in patients’ cells, rather than the accumulation of protein tangles, as the root cause of the neurodegenerative disease.

During her time as a postdoc at the University of Basel in Switzerland, Sarah Shahmoradian decided to study the abnormal aggregates of protein that develop inside nerve cells and contribute to Parkinson’s disease. The protein clumps develop over time in the brains of Parkinson’s patients, leading some scientists to think they wreak havoc on nerve cells, causing severe damage and hastening their death. A fresh look at the clumps, called Lewy bodies, with cutting-edge microscopy tools could reveal insights that might lead to new treatments for Parkinson’s, Shahmoradian recalls thinking. “The original goal was to really find out what the building blocks of Lewy bodies are, what they are made of, and what they actually look like.”

The clumps were first identified in the early 1900s, appearing as abnormal material in nerve cells viewed under a microscope. Additional studies using antibodies that bound to various proteins revealed that the clumps contained a protein called α-synuclein, and after more work probing Lewy bodies, scientists developed a rough sketch of their structure—essentially, a dense mass surrounded by a halo of twisted filaments of α-synuclein. It’s these filaments, known as fibrils, that Shahmoradian and her colleagues were most interested to analyze in postmortem human brains. Fibrils had been repeatedly produced in cultured cells and in animal models, but no one had ever gotten a clear view of them in human brain tissue.

“We were originally looking for fibrils,” Shahmoradian says, “but unexpectedly, we found an abundance of . . . mitochondria, other organelles, and lipid membranes in the Lewy bodies.” The researchers also found evidence of lysosomes, organelles that facilitate cellular waste removal. They did see α-synuclein in the Lewy bodies, as well, but the cores of the structures weren’t composed of twisted and tangled fibrils as researchers had thought. Instead, the protein was intermingled with other cellular material.

The study is one of many that raise questions about the prevailing idea that α-synuclein accumulation is the underlying cause of the neurodegeneration in Parkinson’s disease. Rather, α-synuclein buildup may be just one symptom of a more fundamental problem: the cells’ inability to break down excess lipids and proteins, including α-synuclein. Some Parkinson’s patients carry mutations in genes associated with lysosomal function, and studies in mice have revealed that natural aging leads to the build-up of lipids associated with Parkinson’s disease. These findings have led a small but growing set of scientists to propose that for a vast majority of Parkinson’s patients, the disease is fundamentally a cellular machinery problem, not a protein problem.

“In this new story, α-synuclein is actually a reaction to the root cause of Parkinson’s,” Ole Isacson, a neuro-scientist at Harvard Medical School, tells The Scientist.

Parkinson’s in the gut

In 1912, Fritz Heinrich Lewy, a doctor working in Berlin, studied the brains of patients who had died from Parkinson’s disease (then known as shaking palsy) and found odd clumps of proteins in their nerve cells. Several years later, Spanish neurologist Gonzalo Rodríguez Lafora, who had identified the protein inclusions in the brain of another patient who had died of shaking palsy, dubbed them Lewy bodies.

Based on additional probes into diseased patients’ brains, neurologists found Lewy bodies to be particularly common in the substantia nigra, a brain region that sits in the center of the head directly behind the eyes. It’s where many of the neurons that produce dopamine, a neurotransmitter involved in movement and learning and in regulating mood, originate. These neurons send signals to another brain region called the striatum, forming a neural pathway that facilitates muscle motion; in Parkinson’s disease, it’s the dopamine neurons in the substantia nigra that are damaged or destroyed. People with Parkinson’s typically have trouble with balance and walking, and they often suffer from tremors in the hands or fingers and other involuntary movements.

Laboratory investigations in the 1990s suggested that Lewy bodies were composed of α-synuclein, while early explorations of the genetics of Parkinson’s published around the same time revealed that patients with an inherited form of the disease often carried mutations in the SNCA gene, which encodes α-synuclein. "Together, the pathology and genetic findings suggested that α-synuclein might be the pathologic protein underlying Parkinson’s disease," pathologist Kelvin Luk of the Perelman School of Medicine at the University of Pennsylvania tells The Scientist.

In the early 2000s, Goethe University Frankfurt neuroanatomist Heiko Braak built on that work, observing that α-synuclein accumulation didn’t just occur in the brain. Postmortem analyses showed that it had accumulated in the nasal cavity, in nerves in the throat, and in the gut of deceased Parkinson’s patients. Braak’s postmortem observations also showed that aggregations of the protein appeared in the vagus nerve—a superhighway of nerve-fiber bundles running between the brain and various organs of the body, including the heart, lungs, and gut. He concluded that "some type of pathogen causing the neuronal cell damage seen in Parkinson’s could invade through the nose or gut and then travel up to the brain via the vagus nerve."

Researchers then started to wonder if aggregates of α-synuclein might move through the body in a similar way—and studies have shown that it can. In 2014, Staffan Holmqvist, then at Lund University in Sweden, and colleagues showed that if they injected α-synuclein into the guts of rats, the protein could travel up the vagus nerve to their brains. And this June, Johns Hopkins University neuroscientist Ted Dawson and an international team of researchers showed that the fibrillar, pathological form of the protein can travel in a similar way in mice and lead to Parkinson’s-like symptoms in the rodents. “Not only do the mice have the motor features of Parkinson’s disease, they also have the nonmotor features,” Dawson told The Scientist at the time. “They’ve got cognitive dysfunction, anxiety, depression, problems with smell—all symptoms seen in human patients with Parkinson’s."

These studies led researchers to propose that Parkinson’s might start in the gut years before the disease manifested as neurodegeneration in the brain. Despite the growing popularity of this hypothesis, however, new work is challenging the idea. For example, according to one study, there is no change in the risk of the disease among patients who have had their vagal nerves cut to stop the development of gastric ulcers. Moreover, in a recent study of more than 2,000 Parkinson’s patients, only 0.05 percent had mutations in the SNCA gene, leaving scientists questioning how α-synuclein accumulates in the other 99.95 percent of cases, and therefore if the protein is, in fact, at the root of Parkinson’s disease.

Hints that something other than α-synuclein might be to blame started to circulate in the late 1990s and early 2000s. In 2004, for example, Enza Maria Valente, then at the Mendel Institute in Rome, and colleagues found that early-onset Parkinson’s disease appeared to be caused by mutations in the gene PINK1, which plays a role in mitochondrial function. In 2009, Ellen Sidransky, a neurogeneticist at the National Human Genome Research Institute, and colleagues reported results suggesting that Parkinson’s might stem more from a fundamental cellular problem than from the accumulation of a particular protein. In an analysis of a genetic panel taken from more than 5,600 Parkinson’s patients and more than 4,800 healthy individuals from around the world, the team found genes associated with Parkinson’s disease that encoded lysosomal components. For example, 15 percent of Ashkenazi Jewish patients with the disease and 3 percent of non–Ashkenazi Jewish patients had a mutation in a gene called GBA, which encodes a protein active in lysosomes that helps clear cellular waste. The faulty protein made by the mutated GBA gene prevents the breakdown of an intermediary compound in the metabolism of carbohydrate-containing lipids, or glycolipids. Other mutations in the same gene can cause the metabolic disorder known as Gaucher disease, which can lead to brain damage, among numerous other outcomes, strengthening the suspicion that lysosomes play a role in Parkinson’s.

Intrigued by the results, Baylor College of Medicine geneticist Joshua Shulman looked into the genomes of Parkinson’s patients for mutations in lysosomal genes other than GBA. In 2017, he and colleagues reported that more than 50 percent of Parkinson’s disease patients carry a putatively damaging mutation in one or more genes that are known to cause lysosomal storage diseases, inherited metabolic disorders caused by enzyme deficiencies that allow the buildup of toxic materials inside cells. "That result sent a signal to the community that we need to be looking at the lysosome critically to try and understand what the mechanism is . . . that makes dopaminergic neurons so dependent on normal lysosomal function,” Frances Platt, an expert in lysosomal storage diseases at the University of Oxford, tells The Scientist.

As it turned out, Isacson was already at work on the question, and in 2015 his team found that the enzymatic activity of GBA decreased in mice and in human dopamine neurons (examined postmortem) with increasing age. This resulted in the accumulation of glycolipids that could disrupt neuronal function, suggesting that natural aging alone was enough to reduce GBA activity, leading to lipid buildup. That same year, Isacson’s group also showed that blocking the activity of the GBA enzyme—a proxy for lysosomal dysfunction—caused a dramatic accumulation of α-synuclein in neurons, spurring neuroinflammation, which is characteristic of Parkinson’s.

“The genetics, the biochemistry, and the cell biology tell us that the lysosome plays a major role in disease pathogenesis of Parkinson’s," cell and molecular biologist Andres Klein of Universidad del Desarrollo in Santiago, Chile, tells The Scientist.




Malfunctioning Mitochondria

While some researchers are studying lysosomal dysfunction as a potential cause of Parkinson’s disease, others have been probing the connections turned up by genetic studies, such as the link between mitochondrial dysfunction and α-synuclein accumulation. For example, immature human neurons carrying knockout mutations in the PINK1 gene, which encodes a protein involved in mitochondrial function and has been linked to Parkinson’s, died sooner than cells without the mutation.

Recently, researchers found that the PINK1 protein is vital to stabilizing another protein, MIC60, which is essential for mitochondria to generate energy. Young fruit flies that didn’t produce PINK1, and therefore didn’t have healthy mitochondria, didn’t crawl well and died relatively early in adulthood. But when researchers over-expressed the protein MIC60 in the brains of flies lacking PINK1, the animals’ neuronal mitochondria started generating more energy—enough to prevent dopamine-producing nerve cells from dying . The study suggests that mitochondrial problems might spark a cascade of cellular issues that cause Parkinson’s disease.

Other new research indicates that Parkinson’s could stem from a combination of lysosomal and mitochondrial problems. Using dopaminergic neurons derived in culture from samples of Parkinson’s patients’ skin cells, Northwestern University Feinberg School of Medicine neurogeneticist Dimitri Krainc and colleagues found that reactive oxygen species in the cells damaged mitochondria and that oxidized dopamine began to build up. This caused a drop in GBA enzyme activity, lysosomal dysfunction, and eventually α-synuclein accumulation.

“Lipid regulation, lipid function, and lysosomal function are tightly regulated normally,” says the University of Oxford’s Frances Platt, who studies lysosomal storage diseases. “If you cause an imbalance . . . you end up causing collateral problems for other organelles, and ultimately you trigger cell death pathways and neurodegeneration."

Imaging living cells, Krainc’s group has found that lysosomes and mitochondria come into direct contact in a cell, providing a mechanism by which damaged mitochondria might interact with and disrupt the function of lysosomal enzymes. "The work," says Universidad del Desarrollo’s Andres Klein, "suggests that problems with the mitochondria and lysosomes may create a problematic loop that lies at the heart of Parkinson’s disease."

Parkinson’s as a waste problem

In an August 2018 review published in Brain, Klein and neuroscientist Joseph Mazzulli of Northwestern’s Feinberg School of Medicine laid out all of the evidence for Parkinson’s disease as a lysosomal disorder. In animal models of the disease and in neurons cultured from induced pluripotent stem cells (iPSCs) of Parkinson’s patients, when researchers treat the lysosome to correct for the cell clearance problems, the toxic buildup of lipids and proteins, including α-synuclein, is halted, and memory improves in mice. There are now even a few clinical trials for Parkinson’s disease drugs that target faulty lysosome function instead of α-synuclein aggregation, Klein says. Considering all the evidence together, “we really had . . . the guts to [say] that Parkinson’s is a lysosomal disease.”

Failure to clear

Many patients with Parkinson’s disease carry gene variants that lie at the root of problems with cellular waste-clearing processes, mediated by the lysosome. One of the proteins that must be cleared from cells is α-synuclein—the protein that scientists have long-fingered as a prime pathogenic suspect in Parkinson’s. When α-synuclein isn’t cleared from neurons, it can become misfolded and clump together in Lewy bodies that prevent these cells from functioning and ultimately cause them to die, leading to telltale symptoms of the disease. But α-synuclein is not the only material accumulating in the neuron when the lysosomes aren’t functioning properly; Lewy bodies are composed of a mix of cellular material.

Further evidence that Parkinson’s disease might be driven by problems with cellular waste-clearing processes comes from genes that are related to mitochondrial dysfunction. Certain gene variants related to Parkinson’s can cause the mitochondria to form reactive oxygen species and other compounds that can damage the lysosome, leading to problems with waste removal.

Healthy cells

Unneeded proteins, lipids, and other cellular materials are typically gathered into vacuoles, which fuse with lysosomes to clear the cells of the waste.




Diseased cells

In the neurons of Parkinson’s patients, something appears to have gone wrong with the cellular waste-clearing process. Reactive oxygen species (ROS) released from mitochondria may play a role, damaging lysosomes. If the lysosomes don’t function properly, then cellular waste products are left in the cell to accumulate.




Even as Klein and Mazzulli were collating the findings for their review, researchers were publishing more data to support their argument. Isacson and Platt reported in 2018, for example, that in healthy mice, aging alone causes an accumulation of glycolipids also involved in Parkinson’s disease. Later that same year, Isacson and another group of colleagues published data showing that aging causes α-synuclein and lipids to stick to each other and then to the membranes of dopamine-containing vesicles in neurons. These results reveal how natural aging changes lipids and lysosomes, accelerating neuronal degeneration—a direct challenge to the hypothesis that Parkinson’s is primarily a protein problem, as changes to the lipids and lysosomes would precede or provoke α-synuclein aggregation.

