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Posted On: 02/08/2021 8:48:32 PM
Post# of 69
Reddit DD Post - r/MindMedInvestorsClub
Posted by u/OldApp
[flair]Psychedelic Advocate
Mind Medicine: Pipeline, Trials, and Science
[flair]Due Diligence
Hey!
With so many new investors and people joining this community, I thought it would be a good idea to give an overview of the company’s current pipeline. Science is the substance of the company, so hopefully, this gives prospective/current investors an avenue for beginning to understand a lot of the treatments being developed.
I am not a professional scientist, so if I screw anything up here please comment and I’ll correct it. Otherwise, all studies will be sourced so if you would like to read more about them just smack that hyperlink. I pull from external sources as well to use as supporting evidence for these therapies. Will go over some question marks and concerns as well so that this isn’t just a bull thesis, but a fair overview of current lit. Feel free to DM me if you want to chat about this stuff or if you have anything you think should be added to this! Science is evolving so it’s best if we stay on top of it.
Sections in Order:
LSD Neutralizer
Cluster Headaches
LSD for Adult ADHD/ADD
LSD for Anxiety
18-MC for Addiction
LSD Neutralizer
As I’m sure a lot of you know, LSD trips last a while. When we are looking at LSD as a compound to be used in assisted therapies, that trip duration brings up some major question marks.
Assisted therapies require trained professionals to guide the sessions. Therapy sessions aren’t cheap; the cost of therapy alone is a major barrier for many people seeking out mental health support. Couple the cost of the compounds and the specialization required for extended psychedelic-assisted psychotherapy sessions and you have a recipe for some potentially pricey treatments.
LSD is not toxic to the human body. You don’t see the same type of physiological or neurotoxic potential that traditional drugs have. However, that does not mean we’re home free here. It’s important to recognize that LSD does have some potential health harms that we should all be aware of. Improper use can lead to potential physical harm. Bad trips can lead to emotional distress. If you don’t screen for underlying psychological conditions like psychosis and schizophrenia some people can experience serious cognitive harms.
This neutralizer technology is purported to act as an off switch for LSD trips. Quick pill and a little while later the trip is over. This funky little compound is called Ketanserin and it’s a major part of dealing with the two issues I mentioned above. If you’re able to control and attenuate the trip, you’re able to reduce the time needed to conduct the therapy session. This can reduce costs related to therapy making it more affordable for a greater number of people. In theory, it could also allow people to take higher single doses, should the therapy demand it, and have the effects neutralized when needed.
Now onto the harms… Luckily for all of us, the harms mentioned above can be managed/mitigated. Proper psychological screening can work out issues related to underlying conditions. Managing set and setting helps reduce the potential for harms related to improper use like stupid behavior and bad trips. This LSD neutralizer is just another great tool in the therapist's tool belt that can be used to mitigate harm during therapy. Being able to stop the experience allows for a failsafe on the therapy sessions which ensures that no one comes out of it worse than they went in. As an add-value, this compound could be sold to recreational users (in theory) to ensure safe at-home use and could also be used in ER departments where occasionally, I'm sure some people come in experiencing bad trips.
Cool beans, so how does it work? Well, let me use a quick analogy to get the ball rolling.
We are all aware of opioids and how people can easily overdose on them. Guaranteed many of you have also heard of Naloxone, the antidote for an opioid overdose. Think of Kertanserin as you would think of Naloxone.
Naloxone and Kertanserin are both antagonists that act against the effects of their respective counterparts. Opioids produce their effects by interacting with the four opioid receptors we all have in our brains. Naloxone is an opioid antagonist that works by binding to those receptors and knocking the opioids off of the receptors for a duration of time; allowing for people to seek the additional help that they need. Source here (If you’re in Canada, go to the pharmacy and get a free Naloxone kit.. you could save a life)
This brings us to Kertanserin and LSD. The psychedelic effects of LSD have been theorized to produce their effects through partial serotonin 5-HT2A receptor agonism. (Agonism being the opposite of Antagonism) Kertanserin works as an antagonist to the same receptor, allowing for the effects of LSD to be attenuated. Here is a study that substantiates the claim that Kertanserin fully blocks the subjective effects of LSD. Here is another one
Here's a link to the current trail that MMED is doing on this very subject in case any of you were hoping to follow it, or maybe even apply to be a part of it?
Questions:
Can it work on other psychedelics? If so which? In theory, it should be effective for Psilocybin as well given it's similar mechanism of action.
Are there any negative side effects of note related to its serotonin receptor antagonism?
Cluster Headaches
Yeah, you get headaches, but do you get cluster headaches? I sure hope not. If you do, oh boy does MMED have the treatment for you. Cluster headaches multiple short, debilitating headaches that can occur repeatedly for expended durations of time. Cluster headaches can go away for a while and then spring back up on you years later. They don’t affect many people (~0.1%) and there isn’t a lot of information out there on what causes them. Regardless, they are painful and people shouldn’t have to deal with it if they don’t have to.
Traditional treatments for cluster headaches include oxygen and sumatriptan for single attacks; and verapamil, lithium, corticosteroids, and more for cluster attack periods. However, anecdotal evidence has suggested that LSD and Psilocybin are both more effective in dealing with individual attacks and attack periods.
