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I'm speaking about a [possibly] partially non-psychedelic topic, but it originated
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in the psychedelic field. It's also an interesting story about a discovery.
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[You] will mainly hear here from me about bromo-LSD, which is a compound which [was]
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originally synthesized by Hofmann in the mid-'50s, by Albert Hofmann,
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the discoverer of LSD. So it seems that his LSD placebo will at last become a medication.
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So that's quite interesting, but it's posthumous. He didn't know about that.
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This is Albert Hofmann, as you may know. So...to give a short overview, I will tell you
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very [briefly] about cluster headaches and what it means. I will also tell you
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about the initial self-trials with LSD and psilocybin in cluster headaches.
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Then I will talk some about bromo-LSD and the treatments [which] we have done
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with bromo-LSD already and the future which may happen [with] bromo-LSD,
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if everything works out well. What is [a] cluster headache?
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One or 2 or 3 out of a thousand people have cluster headache[s], which [are] a very malign
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form of migraine. There is a male-female...which is opposite to migraines, right?
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It's called "suicide headache" because the people [who] have that disease are
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so much [in] pain that they sometimes have these attacks a few times a day,
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and...a lot of times in a row. Some people are even chronic that way. So they do [commit] suicide
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to avoid the pain. It typically begins at the [age of] 20. There are episodic and chronic forms.
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Some people have only these cycles, like having three months of cluster headaches,
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then three months symptom-free, then another three months, or in a [slightly] different pattern,
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they have these [attacks]. These are in fact very severe and repeated headaches,
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which are occurring in cycles, so-called clusters. So it's a serious disease and we don't have
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the real medication for it up to now. Here is a picture which may give you an idea
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[of] how terrible that is, because you feel like a spear is in your head, going through it,
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and you feel all that pain. It's really hard, and you also have lacrimation [crying]
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and sometimes a [stuffy] nose and so on, but it's a really hard pain.
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If you look up these videos [which] are on Youtube about this disease and how
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the pain is going on, it's terrible. You wouldn't even believe it, if you can't see that.
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So what are the conventional treatment[s]? We have treatments which are trying to
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cope with acute headaches as well as giving prophylactic effects if taken on a daily basis.
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That's the usual medications [which] we used up to now. But there may be
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a new kind of treatment with bromo-LSD and maybe with LSD/psilocybin,
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which may be called preventative, because you're doing the drug and then afterwards,
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you have a kind of after-effect which is remission...so you don't have any cluster headaches,
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even without taking the medication...additional times.
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Breathing pure oxygen may help a lot of these people in acute attacks, around 70%.
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But you always have to carry a tank with you. So it's hard to do sometimes.
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[Triptans], which are used for treatment of migraines, are also effective in a lot of people,
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but they have some side effects. Especially if you take them a few times a day,
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you will get serious side effects which are really [dis]agreeable, and [there is]
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also a cost factor. A lot of health insurance companies in the US don't pay
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for that amount [which] you really need.
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Verapamil is another medication, usually for cardiac purposes. It is used as
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a prophylactic treatment, but that's off label, still. It also has a lot of side effects
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which a lot of people can't tolerate. There's another medication, prednisone,
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which is a cortisol preparation. That can have a lot of serious side effects,
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immuno-modulatory effects, psychosis, osteoporosis, and so on. So you can't take that,
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really, on a regular basis. Some new ideas are: because the illness is so severe in the pain
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...some people even searched...for neurostimulators, where you put some wires
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in the brain and stimulate [it] so that you have less pain. But it was found out recently,
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because it's a [rival] approach to BOL in a way, it was recently found out
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that they have a lot of complications, infections and everything. So everybody had complications,
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in fact, every patient. So they're staying away from it right now.
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Also it is the case [that] if you have the headaches on one side, for example,
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and you put a neurostimulator in there, it may change to the other side.
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So you've got one surgery after another, and it really doesn't work out that well.
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The history is interesting, because a Scottish person with severe episodic cluster headaches
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was having [them] for 18 years and then he wondered why he didn't get the attacks
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[during] one year at a certain point. He always got it [then], at that point [in the year],
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[but then] he didn't, for months. So he was looking up his diary and his memory, and said,
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"what did I do [differently] than usual?" He found out that he took LSD in 1993,
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two times that year. So he didn't get the cluster headaches [the] next year.
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So he made that kind of causal [connection] about it.
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This is what I already said.
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So he was, on his own, taking LSD [on] a regular [schedule], [at] a hallucinogenic dose, to treat it.