Last December, Isacson and colleagues found more evidence to challenge the proteinopathy view of Parkinson’s. In the substantia nigra of deceased patients, levels of a glycoprotein called GPNMB were elevated compared with age-matched controls. Transgenic mice modeling Parkinson’s with excess α-synuclein did not show higher levels of GPNMB, but when wild-type mice were given lipid-based drugs to simulate lysosomal dysfunction, their levels of GPNMB skyrocketed, mirroring relative levels of the glycoprotein in the Parkinson’s patients’ brains. An accumulation of stray lipids in nerve cells might be enough to spur inflammation and cause neuronal damage and death, Isacson says.

If Parkinson’s is in fact a lysosomal disorder, it raises the question of whether “some of the treatments that are being developed for lysosomal diseases may unexpectedly turn out to be useful in Parkinson’s,” Platt notes. Several clinical trials have begun or are being planned to test whether drugs already used to treat well-characterized lysosomal storage disorders might also work as Parkinson’s therapeutics. One sponsored by University College London is testing ambroxol, a drug that reduces mucus production in the respiratory tract, for its ability to increase activity of the lysosomal enzyme GBA and, as a result, reduce the buildup of excess lipids and proteins, such as α-synuclein. Another, sponsored by Sanofi Genzyme, is recruiting Parkinson’s patients with GBA mutations and treating them with GZ/SAR402671, a drug designed to lower glucosylceramide, a compound that accumulates as a result of lysosomal damage and can cause the aggregation of α-synuclein.

By and large, however, the field seems to be sticking with the idea of α-synuclein as the underlying pathological driver of Parkinson’s disease, Isacson says. Luk concedes the field’s focus on the protein is probably not going to shift any time soon, mainly because an overwhelming majority of Parkinson’s patients have Lewy bodies. “It’s very hard to find Parkinson’s cases that don’t have Lewy pathology,” Luk says, and notes "most scientists still think α-synuclein is their major constituent. It’s hard to ignore synuclein.” Dawson agrees. But he adds that "more researchers are starting to integrate the data on mitochondrial and lysosomal dysfunction into their ideas on the disease. They are realizing 'it’s all intertwined.' ”

 
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mr peabody

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Ibogaine and Parkinson’s – case study

By Trevor Millar

It’s been recently discovered that Ibogaine may work to reverse the debilitating effects of Parkinson’s Disease (PD). A recent article published on the Global Ibogaine Therapy Alliance website prompted a PD sufferer to contact Liberty Root to see if we might be able to help him follow a protocol to work on his disease. Having heard that the study at Columbia University was using a low-dose protocol, a mere 4 mg of ibogaine a couple of times a day, which is sub-perceptual, and very low-risk dose, we were excited to provide this gentleman with some medicine and see what the effects might be.

Bill is a 52 year old male who was diagnosed with PD more than two years ago, but had early signs four years ago. He’s been very proactive since his diagnosis in trying to mitigate the onset of the symptoms of the disease, which include tremors, slow movement, rigid muscles, impaired posture and balance, loss of automatic movements; speech and writing impairment. Bill has changed his lifestyle so as to include daily exercise (yoga, cycling, PD specific exercises) as well as switched to a clean diet, avoiding processed food, and including organic vegetables and other nutrient dense foods. He’s been taking Apo-Levocarb daily, which is a dopamine medicine that helps reduce the symptoms of PD, but as Bill told me, it has diminishing returns – the more you take, the less effective it is.

Bill has been spending the winters in Tucson, Arizona, as it’s got a large community of PD patients, and specifically the Parkinson’s Wellness Recovery, which Bill speaks very highly of. When I first met him, he had just finished driving from AZ to BC, and stopped by our facility on the last leg of his journey to pick up some tablets that contain Ibogaine prior to heading to his home on Vancouver Island. Meeting Bill it was obvious he suffered from PD, especially after that long drive. He was bent over, had a hard time walking, was shaky, his speech was slurred, with a slight facial paralysis. During our initial consultation he needed to sit, and had a hard time getting up afterward. Some other symptoms he described to me were a loss of movements that had been automatic, like with using the turn signal on his car he needed to be very conscious when making that happen, or once he finished urinating in the toilet, that first step backing up afterward needed to be very consciously thought out; it didn’t just happen automatically anymore.

Initially we gave Bill a supply of tablets each containing 4 milligrams of Ibogaine HCL and once we saw there was no adverse reaction, with plenty of improvement, some 10 mg doses were compounded. As mentioned, this is a very low dose of Ibogaine compared to what we would give to a person so as to interrupt an addiction (we might use a gram and a half or more of ibogaine for addiction therapy). Bill started by taking one of these in the morning, along with his dopamine med, and then one in the afternoon. Here are some comments relating to his couple of months with low-dose protocol and its effects:

10 mgs or less of Ibogaine twice daily:
– Feeling of looseness in my arms neck, shoulders and chest
– Able to shoulder check when driving
– More power in left arm while driving
– Able to back up easier when driving with left-handed steering
– Easier exiting car
– Easier doing up seatbelt (reaching and clasping)
– More torque in left hand when turning on water taps and door knobs
– Opening jars much easier
– Sweeping and raking much easier
– Able to let go of objects without thinking about it first (left hand)
– Dopamine medicine much more effective, works faster lasts a little longer
– Fewer left hand cramps
– Less restless arm and legs at night
– Stronger voice
– Way less need to stretch during the day and morning
– Just more coordination in left hand and right hand as well
– Walking gate improved, less clop in left foot longer steps
– Late night and early morning walking more steady (getting up to pee in the night and waking up in the morning )
– Don’t feel a sense of depression on off days and haven’t cried since starting Ibogaine

Once we started seeing such great improvements in Bill’s condition, we upped the dosage and compounded some 20 mg caplets of Ibogaine, which is still a very low dose; he continued to experience zero psychedelic effects.

20 mgs of Ibogaine twice daily:
– All of the above with more vigour, speed, and strength
– Knocked 10 minutes off time for regular 34 km bike ride; way stronger on hills and head winds
– Less fatigue when walking and more improvements in gate
– Grades less noticeable when walking uphill
– Stepping backwards easier with larger steps
– Less shaking on exertion with left arm (lifting weights)
– Much easier pulling up spandex cycling shorts
– Reduction of getting stuck (less often and shorter duration)

As a general rule, with Ibogaine and addiction interruption, the more you take, the better it works, to a point at least. So we figured we’d bring Bill into our facility for a larger dose. After clearing it with his doctor, and having the standard tests we have done prior to a larger dose (ECG, blood work) we welcomed Bill to Liberty Root for him to go on a little ‘journey’ with the medicine. After two days of larger dosing (>250 mgs) Bill had this to report:

– Feel no need for dopamine, moving better than even with dopamine supplement
– Left hand no longer hyper-extended at rest and has stopped “locking” open
– Using left hand in more spontaneous fashion, no self-correction
– Washing easier, dressing easier, tying shoes easier
– Improved sense of smell and taste
– Haven’t been stuck since last dosage

It’s only been a few days since Bill left our facility. In speaking with him today, he mentioned that his left hand has become a bit more stiff than it was upon his departure. There is obviously a lot more research and experimentation that needs be done, but the preliminary findings are very encouraging, and have offered Bill a degree of liberty he hasn’t seen in years.


 
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mr peabody

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B. caapi and Parkinson's

Samoylenko, Rahman, Tekwani, Tripathi, Wang, Khan, Miller, Joshi, Muhammad

Parkinson’s disease is a neurological disorder effecting the elderly. Currently there is no definitive treatment or cure for this disease. Therefore, in this study the composition and constituents of B. caapi for monoamine oxidases inhibitory and antioxidant activities were assessed, relevant to the prevention of neurological disorders, including Parkinsonism.

Banisteriopsis is a tropical South American genus with 92 species distributed mainly in Brazil, Bolivia, Colombia, Ecuador, and Peru. B. caapi is an ingredient of the popular sacred and psychoactive drinks Ayahuasca, also known as Caapi, Pinde, Natema or Yaje, which is widely used for prophecy, divination, and as a sacrament in the northern part of South America. However, to the best of our knowledge, no traditional drink prepared only from B. caapi has been consumed for such uses. Earlier chemical investigation have reported the presence of B-carboline alkaloids (B-CA) harmine, harmaline and tetrahydroharmine (THH) as the principal MAO inhibitors, together with other B-CA’s, from B. caapi. In addition, two pyrrolidines, shihunine and (S)-(+)-dihydroshihunine, and terpenoids were also reported. The alkaloid content of B. caapi was determined previously by GC/MS, LC/MS, and HPLC, suggesting the content of harmine is highest among B-CA’s, followed by THH and harmaline.

Parkinson’s disease (PD) is caused by a loss of neurons from substantia nigra of the brain. Once damaged, these neurons stop producing dopamine and compromise the brain's ability to control movement. It is not known what damages certain neurons in PD patients. One reason is that free radicals/ toxic particles normally deactivated in the body are responsible, which can be controlled by antioxidants as adjuvant with dopamine agonist or MAO inhibitors. The usefulness of B. caapi was established for alleviating symptoms of PD, which contains MAO inhibitor harmine as active constituent used in PD treatment. A double-blind, randomized placebo-controlled trial of B. caapi, using a single dose, revealed a significant improvement in motor function of PD patients. Tests for MAO inhibition using liver homogenate showed that B. caapi stem extract and harmine showed a concentration-dependent inhibition of MAO-A, and an increase in release of dopamine from rat striatal slices.

During the course of chemical and biological standardization of B. caapi, an extract of B. caapi cultivar Da Vine, collected in Oahu, Hawaii, demonstrated potent in vitro MAO-A inhibitory and antioxidant activities. This led to the bioassay guided isolation of two new B-carboline alkaloidal glycosides, banistenoside A, a new tetrahydronorharmine, four known B-carbolines harmol , using regular and RP silica gel chromatography. In this paper, we report the isolation, characterization and bioactivities of isolated compounds, and HPLC analysis of B. caapi cultivar Da Vine and two regular/ commercial samples of B. caapi.

Conclusion

Inhibition of MAO-B activity by B-carbolines harmine and harmaline, in addition to potent MAO-A inhibition responsible for antidepressant activity, provide protection against neurodegeneration, and has a potential therapeutic value for the treatment of Parkinson's diseases. In addition, oxidative stress induced by ROS has been strongly associated with the pathogenesis of neurodegenerative disorders, including Parkinson’s and Alzheimer’s. Therefore, the presence of two potent antioxidants, epicatechin and procyanidin, have significant added value for the protection of neuronal cells damage by oxidative free radicals. Their selective MAO-B inhibitory activity benefits them even more. Collectively, these results give additional basis to the existing claim of B. caapi stem extract for the treatment of Parkinsonism, including other neurodegenerative disorders.

https://www.ncbi.nlm.nih.gov/pmc/art...ihms156585.pdf



Ann and Alexander Shulgin
 
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mr peabody

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The effects of B. caapi on Parkinson's

Marcos Serrano-Duenas, Fernando Cardozo-Pelaez, Juan Sanchez-Ramos

Abstract

A substance extracted from the vine Banisteriopsis caapi was shown in the 1920s to alleviate Parkinsonism. These studies were criticized and forgotten for a number of reasons, including questions as to the identity of the active agent and failure to conduct strictly controlled studies. We now re-port the first double-blind, randomized placebo-controlled trial of a Banisteriopsis caapi (BC) extract for treatment of Parkinson’s Disease (PD). A single dose of BC administered to de novo PD patients resulted in significant improvement in motor function evidenced by decline in the Unified Parkinson’s Disease Rating Scale (UPDRS) score. The beneficial effects were maximal by the second hour and persisted until the last evaluation of the patients at 4 hours. However, tremor was not improved and in some patients tremor was exacerbated. All patients also experienced a degree of transient nausea or vomiting. We measured the concentrations of the putative active agents (harmine, harmaline, and tetrahydroharmaline), and hypothesize that the beneficial effects were primarily due to glutamate receptor antagonist actions of the harmalines.

Introduction

Ayahuasca is a beverage prepared from a combination of two plants, the vine Banisteriopsis caapi (BC) and the leaves of other plants, most commonly Psychotria viridis, which contains the psychedelic dimethyltryptamine (DMT). Ayahuasca, has a long history of use in medico-magical-religious ceremonies by natives of the Amazonian rain forests. The banisteriopsis vine contains contains b-carbolines such as harmine, harmaline, and tetrahydroharmine, which normally do not produce the desired psychotropic effects unless they are used with the DMT-containing plant. When taken orally, DMT is metabolized by monoamine oxidase (MAO) and is inactive, but the combination of DMT and the MAO inhibitor banisterine results in psychotropic effects.

The active agent of the banisteriopsis vine was identified by Louis Lewin, who named it Banisterine. Based on the subjective sensations experienced by Lewin following self-adminstration, he recommended it for treatment of rigid-akinetic syndromes in the late 1920s in Germany; all the reports mention improvement in rigidity, but conflicting results regarding tremor. Rustige also noted improvement in mood and affect. Later, Halpern studied the subjective effects on herself, and noted a sensation of lightness of body and a belligerent, aggressive mood.

From the 1930s to the present, the use of banisterine in treatment of PD has been virtually forgotten.

One of us (MS-D) had previously evaluated 13 patients who admitted use of ayahuasca occasionally, and who felt it helped alleviate the signs and symptoms of PD. In 4 of these patients we were able to directly observe the effects of consumption of ayahuasca. In one of these, extract of Banisteriopsis caapi (BC) was taken alone (no admixture of plants) and in the other 3 patients, the admixture of plants was ingested. About 20 minutes after ingestion of the beverage, there was an improvement in rigidity with exacerbation of tremor and appearance of abnormal involuntary movements as well as the induction of a hallucinatory state. The motor effects and hallucinations were much less evident in the single patient who took only the BC extract.

L-dopa is the gold standard of PD treatment, but its use is limited by the development of motor complications, including dyskinesias, in 30 to 80% of chronically treated patients. As a result, additional therapies have been developed that increase and stabilize synaptic levels of dopamine without augmenting the administered dosage of L-dopa, as for example by inhibiting dopamine metabolism with MAO inhibitors or with catechol-O-methyl transferase inhibitors.