One study using a non-hallucinogenic analog of LSD, 2-Bromo-LSD (BOL), found that three single doses of BOL can either break a series of cluster headache attacks or reduce their frequency and intensity. Furthermore, for some, BOL allowed them to achieve remission from their previous chronic cluster headaches. No adverse outcomes were observed in the study. The interesting thing about this study is that the researchers hypothesize that the mechanism of action is unrelated to the serotonin receptor agonism that scientists are theorizing is responsible for hallucinations. This means that it isn’t so much about the hallucinations, but something else that these beautiful compounds have in store. They theorize that the positive effects are the result of serotonin-receptor-mediated vasoconstriction.
A very recent 2020 study backs this up when evaluating the migraine suppressing effects of Psilocybin. The study found that ONE SMALL SINGLE DOSE of shroomies magic chemical, psilocybin, was far more effective than traditional treatments in dealing with migraines. Furthermore, the suppressing effects of the psilocybin on migraines were sustained over two weeks. Again, this study backs up the previous claim that the effects are independent of the hallucinogenic properties of the drugs.
The current phase 2 study going on at UHB in Switzerland can be found here!
Some questions:
Are the effects sustainable over the long-term through many doses?
What exactly is the mechanism of action?
Since the hallucinations aren’t needed, will the focus be on creating non-hallucinogenic analogs? If so, who has the IP on these babies?
LSD – For Adult ADHD
This one is close to my heart. I am a 23-year-old student and I suffer from adult ADHD. I’ve been on Vyvanse for several years and it sucks sometimes. Additionally, it doesn’t appear to be the safest drug in terms of cardiovascular health. Over the past few years, I’ve experimented with micro-dosing LSD in an attempt to experiment with my ADHD. While my supplies have never lasted long enough to do any extended evaluation of its efficacy, there were significant improvements in focus, mood, energy, empathy, and overall just a better day-to-day mental condition. Starting this week I am going to try a psilocybin micro-dosing regime to see how it compares. Not encouraging anything here, just thought I would share my anecdote since the majority of this section is based on anecdotal evidence.
Stimulants suck for a lot of people. They often kill your sex drive, they make you irritable, and they sometimes make you lose weight among many other things. Having a viable alternative is something many of us have dreamed of for a long while. I guarantee you’ve all heard the stories of Silicon Valley execs micro-dosing LSD to improve their productivity and creativity. Well, it looks like our ex-silicon valley CEO now wants to lay down some hard science on this practice.
So what does the anecdotal evidence say?
Study 1:
General effects have been described as “a really good day”.
80% of people surveyed reported a positive or neutral experience.
The most common reason for stopping the micro-dosing regime was that people felt the practice was ineffectual.
Many patients reported positive impacts on depression and anxiety.
Some patients felt that micro-dosing long-term exacerbated their mental health issues.*
69% person of surveyed college students who micro-dosed reported at least one negative side effects from the practice. The most common negative side effect was hallucinations (44.2%). (Maybe from inaccurate dosages?)
One other very common concern was the legality of the practice. (Gotta hate those stupid laws)
Multiple studies reported that people consistently felt great improvements in creativity.
Study 2:
Many patients reported that they wanted to microdose for their diagnosed ADHD/self-diagnosed attention issues.
Most surveyed reported productivity increases and that they procrastinated less.*
This study proposes that despite LSD and Psilocybin acting on different neuroreceptors than traditional stimulants, that their effects could be positives because they are still stimulating drugs.*
A substantial amount those surveyed reported substituting micro-dosing for their stimulants.
Participants reported improvements in home life including a more giving, patient, and open attitude with family members.
Study 3:
The most prevalent mental disorder diagnoses in this study were depressive disorders, anxiety disorders, and ADHD/ADD.
Microdosing was rated more effective than traditional treatment options for ADHD/ADD.
The study theorized that micro-dosing is often preferred because it doesn’t come with as many negative side effects.
Specifically for ADHD, micro-dosing did not come with the same crash that stimulants did.
An additional advantage was that there was not a need to microdose daily. Rather the psychedelic doses were taken every few days (usually).
Study 4:
The most commonly reported effects of micro-dosing were improved mood and creativity.
A previous study found that participants performed significantly better on a divergent creativity task following a small dose of psilocybin.
A 2019 study found that the acute effects of a microdose of LSD were an increased feeling of vigor, friendliness, energy, and social benefit.
The most commonly reported challenge related to micro-dosing was reported to be “none” (lol)
Some challenges include impaired focus and physiological discomfort. These may be once again due to improper/high dosages.
Lack of precision in terms of the compound you are purchasing can also contribute to negative effects.
If you are wondering about the theorized mechanisms of actions and stuff I would recommend you check out this study. There is a lot to it, but you can sift through the section titles quickly. I would recommend reading Question 5, 6, 7, and 8. (Page 1043-1046)
Ultimately there isn’t much clinical evidence to back this one up. I’m glad MMED is taking the steps needed to address this gap in the literature. It will for sure be one that I am paying attention to. Consistent themes in the studies included some negative effects related to dosage. I think that a clinically dosed regime would resolve a lot of these issues especially if a determined dosage scale based on body weight, metabolism, and other factors was developed. However, one major concern I have is that there is anecdotal evidence of microdosing exacerabting underlying mental health issues.
Questions:
What are the long-term health harms that could occur from micro-dosing? Psychedelic use has been previously related to increases in neuroticism and the exacerbation of underlying cognitive predispositions; is this a consideration?