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He really prevented all [the] headaches. So no cluster headache was showing up
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[during] this time. Then he tried to stay away from LSD to test if [there was] really a connection,
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and the cluster headache showed up again. So this guy was posting these
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very personal findings on the internet, and so, some other people became aware of that.
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Some of them are also psychedelic aficionados, I guess, so they don't mind
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taking such a medication, so it was tried on a larger basis.
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They found out [that] it was very effective. So we have right now evidence
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that three substances can treat cluster headaches in [a] way I will tell you about.
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One is psilocybin; it was tried out too, and it works as well. The other is LSD,
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not allowed in these preparations, right now. The next thing is bromo-LSD,
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which I will talk about. Here are some batches from the '60s for analytical purposes.
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What they have done, then, is, my colleagues from Harvard...had the idea, initiated by Bob Volt,
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head of the organization Cluster Busters, [which] was founded around these findings,
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and he's also announcing that he is preparing material here where you can
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look up our studies as well as some brochures related to that kind of research.
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In the year 2004-2005, Bob Volt was asking the Harvard guys, John Halpern, in fact,
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to do a kind of survey about these cases. So these people were contacted by the internet,
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and some of them, 53, were interviewed and gave their okay for getting their medical records,
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[to show that] they [were] really diagnosed that way, so that we [were] really sure
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they [had] that disease. Nearly 60% hadn't used any psychedelics recreationally,
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but they took it because of the cluster headache, and it worked for them.
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These were the participants. There was a use of psilocybin; out of 19 cases,
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17 had success treating their cluster headaches with that. This study was done with
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[R.] Andrew Sewell in cooperating with [John] Halpern and the [department] chief.
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With the episodic cluster headaches, 29 of the 53 took the LSD for prophylactic purposes,
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or the psilocybin. This is not a very good thing here.
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In more than 50% it was effective... for breaking the cycle, but they didn't take it
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on a daily basis. They only took it one time and then the cluster cycle was broken
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in more [than] half of them. There is no medication out there which can do that.
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I need to make that clear. [For] forty percent it was partially effective.
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It diminished the pain, it diminished the frequency. So they may have at that point [in] time
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not really figured out what the right treatment regime would be, and how often
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you have to take it and at what doses and so on. This evaluation, this survey,
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gave some ideas about that. The LSD users [also broke] the cycle and had some
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preventative effect also. Twenty out of the psilocybin users [had] taken psilocybin
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in between the cycles and had a preventative effect. It is still, by the way,
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a miracle what the mechanism of that is. You may think about epigenetics or whatever,
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but there is no idea about it as far as I know.
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Here I will give you some numbers of the conventional things, like oxygen.
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You see it's partially effective in the acute attacks, but it doesn't break the cycle.
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Please understand that. So [with triptans], the same is going on. [They] can reduce
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[the pain of an acute] attack, sometimes even eliminate it, but with all these side effects and stuff.
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But psilocybin, with...not so much side effects, I would say, is giving
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a much higher number, and it's only ineffective in a very few patients.
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So now we're going to the prophylactic type of treatment, what they have tried
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in these self-medication trials, if you [will]. Lithium is not very effective
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in having these prophylactic effects. Verapamil is also not very effective,
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but partially effective. Prednisone is much more effective, but it has these serious side effects,
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so you can't take it on a longer basis; it's not allowed by the FDA.
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Psilocybin is really effective in a way, [for] more than half of the patients, and with some...
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it's partially effective, and you can see LSD is quite effective, maybe even more so
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than psilocybin. We are not quite sure because there are no controlled trials out there
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which compare these [two] medications. So how did we [come] up with that bromo-LSD idea?
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At first, we were at McLean hospital, Harvard University, Harvard Medical School,
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with Bob Volt who is here, and professor John Halpern from McLean hospital.
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We were discussing LSD and how to do an LSD research project, how it may be
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connected to serotonin and the activation of serotonin receptors. But the preventative
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effect can't be explained that way, because the acute effects are over after a day,
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so the material is out of the system. So we were talking about genes...We may apply
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for a psilocybin study which was planned, and we were doing stuff on the research protocol
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and so on. We were also thinking about LSD derivatives, and how did that come?
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We [showed up] with Bob Volt as our sponsor from the Cluster Busters,
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at the Harvard research administration, and we were sitting in a room with two fireplaces and
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a big desk there, and these big chairs and stuff, and they were sitting in front of us.
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We were talking with them, flexible at that moment, and then there was a pause
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in the conversation, and the leading guy on the other side said, "You know what?"