Based on the remarkable effects of banisterine reported in the late 1920s and the dramatic effects noted in the few patients described above, we undertook a double-blind, randomized, placebo-controlled study of the acute effects of a single dose of BC extract in a cohort of 30 de novo PD patients.

Discussion

In this double-blind, randomized, placebo-controlled trial, we demonstrated that a single dose of BC administered to de novo PD patients resulted in significant improvement in motor function evidenced by decline in the motor component of the UPDRS score. The beneficial effects were noted by 1 hour and motor function continued to improve for the 4 hours during which the patients were studied. However, all patients who received BC experienced a worsening of resting tremor and the development of action and postural tremors,with some abnormal choreiform movements. All patients also experienced a degree of transient nausea or vomiting. With the exception of the single patient who experienced confusion and hallucinations, these side effects were much less severe than those experienced by users of the complete ayahuasca beverage.

The levels of harmaline in the banisteriopsis extract ingested by the subjects in this study were almost identical to those measured by Callaway and colleagues in the preparations of ayahusaca used by members of the Uniao de Vegetal in Brazil. But the mean harmine and tetrahydroharmine levels were 25% and 35%, respectively, of the levels measured in their Brazilian subjects, who ingested the complete brew prepared from a combination of plants. The proportion of banisteriopsis vine to Psychtria viridis leaves and the exact methods for preparation of the brew were not noted in the Callaway paper.

In the shamanic use of ayahuasca for religious, magical, or healing purposes, the infusion is prepared from a mixture of plants. A critical component of the shamanic beverage is the presence of the DMT-containing Psychotria viridis. DMT is a potent psychedelic when given systemically or when smoked; when taken orally, it is inactive due to its metabolism by gut and liver MAO. BC is an inhibitor of MAO and, when ingested orally with DMT-containing plants, allows the DMT to produce a range of psychotropic effects, with prominent visions, hallucinations, and illusions.

The dramatic improvement in signs and symptoms of PD produced by the extract of BC may be due to a combination of two known mechanisms of action of the harmalines, the putative active agents. Harmaline, a b-carboline compound with a structural resemblance to serotonin, is a known non-selective inhibitor of MAO. MAO inhibitors can potentiate the actions of endogenous dopamine, but the symptomatic benefits in Parkinson's are very mild. It is difficult to conceive that the dramatic improvement produced by BC can be due solely to MAO inhibition. It is possible that the interaction of harmaline at glutamatergic receptors plays a significant role in restoring motor function in PD. Harmaline has been shown to be an NMDA receptor antagonist. Harmaline displaces [3H]MK-801, which binds to the cation channel of the NMDA receptor, from membranes prepared from rabbit brain tissue.

Glutamate is an excitatory amino acid that plays a role in the symptomatic expression of Parkinson's that has also been implicated in the process of neurodegeneration of dopaminergic neurons of the substantia nigra. When dopamine deficiency develops, the adaptive changes in the striatal outflow pathways result in disinhibition of the subthalamic nucleus. In turn, the hyperactive subthalamic-pallidal glutamate projection results in decreased outflow from globus pallidus internal segment (GP-int) to thalamus, to produce the clinical manifestations of slowness and rigidity. Blockage of glutamatergic receptors corrects the imbalance that results from dopamine deficiency and helps restore normal motor function.

In the rat, local infusion of NMDA re-ceptor antagonists to the GP-int/SNr has been shown to reverse the signs of parkinsonism. In both rats and primates, the NMDA receptor antagonist LY235959 has been shown to potentiate the anti-parkinson effects of L-dopa, to stabilize the motor fluctuations and to alleviate choreiform dyskinesias. However, MK-801, a glutamate NMDA receptor antagonist with psychedelic side effects has been reported to induce dystonia when used with L-dopain a primate model of parkinsonism. In naive rats, MK-801 increases locomotor activity and potentiates the motor effects of L-dopa. The AMPA antagonist NBZX improved tremor, posture, and manual dexterity in parkinsonian monkeys. When glutamate antagonists are given together with L-dopa, the dosage of L-dopa can be greatly reduced without lessening motor function.

Conclusion

To conclude, we are suggesting that the anti-glutamate actions of harmaline are most likely responsible for the anti-parkinson effects observed in the BC group of patients. The transient worsening of tremor and induction of postural and action tremor by banisterine has been been noted before by early investigators and, in fact, harmaline was used in the 1960s to study the mechanism of action tremor that could be induced by harmaline in primates.

Interestingly, L-dopa-induced dyskinesias are associated with a decrease in the activity of the glutamatergic projection to the GP-int. Paradoxically, glutamatergic receptors are apparently involved in these dyskinesias, since adminstration of glutamate antagonists (of the NMDA receptor subtype) have been shown to be useful in controlling L-dopa-induced dyskinesias.

There is little concern for the possibility that the harmalines in the ayahuasca tea are cytotoxic at concentrations found in the tea. Harmaline and a related b-carboline, ibogaine, are cytotoxic in rats only following extremely high doses of 100 mg/kg or 100 mg/kg x 3. Two recent studies clearly demonstrated that even lower doses (25 and 40 mg/kg) given to rats did not produce Purkinje cell degeneration.

To summarize, extracts of BC were shown to have remarkable symptomatic benefit in drug-naive de novo patients. This was the first double-blind, randomized, placebo-controlled trial of a BC extract for treatment of PD. Studies with banisterine done in the late 1920s were criticized because the benefits were believed by many to be psychological. We measured the concentrations of the putative active agents, and hypothesize that the beneficial effects were primarily due to glutamate receptor antagonist actions of the harmalines. The most common side effect was transient nausea/vomiting, which could inthe future be prevented by pre-treatment with domperidone. Hallucinations in a single case may reflect a higher sensitivity in that patient to the NMDA receptor antagonists. A complete dose-response study needs to be done in human volunteers in order to determine the optimal concentrations of b-carbolines to produce maximal symptomatic relief and minimal side effects.

https://www.scribd.com/document/9201...-Caapi-Extract


 
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mr peabody

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Ketamine may ease spasticity in Parkinson’s patients

Levodopa is the best-known treatment for Parkinson’s, but it can cause some other debilitating side effects. Now, researchers at the University of Arizona are testing an old drug, in addition to levodopa, to see if it brings relief.

Sharon Kha started taking levodopa for Parkinson’s in 2005. Now, she has dyskinesia, or uncontrollable movements of the body.

Kha shared, “It is so frustrating when you start having these large involuntary movements, because they’re intrusive.”

Neuroscientist Torsten Falk’s research indicates that the anesthetic ketamine eases dyskinesia in rodents and also in five Parkinson’s patients who were already taking it for pain relief.

“In a way, it's almost like a reset button where you get a treatment and you have weeks to months-long benefit,” said Torsten Falk, PhD, Associate Professor of Neurology and Pharmacology at the University of Arizona.

Re-purposing ketamine for dyskinesia could get it to patients quicker. It’s already been safely tested at higher doses than Falk plans to test.

"If you start with something fresh and new, the problem can really be that it can be five to 10 years of safety testing before you can really do a proper trial to look for efficacy,” explained Falk.

Kha says this is great news.

“It sounds like a wonderful treatment because these large involuntary movements are so irritating," she said.

Falk hopes to start a phase-one trial in the coming months.

Ketamine can raise blood pressure and cause feelings of dissociation in higher doses. Researchers expect the dosage needed to control dyskinesia will be much lower than that.

https://www.wctv.tv/content/news/Ketamine-may-be-used-to-ease-uncontrollable-movements-in-Parkinsons-patients-495135131.html
 
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CKBR-12 for Parkinson’s

CKBR-12, an Ibogaine derivative medicine developed by Phytostan Pharmaceuticals, is currently being investigated as a medication to treat Parkinson’s Disease. It has been found to upregulate glial cell line-derived neurotrophic factor (GDNF) expression in the mid brain and increase GDNF secretion 6 and may represent a powerful new method to upregulate GDNF in the treatment of PD and other neurodegenerative disorders.

REDUCTION OF PD SYMPTOMS In Patients With CKBR-12

1. Decreased or elimination of Saliva and drooling. No problems in swallowing
2. Loss of any depression or anxiety.
3. Improvement in his speech, diction, and tongue control.
4. Increased facial activity, muscles coming alive. Loss of facial rigidity.
5. Regaining hand movement and use.
6. Free flowing handwriting.
7. Motor Skills: 50% or 75% better within 30 days.
8. Return of self dressing and dexterity with fingers
9. Naturally eating, cutting own food, don’t need assistance. Able to hold a fork and knife differently .
10. Balance: Standing up for long periods of time and regaining a sense of balance. Loss of feeling of falling.
11. Walking: Able to walk up and down stairs much faster and longer distances.
12. Loss of tremors.

One reason Ibogaine is so interesting is that it increases levels of glial cell line-derived neurotrophic factor (GDNF) in the brain, and this in turn appears to be a potent survival factor for several different neuronal populations in different brain regions and has neuroprotective properties that promote the survival of both dopaminergic and motor neurons, which may be one of the reasons for the prolonged afterglow often experienced following treatment with the drug.

Furthermore, GDNF can cause sprouting of dopaminergic fibers and clinical improvement in experimental animal models of Parkinson’s disease, as well as a similar sprouting of dopaminergic fibers in humans with the disease, with the resultant clinical improvement in symptoms. GDNF has also been identified as having anti-addictive properties. This may be one of the reasons for Ibogaine’s effectiveness in treating drug addicts with impaired receptor function, but this drug may also be a considerable ally to those with degenerative neurological diseases.

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 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. Furthermore, after one year, no serious clinical side effects were observed.

Both Parkinson’s disease, motor neuron disease and Alzheimer’s Disease 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.

The use of Ibogaine would provide a longer term and much less invasive method of GDNF administration than direct brain infusion. Ibogaine therapy offers a non-invasive and low-toxicity method of treatment for sufferers of this disease.

http://genesisibogainecenter.com/ckb...or-parkinsons/

-----

One Promising Case

Patient D* was 69 years old in 2012 when he was diagnosed with Atypical Parkinson’s, a Parkinson’s-like syndrome that does not include the characteristic palsy. By last year Patient D’s symptoms had advanced to the point where his facial muscles felt frozen. He had difficulty finding his balance, talking or using his hands. As a writer and artist, he noted that emotionally it was the first time in his life he had lost his desire to do anything creative.

In December 2014, Patient D was treated with CKBR-12, an experimental natural health product and “ibogaine-derivative” at a medical center in Rosarito, Mexico. He took a small dosage twice a day for 30 days, and after the first two weeks began to notice that he could use his fingers to pick up objects again. After a month he had seen a gradual improvement in all of his symptoms to the point where he could carry on normal conversation, and coordinate previously impossible tasks such as buttoning his shirt.

In a post-treatment interview that was published on YouTube, Patient D says, “It’s difficult to explain what Parkinson’s is, but you lose your edge. And I’ve got my edge back in a few areas… It may be small things to some, but they are big things for me. I’m anxious to see what happens next.”

When we spoke, to Patient D, he said that he had continued to have improvements with further treatment. His case has been reviewed by several doctors, including Dr. Susanne Cappendijk of Florida State University Medical Center, who relayed some of the results at a conference at the New York Academy of Sciences on April 27th.

https://www.sociedelic.com/could-ibo...nsons-disease/
 
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MDMA shown to have a dramatic effect on Parkinson’s symptoms

By David Concar

MDMA is being hailed as the key to better treatments for the Parkinson’s disease, marking a complete turnaround from a few weeks ago when ecstasy was condemned for causing the disease.

New animal studies have confirmed anecdotal reports that ecstasy can dramatically curb the uncontrollable arm and leg movements that plague so many people with Parkinson’s. But the finding may be of little immediate help to sufferers.

The researchers are not calling for patients to be given legal supplies of ecstasy (MDMA). Instead, they want to look for related drugs with the same beneficial effects. And patients are being warned against trying MDMA for themselves. “It’s impure, illegal and dangerous,” says Robert Meadowcroft, policy director of Britain’s Parkinson’s Disease Society.

Others are calling for further animal studies to establish the effective dose, followed by human trials. “People who are suffering should have the right to decide carefully for themselves whether or not to take MDMA,” says American drugs policy campaigner Rick Doblin. His organisation, MAPS, recently won approval from the Food and Drug Administration for a human trial of ecstasy for treating post-traumatic stress disorder.

Regaining control

The latest study was prompted by the experiences of a former stuntman, Tim Lawrence. He made headlines when he claimed in a BBC TV documentary that “E” enabled him to regain control of his body for hours at a time.

Parkinson’s experts at the University of Manchester decided to test Lawrence’s claims. Concerns about the dangers of MDMA ruled out human trials, says team member Jonathan Brotchie, who now runs Manchester-based biotech company Motac. So the researchers turned to marmosets with a form of the disease.

Parkinson’s is caused by a loss of the dopamine-producing cells in the brain. Symptoms include rigidity and a shuffling gait. Since the late 1960s doctors have treated it with L-dopa, a chemical precursor to dopamine that can “unfreeze” patients.

The downside is that patients develop uncontrollable movements after taking L-dopa for a while. Their condition tends to oscillates between flailing limbs while on the drug and immobility off it.

To mimic Parkinson’s, they gave six marmosets a chemical that kills dopamine neurons. Then, over the next few months, the monkeys had daily doses of L-dopa until they developed the usual side effect of uncontrolled movements. At this point the animals were given MDMA.

Dramatic effects

The effects were dramatic. Normally, monkeys on L-dopa move their arms and legs around in a repetitive and uncontrolled way virtually all the time. But in the six hours after a dose of MDMA, these movements happened no more than 15 per cent of the time. MDMA somehow reduces the debilitating side effects of L-dopa without blocking its beneficial effects.