What is the ideal dose?
What is the ideal dose regime?
What conditions is it NOT effective for?
Can it be paired with stimulants or should it be substituted?
LSD – For Anxiety
A lot of the current focus in terms of LSD and anxiety has been its use in palliative care. People who are faced with some pretty scary diseases have reported some great improvements in their condition after psychedelic experiences. Anxiety is a very very broad category of diagnosis. I won’t be able to cover them all here but I will list the 12 broad diagnosis possibilities the DSM-V gives us. The ones I focused my research on are bold.
Separation Anxiety Disorder
Selective Mutism
Specific Phobia
Social Anxiety Disorder
Panic Attack
Agoraphobia
Generalized Anxiety Disorder
Substance/Medication-Induced Anxiety Disorder
Anxiety Disorder Due to Another Medical Condition
Other Specified Anxiety Disorder
Unspecified Anxiety Disorder
Study 1: LSD-Assisted Psychotherapy for Anxiety Associated with a Life-Threatening Disease
This study interviewed 10 participants who had undergone LSD-assisted psychotherapy to assist in dealing with their palliative-related anxiety. After 12 months the patients were interviewed and none of them reported any lasting adverse reactions or effects. 77.8% of patients reported a reduction in anxiety and 66.7% reported a rise in quality of life.
If you’re interested in reading about the first-hand accounts I would recommend reading more into this particular quallatative study. Some of the effects and stories are very profound.
Study 2: Modern Clinical Research on LSD (Very Comprehensive)
Mechanism of Action: (For the Science People)
LSD potently binds to serotonin 5-HT receptors (1a, 2a, 2c), dopamine d2 receptor, and a2 adrenergic receptor.
The hallucinogenic effects are mediated by the drugs affinity for 5-HT2A receptors. This has been proven due to the ability to block these subjective effects using an antagonist (See the LSD Neutralizer).
The full scope of the mechanisms of actions has not been fully identified. However, one key mechanism is the activation of frontal cortex glutamate transmission.
LSD binds more potently to 5-HT2A receptors than does psilocybin.
Unlike other serotonergic hallucinogens, LSD binds to adrenergic and dopaminergic receptors. In humans, LSD may enhance dopamine neurotransmission. (COOL)
LSD increases functional connectivity between various brain regions. (COOL)
Functional brain imaging showed more globally synchronized activity within the brain and a reduction of network separation while under the pharmacological effects of LSD.
LSD decreased default mode network integrity.
LSD reduced left amygdala reactivity to the presentation of fearful faces. (COOL)
Adverse Effects:
Moderate increases in blood pressure, heart rate, body temperature, and pupil side.
Adverse effects 10-24 hours after administration include difficult concentration, headaches, dizziness, lack of appetite, dry mouth, nausea, imbalance, and exhaustion.
No severe side effects have been found and it is physically non-toxic.
Hallucinogen Persisting Perception Disorder (HPPD) is a rare disorder stemming from psychedelic use. Occurs almost exclusively in illicit use or patients with underlying cognitive predispositions like anxiety. (Uh oh)
Effects on Patients:
Profound anxiety or panic was not experienced by patients of one study.
LSD mainly induced blissful states, audiovisual synesthesia, changes in the meaning of perceptions, and positively experiences derealization and depersonalization.
At 200 micrograms, LSD acutely induced mystical experiences in patients undergoing psychotherapy. This is important because previous studies with psilocybin have shown that mystical experiences are correlated with improvements in mood and personality and better therapeutic outcomes in patients with anxiety, depression, and substance use disorders.
Music has been used to produce greater feelings of transcendence and wonder in patients.
LSD impaired the recognition of sad and fearful faces and enhanced emotional empathy.
LSD produced moderate ego dissolution.
LSD produced lower fear perception which may be useful in psychotherapy.
Mid/Long Term Effects:
The use of classical psychedelics is associated with lower psychological distress, lower suicidality, and lower mental health problems.
LSD in healthy subjects increase optimism and trait openness 2 weeks after administration and produced trends towards decreases in distress and delusional thinking.
Study 3:
In all considered studies psilocybin has been found to be a viable treatment for patients with anxiety. The decreases in anxious symptoms lasted for at least three months in all studies and lasted for at least 6 months in ¾ studies.
The existing literature on LSD is limited, there are very few studies that have been conducted to-date using LSD to treat anxiety. I mentioned one of the above. You can find one here.
It is essential that the therapist guiding the therapy develops a positive rapport with the patient. These are intense sessions that last for many hours. There needs to be a strong, trust-based connection so that the patient feels open enough to share experiences during the session.
The therapist also needs to be able to deal with any adverse effects that may arise during the treatment. (See LSD Neutralizer)
There isn’t a ton of research on LSD for treating anxiety out there right now. You’re far more likely to find literature on psilocybin. This could be for a variety of reasons but regardless it is fantastic that MMED is again, researching to fill the gaps here. My biggest takeaways here are that LSD is showing some significant promise concerning treating anxiety. The effects that it has on the human brain make it a fantastic candidate for integration into therapy sessions. However, something that is often overlooked is the importance of the role of the therapist. I’ll have to look harder into what MMED is doing to develop therapeutic processes but like Study 3 iterated, the relationship between the therapist and patient is imperative. Additionally, the patient needs to be equipped to deal with any adverse outcomes or reactions that could arise throughout the treatment. I think this part in particular bodes well for MMED since the LSD neutralizer is a fantastic way to ensure safety throughout the entire therapeutic process.
Here is the current study being conducted out of University Hospital, Basel in Switzerland.
Questions:
Will LSD-assisted psychotherapy be an ongoing therapeutic process?
Will LSD be effective in dealing with a wide range of LSD diagnoses or will it be limited to a few?
If HPPD turns out to be a serious issue for people with anxiety, how will it be managed?
18-MC – For Addiction
Ahhh 18-MC, MMED’s promise child… Addiction is a bitch, there’s no doubt about that. The toll it has and continues to have on the world is horrible. Opioid overdoses are consistently increasing, alcohol dependence continues to destroy families and lives and cocaine abuse is no joke.
STATS
52 million people currently use opioids.
Opioids are responsible for ~2/3 substance abuse-related deaths.
11 million people inject some form of opioid on a daily basis.
I could list all the addictions in the world but I’m sure you get the picture. It’s a serious issue, one that MMED seeks to resolve with 18-MC.
Before we look at 18-MC we have to talk about Ibogaine. This study gives a great overview of Ibogaine but I’ll give you the summary here. Ibogaine is a psychoactive alkaloid that is found within the Tabernanthe iboga plant in West Africa. The plants' root bark can be consumed in both refined and crude forms, and in high doses can produce trance-like states with visual and auditory hallucinations. Ibogaine has been theorized as an effective natural treatment of substance use disorders.
How Ibogaine works on the human body and mind is still speculative. Ibogaine serves as an N-methyl-D-aspartate receptor agonist. This particular receptor is a molecular target for several abused drugs. A previous study on NMDA receptor modulators found that agonism of these receptors has some limited benefit in treating drug addiction. However, without further study, the way it produces its anti-addictive effects are still in question. For all the science buffs out there, this study rules out one other mechanism of action of Iboga Alkaloids.
Ibogaine has previously been investigated as a treatment for opioid use disorder. A study in 1999 focused on ibogaine in the opioid detoxification process. Patients were treated using different doses of ibogaine based on bodyweight. 76% of the participants did not experience opioid withdrawal symptoms after 24 hours. Furthermore, they did not seek out their substances of choice for the three days they were under observation post-treatment. Another 12% of the patients did not experience withdrawal symptoms but still decided to resume drug abuse.
Another study on individuals who sought out treatment for their opioid use disorder found that after 12 months, 75% of participating patients tested negative for opioid use. To back this up, a later study found that one month after treatment, 50% of patients reported no opioid use for the following 12 months.
Despite this promise, Ibogaine has the potential to be a dangerous compound. There have been 19 documented fatalities from Ibogaine, one of which was under medical supervision. Ibogaine induces body tremors at moderate doses. In high doses, Ibogaine is neurotoxic. Ibogaine also has the potential to decrease the human heart rate and impact blood pressure. These possible dangers served as the impetus of Stanley Glick (Big Stud) and colleagues to try and produce a safer synthetic iboga derivative. 18-MC is born
Since 18-MC and Ibogaine are so closely related I’m going to pull from some more recent studies on both of them to give insight into the efficacy of these drugs on addiction.
This study found that the clinical effects of ibogaine on opioid withdrawal symptoms appeared to be comparable to those of methadone. In this particular study, 50% of patients reported no opioid use during the previous 30 days, 1-month post-treatment, and 33% reported no use in the previous 30 days at the 3-month mark. These rates of reduction in use were greater than those who had been treated with buprenorphine. Drug use scores were improved relative to pre-treatments and were (moderately) sustained over 12-months.
In one of Glick’s early studies on 18-MC in rats, he and his colleagues found that it shared all the purported anti-addictive effects of Ibogaine. The advantage of 18-MC is that it is theorized to not have the same hallucinogenic activity as Ibogaine since it does not bind to serotonin receptors. Furthermore, it is less toxic than Ibogaine both physiologically and neurologically.
It is theorized that 18-MC will be able to assist in dealing with more than opioids, however. Alcohol, amphetamines, and cocaine have all been mentioned as possible substances of abuse that can be addressed.
One important thing to take out of all of this is that one of the studies found that abstinence from drug abuse lowered over time. This means that there is a potential for repeat treatments over time. Despite this, the frequency in which this would have to occur appears to be significantly less than current alternatives like methadone treatment.
Some Questions:
What exactly is/are the mechanism(s) of action? This 2015 study delves pretty deep into the potential mechanisms of action of Noribogaine.
Is 18-MC for sure safe in humans? This is what the upcoming studies/trials out of MMED will tell us. Here is the clinical trial so you can all stay up-to-date on the developments.
Will 18-MC be effective in treating addictions outside of opioid use disorders?
I really hope that this helps some people answer questions specific to MMED's pipeline. I try to stay on top of the current literature so as things come up, I could update the information here. If there was anything you think I missed let me know and I will add it to the list! Some great additional resources to check out below!
Stay healthy and happy friends!
Resources:
https://mindmed.co/wp-content/uploads/2021/01...tion-1.pdf (MMED Investor Deck)
https://open.spotify.com/episode/0vBPANu7FOZn...nbSCIYpe2A (Tim Ferriss Podcast Episode on Psychedelics)
https://www.youtube.com/watch?v=ujuOotYe0M0&a...ckerSummit (Mark Haden of MAPS Canada on Psychedelics)
Posted by u/OldApp
[flair]Psychedelic Advocate
Mind Medicine: Pipeline, Trials, and Science
[flair]Due Diligence
Hey!