“The magnitude and quality of the effect took us by surprise,” says Brotchie, whose team’s findings were unveiled this week at the conference of the Society for Neuroscience in Florida. “It was always possible that Tim’s response to ecstasy was unusual.”

The researchers suspect the finding reflects MDMA’s ability to stimulate the release of the neurotransmitter serotonin in the brain. That might make up for a lack of serotonin caused by taking L-dopa for prolonged periods, says Brotchie. However, there are fears that MDMA can damage serotonin-producing cells.

And last month the journal Science published a paper claiming that MDMA can actually cause the type of damage to dopamine cells that can lead to Parkinson’s. But the evidence was far from conclusive.

https://www.newscientist.com/article...sons-symptoms/
 
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CBD and Parkinson’s


The endocannabinoid system and digestive imbalance play major roles in Parkinson's disease. Research on CBD, THC, and THCV has demonstrated that cannabis medicine may help to manage PD symptoms.

Scientists at the University of Louisville School of Medicine in Kentucky have identified a previously unknown molecular target of cannabidiol (CBD), which may have significant therapeutic implications for Parkinson’s Disease (PD).

A poster by Zhao-Hui Song and Alyssa S. Laun at the 2017 meeting of the International Cannabinoid Research Society in Montreal disclosed that CBD activates a G-coupled protein receptor called “GPR6” that is highly expressed in the basal ganglia region of the brain. GPR6 is considered an “orphan receptor” because researchers have yet to find the primary endogenous compound that binds to this receptor.

It has been shown that a depletion of GPR6 causes an increase of dopamine, a critical neurotransmitter, in the brain. This finding suggests GPR6 could have a role in the treatment of Parkinson’s, a chronic, neurodegenerative disease that entails the progressive loss of dopaminergic (dopamine-producing) neurons and consequent impairment of motor control. By acting as an “inverse agonist” at the GPR6 receptor, CBD boosts dopamine levels in preclinical studies.

Parkinson’s affects an estimated 10 million people worldwide, including one million Americans. It is the second most common neurological disorder (after Alzheimer’s Disease). Over 96 percent of those diagnosed with PD are over 50 years old with men being one-and-a-half times more likely to have PD than women. Uncontrolled PD significantly reduces the patient’s quality of life and can render a person unable to care for themselves, trapped in a body they cannot control.

Dopamine depletion

Parkinson’s Disease is most associated with compromised motor function after the loss of 60-80% of dopamine-producing neurons. As dopaminergic neurons become damaged or die and the brain is less able to produce adequate amounts of dopamine, patients may experience any one or combination of these classic PD motor symptoms: tremor of the hands, arms, legs or jaw; muscle rigidity or stiffness of the limbs and trunk; slowness of movement (bradykinesia); and /or impaired balance and coordination (postural instability).

Additional symptoms include decreased facial expressions, dementia or confusion, fatigue, sleep disturbances, depression, constipation, cognitive changes, fear, anxiety, and urinary problems. Pesticide exposure and traumatic brain injury are linked to increased risk for PD. Paraquat, an herbicide sprayed by the DEA in anti-marijuana defoliant operations in the United States and other countries, resembles a toxicant MPTP [methyl-phenyl-tetrahydropyridien], which is used to simulate animal models of Parkinson’s for research purposes.

Within the PD brain there are an inordinate number of Lewy bodies - intracellular aggregates of difficult to break down protein clusters - that cause dysfunction and demise of neurons. This pathological process results in difficulties with thinking, movement, mood and behavior. The excessive presence of Lewy bodies, coupled with the deterioration of dopaminergic neurons, are considered to be hallmarks of Parkinson’s. But mounting evidence suggests that these aberrations are actually advanced-stage manifestations of a slowly evolving pathology.

It appears that non-motor symptoms occur for years before the disease progresses to the brain, and that PD is actually a multi-system disorder, not just a neurological ailment, which develops over a long period of time. According to the National Parkinson’s Foundation, motor symptoms of PD only begin to manifest when most of the brain’s dopamine-producing cells are already damaged.

Patients whose PD is diagnosed at an early stage have a better chance of slowing disease progression. The most common approach to treating PD is with oral intake of L-dopa, the chemical precursor to dopamine. But in some patients, long-term use of L-dopa will exacerbate PD symptoms. Unfortunately, there is no cure – yet.

Gut-brain axis

What causes Parkinson’s? One theory traces the earliest signs of PD to the enteric nervous system (the gut), the medulla (the brainstem), and the olfactory bulb in the brain, which controls one’s sense of smell. New research shows that the quality of bacteria in the gut – the microbiome – is strongly implicated in the advancement of Parkinson’s, the severity of symptoms, and related mitochondrial dysfunction.

Defined as “the collection of all the microorganisms living in association with the human body,” the microbiome consists of “a variety of microorganisms including eukaryotes, archaea, bacteria and viruses.” Bacteria, both good and bad, influence mood, gut motility, and brain health. There is a strong connection between the microbiome and the endocannabinoid system: Gut microbiota modulate intestinal endocannabinoid tone, and endocannabinoid signaling mediates communication between the central and the enteric nervous systems, which comprise the gut-brain axis.

Viewed as “the second brain,” the enteric nervous system consists of a mesh-like web of neurons that covers the lining of the digestive tract – from mouth to anus and everything in between. The enteric nervous system generates neurotransmitters and nutrients, sends signals to the brain, and regulates gastrointestinal activity. It also plays a major role in inflammation.

The mix of microorganisms that inhabit the gut and the integrity of the gut lining are fundamental to overall health and the ability of the gut-brain axis to function properly. If the lining of the gut is weak or unhealthy, it becomes more permeable and allows things to get into the blood supply that should not be there, negatively impacting the immune system. This is referred to as “leaky gut.” Factor in an overgrowth of harmful bacteria and a paucity of beneficial bacteria and you have a recipe for a health disaster.

The importance of a beneficial bacteria in the gut and a well-balanced microbiome cannot be overstated. Bacterial overgrowth in the small intestine, for example, has been associated with worsening PD motor function. In a 2017 article in the European Journal of Pharmacology, titled “The gut-brain axis in Parkinson’s disease: Possibilities for food-based therapies,” Peres-Pardo et al examine the interplay between gut dysbiosis and Parkinson’s. The authors note that “PD pathogenesis may be caused or exacerbated by dysbiotic microbiota-induced inflammatory responses … in the intestine and the brain.”

Mitochondria, microbiota and marijuana

The microbiome also plays an important role in the health of our mitochondria, which are present in every cell in the brain and body (except red blood cells). Mitochondria function not only as the cell’s power plant; they also are involved in regulating cell repair and cell death. Dysfunction of the mitochondria, resulting in high levels of oxidative stress, is intrinsic to PD neurodegeneration. Microbes produce inflammatory chemicals in the gut that seep into the bloodstream and damage mitochondria, contributing to disease pathogenesis not only in PD but many neurological and metabolic disorders, including obesity, type-2 diabetes, and Alzheimer’s.

The evidence that gut dysbiosis can foster the development of PD raises the possibility that those with the disease could benefit by manipulating their intestinal bacteria and improving their microbiome. Enhancing one’s diet with fermented foods and probiotic supplements may improve gut health and relieve constipation, while also reducing anxiety, depression and memory problems that afflict PD patients.

Cannabis therapeutics may also help to manage PD symptoms and slow the progression of the disease. Acclaimed neurologist Sir William Gowers was the first to mention cannabis as a treatment for tremors in 1888. In his Manual of Diseases of the Nervous System, Grower noted that oral consumption of an “Indian hemp” extract quieted tremors temporarily, and after a year of chronic use the patient’s tremors nearly ceased.

Modern scientific research supports the notion that cannabis could be beneficial in reducing inflammation and assuaging symptoms of PD, as well as mitigating disease progression to a degree. Federally-funded preclinical probes have documented the robust antioxidant and neuroprotective properties of CBD and THC with “particular application … in the treatment of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease and HIV dementia.” Published in 1998, these findings formed the basis of a U.S. government patent on cannabinoids as antioxidants and neuroprotectants.

Cannabinoids and Parkinson’s

Although clinical studies focusing specifically on the use of plant cannabinoids to treat PD are limited (because of marijuana prohibition) and convey conflicting results, in aggregate they provide insight into how cannabis may aid those with Parkinson’s. Cannabidiol, THC, and especially THCV all showed sufficient therapeutic promise for PD in preclinical studies to warrant further investigation. Additional research might shed light on which plant cannabinoids, or combination thereof, is most appropriate for different stages of Parkinson’s.

Anecdotal accounts from PD patients using artisanal cannabis preparations indicate that cannabinoid acids (present in unheated whole plant cannabis products) may reduce PD tremor and other motor symptoms. Raw cannabinoid acids (such as CBDA and THCA) are the chemical precursors to neutral, “activated” cannabinoids (CBD, THC). Cannabinoid acids become neutral cannabinoid compounds through a process called decarboxylation, where they lose their carboxyl group through aging or heat. Minimal research has focused on cannabinoid acids, but the evidence thus far suggests that THCA and CBDA have powerful therapeutic attributes, including anti-inflammatory, anti-nausea, anti-cancer, and anti-seizure properties. In a 2004 survey of cannabis use among patients at the Prague Movement Disorder Centre in the Czech Republic, 45 percent of respondents reported improvement in PD motor symptoms.

Cannabis clinicians are finding that dosage regimens for medical marijuana patients with PD don’t conform to a one-size-fits-all approach. In her book Cannabis Revealed (2016), Dr. Bonni Goldstein discussed how varied a PD patient’s response to cannabis and cannabis therapeutics can be:

“A number of my patients with PD have reported the benefits of using different methods of delivery and different cannabinoid profiles. Some patients have found relief of tremors with inhaled THC and other have not. A few patients have found relief with high doses of CBD-rich cannabis taken sublingually. Some patients are using a combination of CBD and THC … Trial and error is needed to find what cannabinoid profile and method will work best. Starting a low-dose and titrating up is recommended, particularly with THC-rich cannabis. Unfortunately, THCV-rich varieties are not readily available.”

Juan Sanchez-Ramos M.D., PhD, a leader in the field of movement disorders and the Medical Director for the Parkinson Research Foundation, told Project CBD that he encourages his patients to begin with a 1:1 THC:CBD ratio product if they can get it. In a book chapter on “Cannabinoids for the Treatment of Movement Disorders,” he and coauthor Briony Catlow, PhD, describe the dosage protocol used for various research studies that provided statistically positive results and a dosing baseline for PD. This data was included in a summary of dosing regimens from various studies compiled by Dr. Ethan Russo:

- 300 mg/day of CBD significantly improved quality of life but had no positive effect on the Unified Parkinson Disease Rating Scale. (Lotan I, 2014)

- 0.5 g of smoked cannabis resulted in significant improvement in tremor and bradykinesia as well as sleep. (Venderov? K, 2004)

- 150 mg of CBD oil titrated up over four weeks resulted in decreased psychotic symptoms. (Chagas MH, 2014)

- 75-300 mg of oral CBD improved REM-behavior sleep disorder. (Zuardi AW, 2009)

A threshold dose

Of course, each patient is different, and cannabis therapeutics is personalized medicine. Generally speaking, an optimal therapeutic combination will include a synergistic mix of varying amounts of CBD and THC – although PD patients with sleep disturbances may benefit from a higher THC ratio at night.

Dr. Russo offers cogent advice for patients with PD and other chronic conditions who are considering cannabis therapy. “In general,” he suggests, “2.5 mg of THC is a threshold dose for most patients without prior tolerance to its effects, while 5 mg is a dose that may be clinically effective at a single administration and is generally acceptable, and 10 mg is a prominent dose, that may be too high for na?ve and even some experienced subjects. These figures may be revised upward slightly if the preparation contains significant CBD content … It is always advisable to start at a very low dose and titrate upwards slowly.”

Lifestyle modifications for PD patients

It is important to treat the patient as a whole – mind, body and soul. The following are a few lifestyle modifications that may provide relief from PD symptoms and improve quality of life.

- Do cardio aerobic exercise: This benefits the body in so many ways, including stimulating the production of one’s endocannabinoids, increasing oxygen in the blood supply, mitigating the negative impact of oxidative stress, and boosting the production of BDNF, a brain-protecting chemical found to be low in PD patients.

- Eat more fruits and vegetables: The old saying “garbage in, garbage out” is so true. The majority of PD patients suffer from chronic constipation. A high fiber diet can be helpful in improving gut motility and facilitating daily bowel movements.

- Get restful sleep: Not getting good sleep can undermine one’s immune function, cognition and quality of life. The importance of adequate restful sleep cannot be over emphasized.

- Reduce protein intake – This may help reduce the accumulation of protein bodies that result in Lewy bodies that appear in the enteric nervous system and the central nervous system and increase the uptake of L-dopa.

- Practice meditation, yoga or Tai Chi: The focus on the integration of movement and breath not only improve mobility but it also improves cognition and immunity. One study showed an increase in grey matter density in the areas of the brain associated with PD. Another showed that yoga improved balance, flexibility, posture and gait in PD patients. Research shows that tai chi can improve balance, gait, functional mobility, and overall well being.

- Consume probiotic food and supplements: Probiotic foods — raw garlic, raw onions, bananas, asparagus, yams, sauerkraut, etc.— are a great source for the good bacteria in your large intestine. Augmenting your diet with probiotic supplements, especially after taking antibiotics, can support the immune system by helping to repopulate the upper digestive tract with beneficial bacteria. Consult your doctor regarding a recommendation for a quality probiotic.

-Drink coffee: The risk of PD is considerably lower for men who consume coffee daily.

https://www.projectcbd.org/science/c...insons-disease
 
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LSD and Parkinson's


In a very real sense the circle is closing with respect to Albert Hofmann's hope, expressed at the time of his discovery of LSD. Because of its psychotomimetic action (ability to mimic certain mental illnesses), the drug might prove useful in their treatment. In fact, LSD has been employed to that end over the years by some psychiatrists, often with beneficial results.