With so many new investors and people joining this community, I thought it would be a good idea to give an overview of the company’s current pipeline. Science is the substance of the company, so hopefully, this gives prospective/current investors an avenue for beginning to understand a lot of the treatments being developed.
I am not a professional scientist, so if I screw anything up here please comment and I’ll correct it. Otherwise, all studies will be sourced so if you would like to read more about them just smack that hyperlink. I pull from external sources as well to use as supporting evidence for these therapies. Will go over some question marks and concerns as well so that this isn’t just a bull thesis, but a fair overview of current lit. Feel free to DM me if you want to chat about this stuff or if you have anything you think should be added to this! Science is evolving so it’s best if we stay on top of it.
Sections in Order:
LSD Neutralizer
Cluster Headaches
LSD for Adult ADHD/ADD
LSD for Anxiety
18-MC for Addiction
LSD Neutralizer
As I’m sure a lot of you know, LSD trips last a while. When we are looking at LSD as a compound to be used in assisted therapies, that trip duration brings up some major question marks.
Assisted therapies require trained professionals to guide the sessions. Therapy sessions aren’t cheap; the cost of therapy alone is a major barrier for many people seeking out mental health support. Couple the cost of the compounds and the specialization required for extended psychedelic-assisted psychotherapy sessions and you have a recipe for some potentially pricey treatments.
LSD is not toxic to the human body. You don’t see the same type of physiological or neurotoxic potential that traditional drugs have. However, that does not mean we’re home free here. It’s important to recognize that LSD does have some potential health harms that we should all be aware of. Improper use can lead to potential physical harm. Bad trips can lead to emotional distress. If you don’t screen for underlying psychological conditions like psychosis and schizophrenia some people can experience serious cognitive harms.
This neutralizer technology is purported to act as an off switch for LSD trips. Quick pill and a little while later the trip is over. This funky little compound is called Ketanserin and it’s a major part of dealing with the two issues I mentioned above. If you’re able to control and attenuate the trip, you’re able to reduce the time needed to conduct the therapy session. This can reduce costs related to therapy making it more affordable for a greater number of people. In theory, it could also allow people to take higher single doses, should the therapy demand it, and have the effects neutralized when needed.
Now onto the harms… Luckily for all of us, the harms mentioned above can be managed/mitigated. Proper psychological screening can work out issues related to underlying conditions. Managing set and setting helps reduce the potential for harms related to improper use like stupid behavior and bad trips. This LSD neutralizer is just another great tool in the therapist's tool belt that can be used to mitigate harm during therapy. Being able to stop the experience allows for a failsafe on the therapy sessions which ensures that no one comes out of it worse than they went in. As an add-value, this compound could be sold to recreational users (in theory) to ensure safe at-home use and could also be used in ER departments where occasionally, I'm sure some people come in experiencing bad trips.
Cool beans, so how does it work? Well, let me use a quick analogy to get the ball rolling.
We are all aware of opioids and how people can easily overdose on them. Guaranteed many of you have also heard of Naloxone, the antidote for an opioid overdose. Think of Kertanserin as you would think of Naloxone.
Naloxone and Kertanserin are both antagonists that act against the effects of their respective counterparts. Opioids produce their effects by interacting with the four opioid receptors we all have in our brains. Naloxone is an opioid antagonist that works by binding to those receptors and knocking the opioids off of the receptors for a duration of time; allowing for people to seek the additional help that they need. Source here (If you’re in Canada, go to the pharmacy and get a free Naloxone kit.. you could save a life)
This brings us to Kertanserin and LSD. The psychedelic effects of LSD have been theorized to produce their effects through partial serotonin 5-HT2A receptor agonism. (Agonism being the opposite of Antagonism) Kertanserin works as an antagonist to the same receptor, allowing for the effects of LSD to be attenuated. Here is a study that substantiates the claim that Kertanserin fully blocks the subjective effects of LSD. Here is another one
Here's a link to the current trail that MMED is doing on this very subject in case any of you were hoping to follow it, or maybe even apply to be a part of it?
Questions:
Can it work on other psychedelics? If so which? In theory, it should be effective for Psilocybin as well given it's similar mechanism of action.
Are there any negative side effects of note related to its serotonin receptor antagonism?
Cluster Headaches
Yeah, you get headaches, but do you get cluster headaches? I sure hope not. If you do, oh boy does MMED have the treatment for you. Cluster headaches multiple short, debilitating headaches that can occur repeatedly for expended durations of time. Cluster headaches can go away for a while and then spring back up on you years later. They don’t affect many people (~0.1%) and there isn’t a lot of information out there on what causes them. Regardless, they are painful and people shouldn’t have to deal with it if they don’t have to.
Traditional treatments for cluster headaches include oxygen and sumatriptan for single attacks; and verapamil, lithium, corticosteroids, and more for cluster attack periods. However, anecdotal evidence has suggested that LSD and Psilocybin are both more effective in dealing with individual attacks and attack periods.
One study using a non-hallucinogenic analog of LSD, 2-Bromo-LSD (BOL), found that three single doses of BOL can either break a series of cluster headache attacks or reduce their frequency and intensity. Furthermore, for some, BOL allowed them to achieve remission from their previous chronic cluster headaches. No adverse outcomes were observed in the study. The interesting thing about this study is that the researchers hypothesize that the mechanism of action is unrelated to the serotonin receptor agonism that scientists are theorizing is responsible for hallucinations. This means that it isn’t so much about the hallucinations, but something else that these beautiful compounds have in store. They theorize that the positive effects are the result of serotonin-receptor-mediated vasoconstriction.
A very recent 2020 study backs this up when evaluating the migraine suppressing effects of Psilocybin. The study found that ONE SMALL SINGLE DOSE of shroomies magic chemical, psilocybin, was far more effective than traditional treatments in dealing with migraines. Furthermore, the suppressing effects of the psilocybin on migraines were sustained over two weeks. Again, this study backs up the previous claim that the effects are independent of the hallucinogenic properties of the drugs.
The current phase 2 study going on at UHB in Switzerland can be found here!
Some questions:
Are the effects sustainable over the long-term through many doses?
What exactly is the mechanism of action?
Since the hallucinations aren’t needed, will the focus be on creating non-hallucinogenic analogs? If so, who has the IP on these babies?
LSD – For Adult ADHD
This one is close to my heart. I am a 23-year-old student and I suffer from adult ADHD. I’ve been on Vyvanse for several years and it sucks sometimes. Additionally, it doesn’t appear to be the safest drug in terms of cardiovascular health. Over the past few years, I’ve experimented with micro-dosing LSD in an attempt to experiment with my ADHD. While my supplies have never lasted long enough to do any extended evaluation of its efficacy, there were significant improvements in focus, mood, energy, empathy, and overall just a better day-to-day mental condition. Starting this week I am going to try a psilocybin micro-dosing regime to see how it compares. Not encouraging anything here, just thought I would share my anecdote since the majority of this section is based on anecdotal evidence.
Stimulants suck for a lot of people. They often kill your sex drive, they make you irritable, and they sometimes make you lose weight among many other things. Having a viable alternative is something many of us have dreamed of for a long while. I guarantee you’ve all heard the stories of Silicon Valley execs micro-dosing LSD to improve their productivity and creativity. Well, it looks like our ex-silicon valley CEO now wants to lay down some hard science on this practice.
So what does the anecdotal evidence say?
Study 1:
General effects have been described as “a really good day”.
80% of people surveyed reported a positive or neutral experience.
The most common reason for stopping the micro-dosing regime was that people felt the practice was ineffectual.
Many patients reported positive impacts on depression and anxiety.
Some patients felt that micro-dosing long-term exacerbated their mental health issues.*
69% person of surveyed college students who micro-dosed reported at least one negative side effects from the practice. The most common negative side effect was hallucinations (44.2%). (Maybe from inaccurate dosages?)
One other very common concern was the legality of the practice. (Gotta hate those stupid laws)
Multiple studies reported that people consistently felt great improvements in creativity.
Study 2:
Many patients reported that they wanted to microdose for their diagnosed ADHD/self-diagnosed attention issues.
Most surveyed reported productivity increases and that they procrastinated less.*
This study proposes that despite LSD and Psilocybin acting on different neuroreceptors than traditional stimulants, that their effects could be positives because they are still stimulating drugs.*
A substantial amount those surveyed reported substituting micro-dosing for their stimulants.
Participants reported improvements in home life including a more giving, patient, and open attitude with family members.
Study 3:
The most prevalent mental disorder diagnoses in this study were depressive disorders, anxiety disorders, and ADHD/ADD.
Microdosing was rated more effective than traditional treatment options for ADHD/ADD.
The study theorized that micro-dosing is often preferred because it doesn’t come with as many negative side effects.
Specifically for ADHD, micro-dosing did not come with the same crash that stimulants did.
An additional advantage was that there was not a need to microdose daily. Rather the psychedelic doses were taken every few days (usually).
Study 4:
The most commonly reported effects of micro-dosing were improved mood and creativity.
A previous study found that participants performed significantly better on a divergent creativity task following a small dose of psilocybin.
A 2019 study found that the acute effects of a microdose of LSD were an increased feeling of vigor, friendliness, energy, and social benefit.
The most commonly reported challenge related to micro-dosing was reported to be “none” (lol)
Some challenges include impaired focus and physiological discomfort. These may be once again due to improper/high dosages.
Lack of precision in terms of the compound you are purchasing can also contribute to negative effects.
If you are wondering about the theorized mechanisms of actions and stuff I would recommend you check out this study. There is a lot to it, but you can sift through the section titles quickly. I would recommend reading Question 5, 6, 7, and 8. (Page 1043-1046)
Ultimately there isn’t much clinical evidence to back this one up. I’m glad MMED is taking the steps needed to address this gap in the literature. It will for sure be one that I am paying attention to. Consistent themes in the studies included some negative effects related to dosage. I think that a clinically dosed regime would resolve a lot of these issues especially if a determined dosage scale based on body weight, metabolism, and other factors was developed. However, one major concern I have is that there is anecdotal evidence of microdosing exacerabting underlying mental health issues.
Questions:
What are the long-term health harms that could occur from micro-dosing? Psychedelic use has been previously related to increases in neuroticism and the exacerbation of underlying cognitive predispositions; is this a consideration?
What is the ideal dose?
What is the ideal dose regime?