Recently, scientists at the School of Medicine of the University of California at Los Angeles have made some significant discoveries about the interaction of LSD with dopamine, one of the neurotransmitter agents in the brain, that may lead not only to a better understanding and eventual treatment of schizophrenia, the mental disorder to which the LSD "high" is a kind of temporary analogue, but even of such physically, rather than mentally, crippling disorders as Parkinson's disease. The investigators, Drs. Sidney Roberts and Kern von Hungen and Diane F. Hill, determined that adenyl cyclase, an enzyme in nervous tissue that is stimulated by naturally occurring neurotransmitter agents, is also stimulated by the action of LSD on receptors for one of these neurotransmitters, dopamine. In addition, LSD blocked the stimulatory actions of dopamine and other neurotransmitters such as serotonin and norepeninephrine. These are themselves structurally closely related to powerful plant growth hormones; dopamine, moreover, has also been identified with the giant saguaro cactus of Arizona and northern Mexico.

Schizophrenia is thought to be a disease of dopamine hyperactivity; victims of Parkinson's disease, on the other hand, suffer from dopamine insufficiency, which is partially offset nowadays by the administration of a new drug, L-dopa, often in combination with Tofranil or some other amphetamine. The adenyl cyclase experiments enabled the UCLA team to show that dopamine receptors are present in the higher regions of the brain, which are concerned with the more complex experiences and thus are more likely to be the seat of alternate states of consciousness, or "hallucinations." Their work, report the UCLA investigators, makes it appear that the psychotic mimicking effects of LSD, first noted by Hofmann more than thirty years ago, may also be related to hyperactivity of brain dopamine systems. These insights have obvious implications for work on new drugs for schizophrenia on the one hand and Parkinson's disease on the other; recognition of their biochemical kinship was, of course, still far off in the distant future when Hofmann correctly predicted the ultimate benefits of LSD for brain research. Nor did he suspect at the time that "primitive" psychotherapy had been making effective use of a natural compound very like LSD for hundreds, perhaps thousands, of years.

"Lysergic acid," Hofmann (1967) has explained, "is the foundation stone of the ergot alkaloids, the active principle of the fungus product ergot. Botanically speaking ergot is the sclerotia of the filamentous fungus Claviceps purpurea which grows on grasses, especially rye. The ears of rye that have been attacked by the fungus develop into long, dark pegs to form ergot. The chemical and pharmacological investigation of the ergot alkaloids has been a main field of research of the natural products division of the Sandoz laboratories since the discovery of ergotamine by A. Stoll in 1918. A variety of useful phannaceuticals have resulted from these investigations, which have been conducted over a number of decades. They find wide application in obstetrics, in internal medicine, in neurology and psychiatry."

https://www.drugtimes.org/hallucinogens-culture/
 
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Ibogaine and Parkinson's

Following is a brief summary on the 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 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 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 (BL)
 
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Ketamine studied for relief of Levodopa-associated involuntary movements


by Patricia Inacio, PhD - July 23, 2018

A Phase 1 trial will test the potential of ketamine — an analgesic medicine used for depression and pain — at reducing the uncontrollable, jerky movements that arise in Parkinson’s disease patients after long-term treatment with levopoda.

Levodopa, probably the most common treatment for Parkinson’s disease, is effective at improving the stiffness and slowness of movement that characterize the disease.

However, up to 40 percent of long-term users eventually experience dyskinesia, which is the uncontrollable and involuntary movements that may be restricted to certain parts of the body, such as head, arms or legs, or affect the whole body.

“The problem is levodopa works great for a few years — we call that the ‘honeymoon’ period — but then you start getting these side effects,” Scott Sherman, MD, PhD, a neurologist at the University of Arizona College of Medicine – Tucson, said in a press release.

The severity of dyskinesia varies among patients, with some experiencing small jerky movements and others being affected by strong, constant bursts. Unfortunately, these side effects go away only after a patient stops taking levodopa.

So, researchers at the University of Arizona will conduct a small Phase 1 clinical trial with 10 Parkinson’s patients to determine the potential of ketamine for rescuing levopoda-induced dyskinesia.

The trial follows earlier work by Sherman and Torsten Falk, PhD, the scientists leading the study. They were using ketamine to relieve pain in Parkinson’s disease patients when they noticed an unexpected effect — the treatment also reduced the patients’ uncontrolled movements. One patient was actually free of the jerky movements for several weeks.

The same results were seen in animal models, where treatment led to a significant reduction in abnormal involuntary movements. The reduction was sustained for three days, and 10 days passed before baseline involuntary movements returned.

Ketamine increases blood pressure, but may cause a sensation of “out-of-body” experience, also known as dissociation, Sherman said. “When people describe it, they have told me that they feel like they are in fish bowl,” said Sherman. Ketamine actually has been used as a psychedelic recreational drug, Sherman said, adding that researchers have established preventive measures and he is hopeful those side effects will not affect the clinical trial.

“We are going to monitor blood pressure closely to make sure it doesn’t get high,” Sherman said. “And we know at what dosage ketamine causes this disassociation; we expect that the dosage needed in Parkinson’s disease will stay well below that level.”

Parallel to the Phase 1 trial, researchers will undertake a rodent study to assess the mechanisms underlying the effects of ketamine in the brain.

“We want to find out exactly what ketamine is doing to have this effect,” Sherman added.

Positive results in both the human trial and the animal study could help researchers establish ketamine as a therapy for patients with Parkinson’s disease.

“Ketamine has been long overlooked. Now it could prove very useful for Parkinson’s patients,” Sherman said.

The Phase 1 human and the animal study are both supported by a $750,000 three-year grant from the Arizona Biomedical Research Commission.

https://parkinsonsnewstoday.com/2018/07/23/ketamine-tested-easing-levodopa-involuntary-movements-parkinsons/
 
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Ibogaine and Parkinson's

After Alzheimer’s, Parkinson’s Disease is the second most common neurodegenerative disease and is currently not curable. The disease manifests itself by the progressive loss of nerve cells, mainly of dopamine neurons in the substantia nigra (part of the midbrain). This results in a lack of dopamine in the striatum (a subcortical part of the forebrain), as well as a dysfunction in motor functions, tremors, stiffening muscles, language problems and a general loss of balance and coordination.

These physical symptoms are also accompanied by psychological effects like dementia and depression. It is thought that the neurodegenerative aspects of Parkinson’s disease are caused by the body’s immune system. Healthy nervous system tissue is attacked when the immune system is no longer able to distinguish between healthy and diseased cells, similar to autoimmune diseases such as multiple sclerosis, fibromyalgia and polyneuropathy.

GDNF (glial cell line-derived neurotrophic factor) is a protein discovered in 1991 with an extraordinarily positive effect on nerve cell tissue. GDNF stimulates nerve cell growth, especially dopamine neurons. In addition to the ability to regenerate nerve cells in the brain, GDNF also appears to possess neuroprotective properties.


In an animal experiment in which rats with Parkinson’s disease had GDNF injected directly into the brain, a significant improvement in the symptoms was observed. After one year, there were still no undesirable side effects of GDNF administration.
 Initial studies have shown that GDNF significantly improves the overall condition of Parkinsonian patients. The resulting data suggests that new nerve cells had formed.

Ibogaine and its metabolite noribogaine lead to a substantial increase in GDNF levels in the brain. This indicates that ibogaine could provide a very effective treatment for neurodegenerative diseases, such as Parkinsons.

Until now, it was not possible to introduce GDNF directly into the desired regions of the brain. But Ibogaine stimulates the glial cells and neurons to produce GDNF itself, increasing GDNF levels throughout the brain.

 Phytostan, a pharmaceutical company focused on developing ibogaine, has developed an ibogaine-based medicine called CK-BR 12. This consists of Ibogaine HCL and a cocktail composed of 12 vitamins.

Patient D is a 69-year-old Parkinson’s disease patient and until now the only human treated with Ibogaine for his condition. Patient D reported numerous positive changes regarding his illness: he could swallow again, speech and facial expressions improved noticeably, the control of the hands increased and he could write again legibly. Also, his general motor skills increased.

He could dress again, eat independently and climb stairs – all activities which were not possible prior to his treatment. The Parkinson’s symptomatology also improved after the treatment was completed. Patient D. was examined by various physicians as well as pharmacologist Dr. Susanne Cappendijk from Semper Clarus Consulting, who presented the promising results at the New York Academy of Sciences conference on April 27, 2015.

The standard symptomatic treatment, is predominantly carried out with drugs with strong side effects. The quality of life of the patients is often characterised by significant suffering in the terminal phase. In contrast, treatment with ibogaine, in particular through the approach of microdosing, allows an increase in the GDNF levels in the brain, without the side effects of conventionally used medications.

It was reported that 4mg Ibogaine HCL can increase GDNF levels in the brain by a factor of 12. The neuroplasticity increased by the growth of new neurons promotes the restoration and the construction of nerve tracts. Also, the challenge of introducing GDNF by injection into the brain is obviated. These results could help to redefine the position of Ibogaine in general research and – as ever-unknown healing properties of the plant are discovered – open up new research areas and thereby achieve a wider social and regulatory acceptance.

At the Ibogaine conference in 2016, Dr. Ignacio Carrera from the Universidad de la Republica Uruguay presented the research of an interdisciplinary group. Novel variations of the ibogaine molecular structure have been developed that enhance the production of GDNF. The group of N-indolylethyl isoquinuclidines appears to be most promising. The synthesis of these molecules is far less complex than that of Ibogaine and there are several promising derivatives. Some of the analogues cause an even higher GDNF-release in vitro than Ibogaine does, but can have cytotoxic effects depending on the structure. The research in this field is still nascent, but it has enormous potential.

http://iboga.info/parkinsons-disease/
 
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More on ibogaine and Parkinson's


After Alzheimer’s, Parkinson’s Disease is the second most common neurodegenerative disease and is currently not curable. The disease manifests itself by the progressive loss of nerve cells, mainly of dopamine neurons in the substantia nigra (part of the midbrain). This results in a lack of dopamine in the striatum (a subcortical part of the forebrain), as well as a dysfunction in motor functions, tremors, stiffening muscles, language problems and a general loss of balance and coordination.

These physical symptoms are also accompanied by psychological effects such as dementia and depression. It is thought that the neurodegenerative aspects of Parkinson’s disease are caused by the body’s immune system. Healthy nervous system tissue is attacked when the immune system is no longer able to distinguish between healthy and diseased cells, similar to autoimmune diseases such as multiple sclerosis, fibromyalgia and polyneuropathy.

GDNF (glial cell line-derived neurotrophic factor) is a protein discovered in 1991 with an extraordinarily positive effect on nerve cell tissue. GDNF stimulates nerve cell growth, especially dopamine neurons. In addition to the ability to regenerate nerve cells in the brain, GDNF also appears to possess neuroprotective properties.


In an animal experiment in which rats with Parkinson’s disease had GDNF injected directly into the brain, a significant improvement in the symptoms was observed. After one year, there were still no undesirable side effects of GDNF administration.
 Initial studies have shown that GDNF significantly improves the overall condition of Parkinsonian patients. The resulting data suggests that new nerve cells had formed.

Ibogaine and its metabolite noribogaine lead to a substantial increase in GDNF levels in the brain. This indicates that ibogaine could provide a very effective treatment for neurodegenerative diseases, such as Parkinsons.

Until now, it was not possible to introduce GDNF directly into the desired regions of the brain. But Ibogaine stimulates the glial cells and neurons to produce GDNF itself, increasing GDNF levels throughout the brain.

 Phytostan, a pharmaceutical company focused on developing ibogaine, has developed an ibogaine-based medicine called CK-BR 12. This consists of Ibogaine HCL and a cocktail composed of 12 vitamins.

Patient D is a 69-year-old Parkinson’s disease patient and until now the only human treated with Ibogaine for his condition. Patient D reported numerous positive changes regarding his illness: he could swallow again, speech and facial expressions improved noticeably, the control of the hands increased and he could write again legibly. Also, his general motor skills increased.

He could dress again, eat independently and climb stairs – all activities which were not possible prior to his treatment. The Parkinson’s symptomatology also improved after the treatment was completed. Patient D. was examined by various physicians as well as pharmacologist Dr. Susanne Cappendijk from Semper Clarus Consulting, who presented the promising results at the New York Academy of Sciences conference on April 27, 2015.

The standard symptomatic treatment, is predominantly carried out with drugs with strong side effects. The quality of life of the patients is often characterised by significant suffering in the terminal phase. In contrast, treatment with ibogaine, in particular through the approach of microdosing, allows an increase in the GDNF levels in the brain, without the side effects of conventionally used medications.

It was reported that 4mg Ibogaine HCL can increase GDNF levels in the brain by a factor of 12. The neuroplasticity increased by the growth of new neurons promotes the restoration and the construction of nerve tracts. Also, the challenge of introducing GDNF by injection into the brain is obviated. These results could help to redefine the position of Ibogaine in general research and – as ever-unknown healing properties of the plant are discovered – open up new research areas and thereby achieve a wider social and regulatory acceptance.

At the Ibogaine conference in 2016, Dr. Ignacio Carrera from the Universidad de la Republica Uruguay presented the research of an interdisciplinary group. Novel variations of the ibogaine molecular structure have been developed that enhance the production of GDNF. The group of N-indolylethyl isoquinuclidines appears to be most promising. Synthesis of these molecules is far less complex than that of Ibogaine and there are several promising derivatives. Some of the analogues cause an even higher GDNF-release in vitro than Ibogaine does, but can have cytotoxic effects depending on the structure. The research in this field is still nascent, but it has enormous potential.

http://iboga.info/parkinsons-disease/
 
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Still more on ibogaine and Parkinson’s

Parkinson’s Disease is a neurodegenerative disorder characterized by the progressive atrophy of the central and peripheral nervous system. Some evidence suggests that the neurodegeneration in Parkinson’s subjects may be caused by the body’s own immune system losing the ability to determine between healthy and unhealthy cells, as is the case with autoimmune diseases such as Fibromyalgia, Multiple Sclerosis and others, in which much of the body’s organs and cell tissue deteriorate because of misdirected attack by the immune system.