What conditions is it NOT effective for?
Can it be paired with stimulants or should it be substituted?
LSD – For Anxiety
A lot of the current focus in terms of LSD and anxiety has been its use in palliative care. People who are faced with some pretty scary diseases have reported some great improvements in their condition after psychedelic experiences. Anxiety is a very very broad category of diagnosis. I won’t be able to cover them all here but I will list the 12 broad diagnosis possibilities the DSM-V gives us. The ones I focused my research on are bold.
Separation Anxiety Disorder
Selective Mutism
Specific Phobia
Social Anxiety Disorder
Panic Attack
Agoraphobia
Generalized Anxiety Disorder
Substance/Medication-Induced Anxiety Disorder
Anxiety Disorder Due to Another Medical Condition
Other Specified Anxiety Disorder
Unspecified Anxiety Disorder
Study 1: LSD-Assisted Psychotherapy for Anxiety Associated with a Life-Threatening Disease
This study interviewed 10 participants who had undergone LSD-assisted psychotherapy to assist in dealing with their palliative-related anxiety. After 12 months the patients were interviewed and none of them reported any lasting adverse reactions or effects. 77.8% of patients reported a reduction in anxiety and 66.7% reported a rise in quality of life.
If you’re interested in reading about the first-hand accounts I would recommend reading more into this particular quallatative study. Some of the effects and stories are very profound.
Study 2: Modern Clinical Research on LSD (Very Comprehensive)
Mechanism of Action: (For the Science People)
LSD potently binds to serotonin 5-HT receptors (1a, 2a, 2c), dopamine d2 receptor, and a2 adrenergic receptor.
The hallucinogenic effects are mediated by the drugs affinity for 5-HT2A receptors. This has been proven due to the ability to block these subjective effects using an antagonist (See the LSD Neutralizer).
The full scope of the mechanisms of actions has not been fully identified. However, one key mechanism is the activation of frontal cortex glutamate transmission.
LSD binds more potently to 5-HT2A receptors than does psilocybin.
Unlike other serotonergic hallucinogens, LSD binds to adrenergic and dopaminergic receptors. In humans, LSD may enhance dopamine neurotransmission. (COOL)
LSD increases functional connectivity between various brain regions. (COOL)
Functional brain imaging showed more globally synchronized activity within the brain and a reduction of network separation while under the pharmacological effects of LSD.
LSD decreased default mode network integrity.
LSD reduced left amygdala reactivity to the presentation of fearful faces. (COOL)
Adverse Effects:
Moderate increases in blood pressure, heart rate, body temperature, and pupil side.
Adverse effects 10-24 hours after administration include difficult concentration, headaches, dizziness, lack of appetite, dry mouth, nausea, imbalance, and exhaustion.
No severe side effects have been found and it is physically non-toxic.
Hallucinogen Persisting Perception Disorder (HPPD) is a rare disorder stemming from psychedelic use. Occurs almost exclusively in illicit use or patients with underlying cognitive predispositions like anxiety. (Uh oh)
Effects on Patients:
Profound anxiety or panic was not experienced by patients of one study.
LSD mainly induced blissful states, audiovisual synesthesia, changes in the meaning of perceptions, and positively experiences derealization and depersonalization.
At 200 micrograms, LSD acutely induced mystical experiences in patients undergoing psychotherapy. This is important because previous studies with psilocybin have shown that mystical experiences are correlated with improvements in mood and personality and better therapeutic outcomes in patients with anxiety, depression, and substance use disorders.
Music has been used to produce greater feelings of transcendence and wonder in patients.
LSD impaired the recognition of sad and fearful faces and enhanced emotional empathy.
LSD produced moderate ego dissolution.
LSD produced lower fear perception which may be useful in psychotherapy.
Mid/Long Term Effects:
The use of classical psychedelics is associated with lower psychological distress, lower suicidality, and lower mental health problems.
LSD in healthy subjects increase optimism and trait openness 2 weeks after administration and produced trends towards decreases in distress and delusional thinking.
Study 3:
In all considered studies psilocybin has been found to be a viable treatment for patients with anxiety. The decreases in anxious symptoms lasted for at least three months in all studies and lasted for at least 6 months in ¾ studies.
The existing literature on LSD is limited, there are very few studies that have been conducted to-date using LSD to treat anxiety. I mentioned one of the above. You can find one here.
It is essential that the therapist guiding the therapy develops a positive rapport with the patient. These are intense sessions that last for many hours. There needs to be a strong, trust-based connection so that the patient feels open enough to share experiences during the session.
The therapist also needs to be able to deal with any adverse effects that may arise during the treatment. (See LSD Neutralizer)
There isn’t a ton of research on LSD for treating anxiety out there right now. You’re far more likely to find literature on psilocybin. This could be for a variety of reasons but regardless it is fantastic that MMED is again, researching to fill the gaps here. My biggest takeaways here are that LSD is showing some significant promise concerning treating anxiety. The effects that it has on the human brain make it a fantastic candidate for integration into therapy sessions. However, something that is often overlooked is the importance of the role of the therapist. I’ll have to look harder into what MMED is doing to develop therapeutic processes but like Study 3 iterated, the relationship between the therapist and patient is imperative. Additionally, the patient needs to be equipped to deal with any adverse outcomes or reactions that could arise throughout the treatment. I think this part in particular bodes well for MMED since the LSD neutralizer is a fantastic way to ensure safety throughout the entire therapeutic process.
Here is the current study being conducted out of University Hospital, Basel in Switzerland.
Questions:
Will LSD-assisted psychotherapy be an ongoing therapeutic process?
Will LSD be effective in dealing with a wide range of LSD diagnoses or will it be limited to a few?
If HPPD turns out to be a serious issue for people with anxiety, how will it be managed?
18-MC – For Addiction
Ahhh 18-MC, MMED’s promise child… Addiction is a bitch, there’s no doubt about that. The toll it has and continues to have on the world is horrible. Opioid overdoses are consistently increasing, alcohol dependence continues to destroy families and lives and cocaine abuse is no joke.
STATS
52 million people currently use opioids.
Opioids are responsible for ~2/3 substance abuse-related deaths.
11 million people inject some form of opioid on a daily basis.
I could list all the addictions in the world but I’m sure you get the picture. It’s a serious issue, one that MMED seeks to resolve with 18-MC.
Before we look at 18-MC we have to talk about Ibogaine. This study gives a great overview of Ibogaine but I’ll give you the summary here. Ibogaine is a psychoactive alkaloid that is found within the Tabernanthe iboga plant in West Africa. The plants' root bark can be consumed in both refined and crude forms, and in high doses can produce trance-like states with visual and auditory hallucinations. Ibogaine has been theorized as an effective natural treatment of substance use disorders.
How Ibogaine works on the human body and mind is still speculative. Ibogaine serves as an N-methyl-D-aspartate receptor agonist. This particular receptor is a molecular target for several abused drugs. A previous study on NMDA receptor modulators found that agonism of these receptors has some limited benefit in treating drug addiction. However, without further study, the way it produces its anti-addictive effects are still in question. For all the science buffs out there, this study rules out one other mechanism of action of Iboga Alkaloids.
Ibogaine has previously been investigated as a treatment for opioid use disorder. A study in 1999 focused on ibogaine in the opioid detoxification process. Patients were treated using different doses of ibogaine based on bodyweight. 76% of the participants did not experience opioid withdrawal symptoms after 24 hours. Furthermore, they did not seek out their substances of choice for the three days they were under observation post-treatment. Another 12% of the patients did not experience withdrawal symptoms but still decided to resume drug abuse.
Another study on individuals who sought out treatment for their opioid use disorder found that after 12 months, 75% of participating patients tested negative for opioid use. To back this up, a later study found that one month after treatment, 50% of patients reported no opioid use for the following 12 months.
Despite this promise, Ibogaine has the potential to be a dangerous compound. There have been 19 documented fatalities from Ibogaine, one of which was under medical supervision. Ibogaine induces body tremors at moderate doses. In high doses, Ibogaine is neurotoxic. Ibogaine also has the potential to decrease the human heart rate and impact blood pressure. These possible dangers served as the impetus of Stanley Glick (Big Stud) and colleagues to try and produce a safer synthetic iboga derivative. 18-MC is born
Since 18-MC and Ibogaine are so closely related I’m going to pull from some more recent studies on both of them to give insight into the efficacy of these drugs on addiction.
This study found that the clinical effects of ibogaine on opioid withdrawal symptoms appeared to be comparable to those of methadone. In this particular study, 50% of patients reported no opioid use during the previous 30 days, 1-month post-treatment, and 33% reported no use in the previous 30 days at the 3-month mark. These rates of reduction in use were greater than those who had been treated with buprenorphine. Drug use scores were improved relative to pre-treatments and were (moderately) sustained over 12-months.
In one of Glick’s early studies on 18-MC in rats, he and his colleagues found that it shared all the purported anti-addictive effects of Ibogaine. The advantage of 18-MC is that it is theorized to not have the same hallucinogenic activity as Ibogaine since it does not bind to serotonin receptors. Furthermore, it is less toxic than Ibogaine both physiologically and neurologically.
It is theorized that 18-MC will be able to assist in dealing with more than opioids, however. Alcohol, amphetamines, and cocaine have all been mentioned as possible substances of abuse that can be addressed.
One important thing to take out of all of this is that one of the studies found that abstinence from drug abuse lowered over time. This means that there is a potential for repeat treatments over time. Despite this, the frequency in which this would have to occur appears to be significantly less than current alternatives like methadone treatment.
Some Questions:
What exactly is/are the mechanism(s) of action? This 2015 study delves pretty deep into the potential mechanisms of action of Noribogaine.
Is 18-MC for sure safe in humans? This is what the upcoming studies/trials out of MMED will tell us. Here is the clinical trial so you can all stay up-to-date on the developments.
Will 18-MC be effective in treating addictions outside of opioid use disorders?
I really hope that this helps some people answer questions specific to MMED's pipeline. I try to stay on top of the current literature so as things come up, I could update the information here. If there was anything you think I missed let me know and I will add it to the list! Some great additional resources to check out below!
Stay healthy and happy friends!
Resources:
https://mindmed.co/wp-content/uploads/2021/01...tion-1.pdf (MMED Investor Deck)
https://open.spotify.com/episode/0vBPANu7FOZn...nbSCIYpe2A (Tim Ferriss Podcast Episode on Psychedelics)
https://www.youtube.com/watch?v=ujuOotYe0M0&a...ckerSummit (Mark Haden of MAPS Canada on Psychedelics)
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