Although the theory is still untested, there is anecdotal evidence and a theoretical framework that suggests ibogaine may have therapeutic benefits in the treatment of Parkinson, and possibly other disorders that cause the degeneration of brain and cell tissues.

The theoretical case is based on the fact that both ibogaine and its metabolite noribogaine have been shown to lead to an increase in levels of glial cell line-derived neurotrophic factor (GDNF) in the brain. It has also been shown to have neuroprotective qualities promoting the survival of both dopaminergic and motor neurons.

In other research, neutrophic factors, specifically GDNF, have been shown to cause sprouting of dopaminergic fibers, with a resulting improvement of clinical symptoms of Parkinson’s in experimental animal models and humans. However, there is little research available using neutrophic factors in the treatment of other neurodegenerative disorders, particularly because administration is usually limited by toxicity or poor bioavailability. Various other methods of administration such as direct brain infusion of GDNF and gene therapy that promotes the expression of neurotrophic factors have been explored.

The direct brain infusion of GDNF into the brains of five rats induced with Parkinson’s disease showed a 39% improvement in 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. After one year, no side effects from the treatment were observed.

In addition to Parkinson’s, one study using gene therapy that promotes the expression of neurotrophic factors, showed a 50% increase in life span, reduced loss of motor axons and improved neuromuscular function in animal models representing Motor Neuron Diseases. The study suggested further research into neurotrophic factor as a treatment for MND.

Parkinson’s has no known cure, and requires management with drugs that have considerable side effects, causing a very poor quality of life for terminal stage sufferers.

Ibogaine therapy, especially low-dose regimens, may facilitate the expression of GDNF without the side effects of other medications or the difficulty of other avenues of administering neurotrophic factor. Anecdotal reports suggest that at least several people with Fibromyalgia, Multiple Sclerosis, and Parkinson’s who have been treated with ibogaine have seen an extended remission of symptoms.

Although there is little clinical research into this particular application, one of the first studies to assess ibogaine efficacy, specifically in the treatment of Parkinson disease in animal models, is currently underway at Columbia University.

https://www.ibogainealliance.org/ibogaine/therapy/parkinsons/
 
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Parkinson's disease dementia

The brain changes caused by Parkinson’s disease begin in a region that plays a key role in movement, leading to early symptoms that include tremors and shakiness, muscle stiffness, a shuffling step, stooped posture, difficulty initiating movement and lack of facial expression. As brain changes caused by Parkinson’s gradually spread, they often begin to affect mental functions, including memory and the ability to pay attention, make sound judgments and plan the steps needed to complete a task.

The key brain changes linked to Parkinson’s disease and Parkinson’s disease dementia are abnormal microscopic deposits composed chiefly of alpha-synuclein, a protein found widely in the brain with a normal function not yet known. The deposits are called “Lewy bodies” after Frederick H. Lewy, M.D., the neurologist who discovered them while working in Dr. Alois Alzheimer’s laboratory during the early 1900s.

Lewy bodies are also found in several other brain disorders, including Lewy body dementia (LBD). Evidence suggests that Lewy body dementia, Parkinson’s disease and Parkinson’s disease dementia may be linked to the same underlying abnormalities in the brain processing of alpha-synuclein. Another complicating factor is that many people with both Lewy body dementia and Parkinson’s disease dementia also have plaques and tangles — hallmark brain changes linked to Alzheimer's disease. Sign up for our e-news to receive updates about Alzheimer’s and dementia care and research.

Prevalence

Parkinson’s disease is a fairly common neurological disorder in older adults, estimated to affect nearly 2 percent of those over age 65. The Parkinson's Foundation estimates that one million Americans have Parkinson’s disease. Recent studies following people with Parkinson’s over the entire course of their illness estimate that 50 to 80 percent of those with the disease may experience dementia.

Causes and risk factors

Certain factors at the time of Parkinson's diagnosis may increase future dementia risk, including older age, greater severity of motor symptoms and having mild cognitive impairment (MCI).

Additional risk factors may include:

- Hallucinations in a person who doesn't yet have other dementia symptoms.
- Excessive daytime sleepiness.
- Parkinson's symptom pattern known as postural instability and gait disturbance (PIGD), which includes "freezing" in mid-step, difficulty initiating movement, shuffling, problems with balance and falling.

Symptoms

Commonly reported symptoms of Parkinson's disease dementia include:

- Changes in memory, concentration and judgment.
- Trouble interpreting visual information.
- Muffled speech.
- Visual hallucinations.
- Delusions, especially paranoid ideas.
- Depression.
- Irritability and anxiety.
- Sleep disturbances, including excessive daytime drowsiness and rapid eye movement (REM) sleep disorder.

Diagnosis

There is no single test — or combination of tests — that conclusively determines that a person has Parkinson’s disease dementia. Guidelines for diagnosing Parkinson’s disease dementia and Lewy body dementia are:

The diagnosis is Parkinson’s disease dementia when a person is originally diagnosed with Parkinson’s disease based on symptoms related to movement and dementia symptoms don’t appear until a year later or more.

The diagnosis is Lewy body dementia when dementia symptoms consistent with Lewy body dementia either develop first; are present along with symptoms related to movement; or appear within one year after movement symptoms.

Outcomes

Because Parkinson’s disease and Parkinson’s disease dementia damage and destroy brain cells, both disorders worsen over time. Their speed of progression can vary widely.

Treatment

There are no treatments to slow or stop the brain cell damage caused by Parkinson’s disease dementia. Current strategies focus on improving symptoms. If your treatment plan includes medications, it’s important to work closely with your physician to identify the drugs that work best for you and the most effective doses.

Cholinesterase inhibitors — drugs that are the current mainstay for treating cognitive changes in Alzheimer's — may help Parkinson's disease dementia symptoms, including visual hallucinations, sleep disturbances and changes in thinking and behavior.

Antipsychotic drugs — a drug category sometimes prescribed for behavioral symptoms of Alzheimer’s — should be used with extreme caution because they may cause serious side effects in up to 50 percent of those with Parkinson’s disease dementia or Lewy body dementia. Side effects may include sudden changes in consciousness, impaired swallowing, acute confusion, episodes of delusions or hallucinations, or appearance or worsening of Parkinson’s symptoms.

Treating movement symptoms in those with Parkinson’s dementia can be challenging, because carbidopa-levodopa — the chief treatment for Parkinson’s movement symptoms — can sometimes aggravate hallucinations and confusion in those with Parkinson’s dementia or Lewy body dementia. Although deep brain stimulation (DBS) is currently contraindicated for Parkinson’s disease dementia, a small clinical trial conducted by University College London scientists and published in the February 2018 issue of JAMA, showed that deep brain stimulation was safe and well-tolerated in participants with Parkinson’s disease dementia.

Depression is common in individuals with Parkinson’s disease dementia and Lewy body dementia, and may be treated with a type of antidepressant called selective serotonin reuptake inhibitors (SSRIs). REM disorder may be treated with clonazepam.

https://www.alz.org/alzheimers-demen...sease-dementia
 
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B. caapi: a forgotten therapy for Parkinson's?

Atbin Djamshidian, Sabine Bernschneider-Reif, Werner Poewe, Andrew Lees

Banisteriopsis caapi is a main ingredient of the famous sacred drink called ‘ayahuasca.’ B. Caapi is one of the natural sources of harmala alkaloids. A summary of early trials with extracts of B. caapi in the 1920s and 1930s on various forms of Parkinsonism is presented here, as well as a brief overview of the known pharmacological properties of harmine. Despite its earlier abandonment because of perceived weaker efficacy than alkaloids like scopolamine and hyoscine, we propose that harmine should be reconsidered as a potential rapidly acting anti-Parkinsonian agent.

Harmine, or methoxyharman, also formerly known as banisterine, telepathine, and yageine, is a beta carboline, which along with harmaline (tetra hydro harmine) was first isolated from the seed pots of the Syrian rue Peganum harmala (P. harmala). Native to North Africa and the Middle East, this drought‐resistant perennial with white flowers and spiky leaves has seeds that fluorescence yellow in water. Incense prepared from its dried capsules has been claimed, in the Koran, to protect against the evil eye. As long ago as 1626, Matthioulos drew attention to its value as a treatment for “melancholy” and it has also been considered to have intoxicant properties. Harmine and harmaline are also found in considerable quantities in the tobacco plant, passion flower and lemon balm plants, and in the wings of several Nymphalid butterflies.




Banisteriopsis caapi (left) and Peganum harmala (right).


On the opposite side of the world, in the jungles of South America, a concoction (yage, ayahuasca, or hoasca) prepared from scrapings of Banisteriopsis caapi (B. caapi) liana mixed with leaves of Psychotropa viridis has been used for centuries by the indigenous tribes of the Amazon as an entheogen. The “vine of the soul” was first identified as a hallucinogen by Richard Spruce during his plant hunting expeditions to South America in 1852, where he observed its use as a potion by the shamans to induce time traveling and clairvoyance.

In 1905, the Colombian naturalist and pharmaceutical chemist, Rafael Zerda Bayon, administered a preparation of “yage” to a soldier far from home who reported visions of his sister's death, which was tragically confirmed by letter to him a few weeks later. Convinced of yage′s mind expanding powers, Zerda Bayon suggested the alternative rubric of “telepathine,” a name that was retained when the active alkaloid was first isolated in 1923 by another Columbian chemist, Guillermo Fischer Cardenas. In 1925, Barriga Villalba, professor of chemistry at the University of Bogota, crystallized some samples of B. caapi and named the active substance “yagine.” In collaboration with Hoffmann‐La Roche (Basel, Switzerland), Elger, and the pharmacist Robinson, isolated the alkaloid and demonstrated that telepathine and yage were both identical to harmine.

Another pharmaceutical company, E. Merck (Darmstadt, Germany), was also interested in the medicinal potential of phantasticants such as mescaline and received a large quantity of yage in 1926 from Colombia. By 1927, they had stockpiled 30 kg of B. caapi extract and 2,000 kg of P. harmala. At that time, it was still thought that these two plants had different pharmacological properties, but in 1928, harmine was shown to be the active alkaloid in both plants.

Eduard Merck asked Louis Lewin (1850–1929), a prominent pharmacologist and medical doctor who worked in Berlin and who devised a systemic classification of psychoactive plants and synthetic drugs based on their pharmacological properties for help to analyze the haramala alkaloids. In view of his previous successful collaboration with the company in relation to mescaline, Lewin was offered a consultancy to further investigate the potential of “the devil's vine” (B. caapi) as a medicine. In 1888, Lewin, who had self‐experimented with mescaline in his private apartment, was unable to publish his findings because of limited supplies and therefore approached Merck for assistance. This collaboration led to several publications, and a variant of the peyote cactus was named Anhalonium lewinii in recognition of his research.

From the samples of B. caapi, Lewin extracted an alkaloid that he named “banisterine,” which he then tested on dogs and monkeys. Lewin also described experiments of the ethnologist, Theodor Koch-Gruenberg, who self‐administered harmine and reported changes of color perception and mild hallucinations, which, however, did not reach the intensity of mescaline intoxication. He ingested banisterine and felt invigorated and had improved and faster motor control, but did not experience the mind altering state that had been reported by the early travelers in the Amazon. Lewin then administered banisterine subcutaneously (SC) to an obese patient who had hemiplegia who reported immediate improvement in her gait. Encouraged by this response, he then gave SC injections of 25 to 70 mg of banisterine to patients with several different neurological diseases in the Neukoelln Hospital, where some of the patients reported euphoria, warmth, and lightness of the limbs in some cases.

Use of Harmine in Parkinsonism

Given his observation that B. caapi can facilitate movement, Lewin speculated that the drug may be efficacious in patients with paralysis agitans and post-encephalitic Parkinsonism. He was nearing retirement and suggested that two younger colleagues from Heidelberg, Karl Wilmans and Kurt Beringer, who had also been supplied with B. caapi samples by Merck should conduct the first empirical trials.

By 1928, Merck reported that P. harmala and B. caapi were chemically identical. Lewin, in contrast to Beringer, was convinced that B. caapi was superior to P. harmala. Shortly before his death in December 1929, Lewin presented 3 patients with post-encephalitic Parkinsonism at the meeting of the Berlin Medical Association, demonstrating a dramatic benefit in neurological handicaps after SC injections of B. caapi. He also regarded banisterine as superior to hyoscine in its ability to alleviate rigor. Given his experiments, he asked for further funding from Merck to import more banisterine from South America, but owing to the recent reports that the alkaloid was not a “rare and extremely precious” commodity, but identical to extracts of the much more common P. harmala, substance funding was denied.

In early 1929, Beringer, whose major research area had been psychosis and mescaline‐induced hallucinations, administered 100 mg of banisterine to a laboratory colleague and noted an “uncontrollable tremor in the arms and legs, similar to what we see in Parkinsonian patients.” He then treated 15 post-encephalitic patients with extracts of P. harmala and noted a dramatic improvement in motor signs in some cases. In one 29-year-old patient with severe post-encephalitic Parkinsonism, a course of P. harmala extract (12 drops three times daily) led to a marked improvement in rigidity and oromandibular dystonia with the patient reporting “Doctor, I am healthy again.” Beringer concluded that the treatment had the potential of alleviating symptoms of akinesia, rigidity, and oculogyric crisis in patients with post-encephalitic Parkinsonism and slowness in paralysis agitans. This therapeutic effect was noted to occur after around 30 minutes, but its effect varied and the benefit could last between several hours and a few days.

Merck dedicated the first 19 pages of their “E. Merck's Jahresbericht ueber Neuerungen auf den Gebieten der Pharmakotherapie und Pharmazie 1928” to harmine and marketed the drug for post-encephalitic Parkinsonism and paralysis agitans in late 1928 in capsules, suppository, and as injectable solution form. Given that extracts of P. harmala were easier and more easily procurable, “Merck's harmine” did not contain extracts of B. caapi. Decourt and Lemaine reported that “Merck's harmine” was mainly effective in young patients with post-encephalitic Parkinsonism without tremor. They also reported that, when taken orally, the drug lost most of its efficacy, whereas Beringer noted good effects when it was administered in keratinized capsules.



Harmine for post-encephalitic Parkinsonism and idiopathic PD was produced by Merck and available as capsules, suppository, and SC injections. Original harmine lyophilized powder and harmine vial for SC injections.


Frank and Schlesinger also stated very good effect in 80% of their patients with post-encephalitic Parkinsonism. Bradykinesia, drooling, hypomimia, gait, and postural stability improved in 10 of 12 patients. Furthermore, mood improved considerably, and in 1 case euphoria ensued (a patient who was unable to move made a handstand in the hospital); in others, pre‐existing anger and aggressive behavior worsened. Tremor was not improved. In their study, Parkinsonian symptoms improved within 15 minutes after SC injections and took approximately 20 minutes when administered orally. The duration of the effect lasted between 3 and 5 hours and 3 and 4 days. Often, motor handicap only lessened after repetitive administration of banisterine, but in some, Parkinsonism improved after the first dose. The average daily dose, which was used for injections, was 20 and 40 mg/day when orally administered. Side effects usually occurred at higher doses (60 mg) and included yawning, nausea, vertigo, headache, agitation, tinnitus, bradycardia, and orthostatic dysregulation.

Schuster treated 18 patients with paralysis agitans and “similar striatal lesions” with SC banisterine, with doses ranging between 20 and 40 mg. After 15 minutes, he noted improvement on rigidity with only minimal side effects, such as nausea and occasional vomiting. Effects were lasting for 2 to 6 hours and in some up to 7 days. However, effects only lasted for a few hours, and therefore Schuster and Lewin tried to extend the effect of banisterine and “Merck's harmine” by constriction of the jugular vein.

A number of other German centers also reported spectacular results with “Merck's harmine.” “Merck's harmine” was used with success in patients with post-encephalitic Parkinsonism, paralysis agitans, and pallidal rigidity, but also in patients with carbon monoxide poisoning as well as in those with arteriosclerotic rigidity.

Ernst Rustige received 27 injections from Merck (3—50 mg) to treat 18 patients and also capsules (3 to 10 mg per day) for 2 patients. He noted a general improvement of motor function with increased speed of movement in 13 patients. In 6 patients rigidity improved, and in 3 of these patients the pronounced rigidity disappeared completely. An objective improvement was observed after 20 to 30 minutes and the effects lasted for a maximum of 1 hour. In 9 patients “Merck's harmine” had a variable effect on tremor with improvement in some, but also worsening in others. Only 4 of the 18 patients did not show any benefit at all from harmine injections. Rustige also injected saline in some patients and reported that only 1 control patient reported improvement, whereas all others reported no effect. However, he also noted that “these patients were pleased, unfortunately overly pleased, with the new agent which would now help them.” They repeatedly showed other patients with pride everything of which they were now capable and were disappointed over the rapid decline of the effect. In 1931, Mueller reported that harmine has been successfully used in all extrapyramidal disorders at Nonne's clinic for the last year and a half. Patients were administered SC injections of harmine in the morning in combination with “Merck's keratinized capsules” at midday for a period of 3 to 4 weeks. They reported that excellent improvement was achieved in 26% of patients and good improvement in 37%.

However, by late 1929, Beringer was already aware of the unrealistic expectations for the drug and emphasized in his presentations that the effects were variable and short lasting and stated that “aroused hopes in the ill could not be fulfilled.” He also warned about the “exaggerated and extravagant reports in the newspapers,” which, in his opinion, were unrealistic and would lead to patient disappointment. Furthermore, the SC administration of “Mercks harmine” or banisterine, which appeared to be the most effective route of administration, was not suitable for all patients. “Meck's harmine suppositories” were found to be efficacious only in a minority of patients. Although Beringer treated some patients with infusions of Peganum extract and noted alleviation of tremor, he suggested that atropine and scopolamine may be more suitable given that their effects were more predictable than harmine. He wrote that: “The brilliant successes are currently a minority and are matched by an equal number of complete treatment failures. In between lie a bulk of cases where only a moderately significant improvement of varying practical and therapeutic degree can be achieved. The reason for this unreliability of the therapeutic effect (…) is unknown as is the mechanism by which the alkaloid acts.”

Given the lack of response of tremor, Jacobi recommended a combination of harmine with scopolamine. Schuster also noted that “Merck's harmine” or banisterine were only effective for a few weeks. Oral administration of harmine seemed to be ineffective, which was considered a severe commercial drawback by Merck. By 1932, Merck's opinion of harmine was far less optimistic. It was stated that “even if the effects of harmine (…) on the symptoms of post-encephalitic Parkinsonism were not sustained, (…) this temporary symptomatic relief, especially on rigidity, often restores inner peace…”

Almost 30 years later, in 1958, the Austrian neurologist, Birkmayer, contacted Merck to reassess the use of harmine for Parkinson's disease (PD). However, his request was rejected, owing to the known lack of oral efficacy recorded in the company's files.

By 1930, it was generally agreed that hypokinesia, drooling, mood, and sometimes rigidity improved with banisterine and parenteral “Merck's harmine,” but that rest tremor sometimes worsened.

Around that time, a German physician, Dr. Halpern, involved himself in self‐experimentation and noted a sensation of lightness in his body with increased aggression. After he took 40 mg of harmine by mouth, he reported that “When lying on a sofa, the lightheadedness increased to a feeling of floating sensation and the weight of the body was subjectively less. These clinical observations should be compared to the state of levitation frequently reported to occur with the crude drug ayahuasca or caapi … … the author who is normally not belligerent started a fight with a man in the street, where he was the one who attacked, even though according to the circumstances the prospect for the attacker was unfavourable.”

Gausebeck compared the effect of harmine with scopolamine in 9 patients with post-encepahlitic Parkinsonism and 1 patient with paralysis agitans. In 9 of 10 cases, scopolamine therapy was superior irrespective of whether a higher or lower dose (20 vs. 40 mg) of harmine was used. The researcher concluded that the effects observed with harmine injections were short lasting and mild to modest. Furthermore, the oral administration of harmine in combination with scopolamine was not significantly better than scopolamine alone. Dermitzel reported, in 1930, that after 0.2 g of intramuscular injection of harmine, severe intoxication with body cramps, tremor, delirium, and faintness occurred.

In Great Britain, Hill and Worster-Drought treated 38 patients with post-encephalitic Parkinsonism with “Merck's harmine.” The group contained 16 patients with severe, 13 with moderately severe, and 9 with mild signs of Parkinsonism, who were all already receiving treatment with SC hyoscine. After hyoscine withdrawal, 19 patients received harmine orally and 19 SC, but none of the patients improved. In fact, all but 1 reported worsening of symptoms, which only improved after hyoscine was restarted. They concluded that, “Harmine in doses up to 0.04g given hypodermically has no perceptible objective or subjective effect in ameliorating any of the symptoms presented in the Parkinsonian syndrome and is of no value in the treatment of this condition.” They also suggested that the benefits reported by Rustige et al. were likely to have occurred as a result of suggestion rather than any pharmacological effects of the drug. They could also not replicate the experience of Wilmans and Beringer that the effects of harmine increased with length of treatment. However, they failed to take into account the possibility that abrupt discontinuation of hyoscine could cause severe deterioration of motor handicap in Parkinsonism and could have masked any potential benefits of harmine.

Gunn, a British pharmacologist working in Oxford who had published preliminary positive results with “Merck's harmine,” concluded, in 1931, that it was weakly efficacious and inferior to hyoscine.

What 5 years earlier had been heralded as a miracle cure in “Der Kompass” on 1 March 1929 was now being used less and less and usually in combination with atropine or scopolamine. Von Witzleben, who also used the drug, reported that the high hopes for harmine had not been fulfilled. Interestingly, however, on 15 April 1945, Morell asked Stumpfegger to treat Hitler with “Merck's harmine” SC in combination with anti-cholinergic drops.

The advent of synthetic drugs with pharmacological effects similar to the solanaceous alkaloids finally led to the total abandonment of harmine even in Germany.

More recently, a few patients with PD reported improvement of Parkinsonism after the use of ayahuasca (a concoction including B. caapi and other plants, some of which contain dimethyltryptamine). Based on the assumption that the beneficial effects were likely to be owing to B. caapi, a double-blind, controlled study was carried out in PD. In this study, 30 drug‐naive, de novo PD patients were enrolled and 15 were given 200 mL of B. caapi extract, whereas the other half were given 200 mL of placebo matched for taste and color. Side effects were reported in all patients receiving B. caapi and included diarrhea, nausea, and in 1 patient transient visual hallucinations. The Unified Parkinson's Disease Rating Scale (UPDRS) part III motor scores improved significantly in the active group. Baseline UPDRS scores dropped from 54 to 41 after 60 minutes, 22 after 120 minutes, and 25 after 4 hours. However, in all patients, tremor at rest, as well as on action and on posture, worsened. The marked improvement observed in this study is perhaps surprising given that earlier studies reported only mild-to-moderate effect of harmine after oral indigestion. It is, however, impossible to compare the patient groups treated in the 1930s, who used “Merck's harmine,” to the study in patients with PD from 2001. “Merck's harmine” contained purified harmine as SC injections whereas the study by Serrano et al. used herbal extracts, which may also contain other active alkaloids.

Pharmacology of Harmine

Harmine, harmaline and norharmine are found in P. harmala and B. caapi and are beta carboline alkaloids. Though harmaline is almost exclusively found in P. harmala seeds, harmine can be extracted from both the seeds and roots. The pharmacological effects of harmine have been attributed mainly to its central monoamine oxidase (MAO) inhibitory properties, but in vivo and rodent studies have shown that extracts of B. caapi and also P. harmala lead to striatal dopamine release.

Harmine is also a N-methyl‐d‐aspartate (NMDA) receptor antagonist. Some researchers speculated that the rapid improvement observed in PD patients might be owing to these antiglutamatergic effects.

Rodent studies have shown that harmine can also reduce cerebral infarct volume and neuronal cell death owing to upregulation of glutamate transporter 1, which attenuates excessive and neurotoxic glutamate levels, leading to speculation that harmine might also possess neuroprotective properties. Harmine is a selective inhibitor of the DYRK1A protein kinase, a molecule necessary for neurodevelopment, and has been shown to support survival of dopaminergic neurons in MPTP-treated mice.

Use of MAO Inhibitors in PD

In 1958, Udenfriend et al. demonstrated that harmine was a nonselective MAO inhibitor. In 1968, two subtypes of MAO inhibition type A and B were identified. MAO-A inhibition has been shown to significantly shorten latency to onset and increase the duration of motor responses after a single dose of levodopa. Furthermore, and in contrast to MAO-B inhibition, MAO‐A is also present within presynaptic dopaminergic terminals. In 1964, harmine was shown to antagonize reserpine-induced Parkinsonism.

Nonselective monoamine inhibitors were reported to have antiparkinsonian effects in the early 1960s and to markedly enhance the therapeutic effects of low doses of l‐dopa. Subsequent research, however, confirmed that they could not be used safely with l‐dopa because of potentially dangerous hypertensive effects. The so‐called “cheese effect,” an increase of blood pressure after consumption of tyramine‐containing foods, was also observed in patients treated with clorgyline, a unselective and irreversible MAO type A inhibitor. Moclobemide is a reversible type A inhibitor that is free of cheese effects and has been reported in studies to have mild anti-parkinsonian effects. Although moclobemide can also alleviate depression in PD, the effects of MAO‐A inhibitors have not been well studied. Caution is required when moclobene is combined with antidepressants given that it may cause serotonin syndrome, which would likely be a limitation of harmine in modern clinical practice.

In contrast, type B MAO inhibitors have been extensively investigated. In the mid-1970s, it was shown that selegiline could modestly prolong the motor response of l‐dopa, have weak anti-parkinsonian effects when used as monotherapy, and can be used safely with l‐dopa without dietaryl tyramine. Interestingly, however, studies have shown that selegiline is not a selective MAO-type B inhibitor, but acts at higher doses also as an MAO‐A inhibitor.

In relation to the responses reported with harmine, it is also of interest that the data sheet for selegiline states that doses beyond 10 mg can worsen tremor. Many opinion leaders have also observed that both selegiline and the more recently marketed type B MAO inhibitor, rasagiline, can spectacularly improve some patients for many months, whereas other patients do not respond at all or notice worsening of tremor similar to the original observations with harmine.

Harmine and Tremor

Harmine triggers an 8- to 14-Hz acute, but temporary, postural and action tremor in rodents, cats, and monkeys. Whole‐body tremor is dose dependent and develops within minutes after an SC injection and can last up to several hours. In healthy volunteers, high doses of B. caapi can induce a transient coarse tremor. Acute harmine intoxication leads to tremor, hyper-salivation, agitation, and subsequently to paralysis, tonic clonic seizures, and eventually to death, whereas repeated daily administration of higher harmaline doses result in tolerance and a progessive diminution of tremor.

The tremor induced by harmine is believed to be a result of activation of the medial and dorsal accessory inferior olivary nuclei and the cerebellum. High doses of harmine can cause Purkinje cell loss in rodents. There are several similarities in phenomenology of harmine‐induced tremor and essential tremor (ET). For example, citalopram, imipramine, and caffeine worsen both harmaline and ET. Approximately half of the drugs that suppress harmine‐induced tremor also supress ET. Alcohol, primidone, and β-blockers can suppress harmaline‐induced tremor, but may exacerbate neural damage. Although slowness of movements has been observed in harmine-treated rodents, it is likely that this phenomenon is secondary to tremor and does not reflect true bradykinesia. Finally, elevated harmane levels, of which harmine is one of its metabolites, has been found in patients with ET. Although the exact putative mechanisms of harmane elevation is unclear, it may involve genetic susceptibility of patients, increased dietary intake, or a combination of both.

Harmine and Depression

Harmine interacts with serotonin receptor 2A and has been shown to have antidepressant‐like effects in rodent models. Acute and chronic doses of harmine increased swimming and climbing time and reduced immobility time in a forced swimming test in rats. Furthermore, harmine increases brain‐derived neurotrophic factor (BDNF) in rat hippocampus. In humans, decreased BDNF levels have been associated with major depression. Furthermore, MAO‐A inhibitors reduce the breakdown of serotonin and noradrenaline and are used to treat depression.

Despite the considerable evidence for antidepressant effects in animal models, harmine was never used as an antidepressant in humans. It was, however, already mentioned, in 1930, that it may be useful in patients with catatonic schizophrenia and has recently been proposed again as a potential treatment option for psychosis.

Discarded Therapies

Many of the treatments and nostrums used to treat PD in the late 19th century and early 20th century have now been discarded on the grounds of lack of proven efficacy. These include calabar beans, Bulgarian belladonna extract, monkey glands, and parathyroid extract. Anticholinergic drugs despite the lack of modern trial evidence were, on the other hand, judged to be efficacious. Others, such as Indian hemp, opium, and amphetamines, although no longer used now, have known pharmacological actions that would make them putative candidates for further trials.

A salutary example of a drug that was forgotten to the detriment of many patients with PD is apomorphine.

In 1951, apomorphine was shown to improve decerebrate rigidity and on empirical grounds was used by Schwab et al. to treat PD patients.49 However, the beneficial effects were noted to be brief, and side effects such as nausea and vomiting were frequently observed. Oral doses of apomorphine were unsuccessful because of rapid first‐pass metabolism. The fact that apomorphine was a potent dopamine receptor agonist and that striatal dopamine deficiency occurred in PD had not yet been discovered, but even in 1978, when these facts were long established, it was stated that, “unfortunately, apomorphine is of no practical use in the treatment of Parkinson's disease because its beneficial effect is of short duration (about 1 hour) and accompanied by side effects….”

In the 1980s, the development of ambulatory pump delivery systems and the marketing of domperidone, a peripheral dopamine antagonist, led to a re-investigation of apomorphine with gratifying results. SC waking-day apomorphine is now an established therapy for refractory motor fluctuations, with efficacy comparable to that observed with l-dopa.

The first human studies with l-dopa, the gold‐standard therapy in PD, also reported conflicting results. In 1960, Sano reported the effect of l‐dopa in PD patients. He administered 200 mg of l‐dopa intravenously and observed a marked reduction of rigidity and tremor 15 to 30 minutes after injection. However, he noted that “the effects were transient and the patients returned to their pre‐treatment status within a few minutes.” Therefore, he concluded that “that treatment with dopa had no practical therapeutic value.” Furthermore, McGeer, in 1964, reported that "only 2 of 10 patients improved after receiving l‐dopa therapy" and concluded “that dopa has little to offer as a therapeutic agent in the treatment of Parkinsonism.”

Conclusions

Harmine has an interesting pharmacological profile with selective MAO type A inhibition, serotonin affinity, NMDA receptor antagonism, and possible antioxidative, as well as neuroprotective, properties and may also cause direct striatal dopamine release.

The view that only selective type B MAO inhibitors are likely to be efficacious in PD is not backed up by the available data. If confirmed, harmine's fast mode of action could be a valuable expansion to currently available therapy in PD. Though it seems improbable that harmine is a potent anti-parkinsonian agent, it could be as efficacious as the commerically available selective type B MAO inhibitors. Furthermore, based on the historical trials and recent preclincal and clinical studies, safinamide, a synthetic molecule that has been granted a license for PD recently, has a pharmacological profile that resembles B. caapi with the exception that it is considered to be a MAO type B inhibitor. Banisteriopsis caapi extracts may be superior to extracts of P. harmala and are worthy of further controlled trials.

https://onlinelibrary.wiley.com/doi/full/10.1002/mdc3.12242
 
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Discovery of hidden brain region could CURE Parkinson's, expert claims

by Tom Fish | Nov 30, 2018

A HITHERTO hidden part of the human brain has been discovered, fueling hopes a cure for disorders affecting motor skills like Parkinson’s disease can be found.

Advances in new imaging technology is allowing the human brain to be studied ever-greater detail. So much so that researchers can now view the brain in situ – in living, conscious people – as opposed to studying it post-mortem. This cutting-edge imaging technology has helped world-renowned brain cartographer Professor George Paxinos to identify a new part of the human brain – the Endorestiform Nucleus – a find he compared to discovering a new star.

Professor Paxinos, of Neuroscience Research Australia, reveals exclusively to Express.co.uk what makes the Endorestiform Nucleus so special. “There are very few differences in the brain between monkeys and humans – even in the cortex of the brain, which is the most recent in evolution," he said.

“And if you find something in the monkey, it is almost 100 percent certain you will find it in the human brain. But not in this case, so there are some differences between them, besides their size."

“This region could be what makes humans unique besides our larger brain size. I have a hard time imagining a monkey or chimpanzee playing the guitar as dextrously as the Rolling Stones."


Although the role of the Endorestiform Nucleus remains a mystery, Professor Paxinos is able to make an “educated guess” about the 2mm wide area’s role.

He said: “Given that it is in the middle of the river of information bringing data from the spinal chord to the cerebellum, it is possibly involved in fine motor control. The spinal chord informs the cerebellum of the limbs’ position and what pressure is being experienced.“But this is only a guess according to its position.”

The discovery of the Endorestiform Nucleus could help in the search for cures for diseases including Parkinson's disease and motor neurone disease.

Affecting one in 500 people, Parkinson’s disease causes muscle stiffness, tremors, chronic fatigue and an overall impaired quality of life.

While motor neurone disease is when specialist nerve cells in the brain and spinal cord called motor neurones stop working.

Neuroscientists researching neurological or psychiatric diseases already use Professor Paxinos' maps to guide their work.

The maps chart the course for neurosurgery and neuroscience research, enabling exploration and the development of treatments for disorders of the brain.

The maps are created using a technique called “staining” – a way of “painting” the brain to clearly visualise the cellular, structural, and molecular components of the organ.

Professor Paxinos' brain atlases have been heralded as the most accurate for the identification of brain structures and are also used in neurosurgery.

An increasingly detailed understanding of the architecture and connectivity of the nervous system has been central to most major discoveries in neuroscience in the past 100 years.

But Professor Paxinos – the author of the most cited publication in neuroscience and another 52 books of highly detailed maps of the brain – is not confident that a cure for motor neuron diseases will be discovered any time soon.

“We have to be pragmatic about what has happened so far in neuroscience," he said. “This finding is one of the many pieces of the puzzle that will have to be connected to make any progress," he said. “But keep in mind that neuroscience has so far not cured any disease.”

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

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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Can cannabis prevent Dyskinesia in long-term treatment of Parkinson’s Disease?

Psychedelic Times | Feb 24, 2017

In 1970, Oliver Sacks wrote five letters to various medical journals in the U.S. expressing his concern about the prescription drug levodopa, which had been developed just a year earlier. As a practicing neurologist, he had used levodopa (L-Dopa) to treat Parkinson’s and encephalitis lethargica (or “sleepy-sickness”) in his patients—both neurological disorders that arise from a deficiency of dopamine—and found it to have serious adverse effects. As he described in his 1985 book The Man Who Mistook His Wife for a Hat, treating people with sleepy-sickness with L-Dopa resulted in an over-correction of motor function: “First they were ‘awakened’ from stupor to health: then they were driven towards the other pole—of tics and frenzy.”

This phenomenon would come to be known as levodopa-induced dyskinesia—an increase in involuntary muscle movements or spasms that results from too much dopamine flooding your brain. It’s one of the most common side effects of conventional treatment of Parkinson’s Disease (PD) and one of the most devastating: some PD patients describe their dyskinesia as worse than the disease itself, causing many to decrease or put off treatment altogether to stave off the inevitable side effects.

The search for a better treatment has pointed more and more researchers toward cannabis because it naturally targets multiple points in the endocannabinoid system, the brain’s neurological center for motor function, mood, and pleasure. Marijuana has been shown to have impressive results in the short term treatment of PD symptoms, like tremors and rigidity, and it also has supplemental therapeutic effects—like easing depression and improving sleep. But perhaps most importantly, cannabis has shown promising results in preventing dyskinesia.

What Is Levodopa-Induced Dyskinesia?

Because Parkinson’s is classically defined as a dopamine deficiency—caused by the death of dopamine-producing cells in a part of the brain called the substantia nigra—it’s most commonly treated with a dopamine precursor like levodopa, which then converts to dopamine in the brain. The effects from initial doses of levodopa are quite immediate—people’s motor functions are restored almost miraculously in some cases—but experience shows that long-term dopamine-based treatment can actually cause an increase in dyskinesia.

The problem arises from dopamine’s role as a neurotransmitter and the tricky balance of the neurons in your brain. In a healthy brain, dopamine transmits signals between brain cells about motor function, mood, and behavior, among other things. But in the Parkinsonian brain, low levels of dopamine mean two parts of the brain related to motor function—the endocannabinoid system and basal signia—are not signaling correctly. This is what causes the most well-known symptoms of Parkinson’s: body rigidity, tremors, and involuntary muscle contractions.

Supplementing dopamine with a drug like levodopa attempts to restore the neurological balance, but history shows the solution isn’t perfect because long-term treatment often results in dopamine hyperactivity, which manifests as dyskinesia. This most often affects younger people with PD, which is particularly disconcerting because they have longer to live with the disease and the side effects of treatment.

Cannabinoids and Parkinson’s Disease

Almost fifty years after Sacks wrote his letters of warning, levodopa is still the most commonly prescribed treatment for Parkinson’s Disease, but the medical community is calling for a more sophisticated medicine that mirrors the function of the lost dopamine cells in the brain. And that leads us to cannabis.

Cannabis has shown tremendous promise in treating PD, both in the laboratory and in practice. A 2004 survey of 339 PD patients showed that smoking cannabis significantly improved symptoms in 46% of participants, including reduced tremors, rigidity, bradykinesia, and dyskinesia. Cannabis has also shown to decrease dystonia, another type of repetitive or twisting movement caused by involuntary muscle contractions.

A look into the relationship between cannabinoids and motor functions show why marijuana is an ideal target for the treatment of motor disorders:

Cannabis activates the endocannabinoid system, which affects motor function, mood, and pleasure. With 113 cannabinoids and counting, cannabis activates parts of the brain that dopamine treatment alone does not. In particular, cannabis activates CB1 receptors in high concentrations in three parts of the brain associated with dyskinesia and Parkinson’s: the globus pallidus, basal ganglia, and substantia nigra. This is important because, as studies have shown, activation of CB1 receptors—which comes from ingesting the marijuana cannabinoid THC—offers neuroprotection and prevents the development of dyskinesia in mice.

Cannabis increases more than just dopamine—it affects other neurotransmitters, too. Historically, Parkinson’s has been understood as a simple case of dopamine deficiency, but recent research from Harvard University suggests that dopamine neurons also transmit GABA, a neurotransmitter that dampens the effect of dopamine. This means that when neurons die in the course of the disease, there would also be a GABA deficiency. Because GABA plays an important role in dampening the effect of dopamine by inhibiting the electrical activity of cells, its decrease in PD would help explain why isolated dopamine treatment sometimes results in dyskinesia.

Conversely, it makes sense then, that a treatment that also increases GABA would inhibit dopamine hyperactivity and so dampen the extreme effects of dyskinesia. The research on cannabis in that area is promising: one study on the synthetic cannabinoid nabilone showed that it decreased the incidence of levodopa-induced dyskinesia, noting that the cannabinoids “enhance GABA transmission and may thus alleviate dyskinesia.” The study went on to suggest that this might be because cannabinoids interact with the globus pallidus, which is thought to be overactive in cases of dyskinesia.

Cannabis treats other common symptoms of Parkinson’s. There are other benefits to cannabinoids in addition to their effect on motor dysfunction. Thanks to their anti-oxidative and anti-inflammatory effects, cannabinoids are also neuroprotective, meaning they help protect against further degeneration of precious neurons. Cannabinoids have also been shown to relieve pain, have antidepressant effects, and improve sleep—all problems PD patients commonly face.

The Trick of Treating Neurological Diseases

In the end, Parkinson’s cannot be summed up simply as a deficiency of dopamine, and Oliver Sacks would agree. “There are also much subtler and more widespread changes,” he concluded in his book. “There are countless subtle paths of abnormality which differ from patient to patient, and from day to day in any one patient.”

That’s to say, neurological diseases are notoriously tricky beasts, with varying symptoms from day to day—what works for one person may not for another. There probably will never be a one-size-fits-all solution for Parkinson’s Disease, but diversifying our arsenal of medicines and continuing studies on medical marijuana can only lead to better long-term treatment without debilitating side effects. With further research and continuing legalization measures, cannabis could become the long-term dyskinesia treatment so many PD patients are looking for.

https://psychedelictimes.com/2017/02/24/can-cannabis-prevent-dyskinesia-in-long-term-treatment-of-parkinsons-disease/
 
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