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"We had Leary here." So it seems like there's a wall you have to go over, and that
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may [not be] easy. So what we did is we came up with the idea, "maybe we should"
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"look...for the derivatives," but mainly for the purpose [of proving]
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that the most appropriate thing you can figure out in respect to the derivatives,
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the most appropriate derivative may not work. Because there was some evidence that
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only a hallucinogenic effect will give you the full treatment effect. It seems it is [dependent],
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maybe, on that. So we had the idea to prove that the other medication, the non-hallucinogenic one,
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is not working. Therefore we could go on with the LSD study, right?
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So we came up with that. We [had] already cooperated for some years.
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The idea was, first, what I told you. The hindrance of psychedelic research at Harvard
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may be a big deal. There may be some dependence on the hallucinogenic effect.
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We have looked for more than 100 derivatives, so I have looked for that before, anyway,
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for no reason. We figured out 3 derivatives which may be appropriate from these few data
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which were generated during the '60s, and we came up with BOL-148, which is bromo-LSD.
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Here you will be okay. So it is LSD, in fact, with one atom done in another fashion, so
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it's a little difference. It was synthesized, I'm not quite sure if it was '55 or '57. I think it was '55.
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They synthesized that as a kind of placebo to compare that with LSD's effect.
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They [did] a lot of trials in animals and human[s] [during] that time. During the '60s, there [was] a lot
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of stuff going on because they [wanted] to know...At that point [in] time they were
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of the opinion that the anti-serotonergic activity, which they [had] measured in a very crude
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[manner] with some tissues...was giving LSD its effects. But they figured out
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that bromo-LSD was doing the same in respect to this crude anti-serotonergic testing,
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but it is not giving you any hallucinogenic effects. So that thing was excluded in a way
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by bromo-LSD in these trials. So what they also found was that there was virtually no
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physiological activity, even in the higher dose range, like 10-20 mg intravenous,
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which they [had] also tried. There was also no hallucinogenic activity, but some kind of
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curious side effects which we will come [to] later in this talk.
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So here we see these [two] molecules, and you can see on the right side, I marked that
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with this orange thing, so you can see [that] there's only one hydrogen changed
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into a bromo. But what is not shown here, as far as I know, [is that] the bromo is much bigger.
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That means it doesn't fit into the receptor anymore that much. There are some receptor
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interactions, but very slightly. They have compared LSD and BOL in humans (you may know that)
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up to really big doses. They also looked...for, partially for military purposes, I guess,
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how they can pre-treat soldiers with BOL, making them resistant to LSD.
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But what they found is [that] the psychic effects were not blocked, but some of the physiological
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effects were blocked. So it may be that it hooked up to the receptor but it [was] not
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pushing the button. I will not go into that because of time reasons.
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But...you can see some differences, mainly in the cerebrum serotonin, BOL is bringing it down,
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LSD is neutral in that respect, and the CNS arousal is even going down with BOL,
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also in animals. You don't have any hallucinations with BOL.
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What we found is it has a much shorter time of action, and it seems that from some evidence...
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it's easily crossing the blood-brain barrier, as LSD does too, as far as I know.
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It has no effect on blood pressure, pulse, ECG, EEG, [or] blood sugar, [or] metabolic rate,
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and so on, and also not on sleep. So it's a kind of side-effect-free material, in a way.
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There were some side effects found, but not in the dose range up to 550 micrograms per kilogram.
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There were virtually no side effects. Some of our patients [who] have gotten
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30 micrograms per kilogram, they told us something. It's like a half-glass of wine;
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you feel tipsy, whatever that means. But in the higher dose range you get this kind of tiredness,
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because you get low arousal, and restlessness, and sometimes, in some patients,
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difficulty [in concentrating]. I myself have [taken] 5 mg, which is a double dose
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[compared with] what we gave to the patients, and one marked effect was a kind of
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dysphoria. It's not euphoria, like most people [get] from LSD; it's dysphoria.
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[It] may be an inverse agonist; I don't know. But that was a marked effect and it's also
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sometimes described, but it wasn't that [bad]. Okay, I hope I can go through these slides.
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We had some people synthesizing BOL. That was quite a big deal, because it's not easy
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to synthesize that much. We also got an analytical certificate for that stuff.
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We used that in a few patients together with my friend and colleague, Professor Karst,
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who is a pain professor [at] Hanover Medical School. We have a specific law
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in Germany, that in treatment-resistant patients, if you take complete responsibility
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and you're not relying on your insurance, you can give every medication. But [that is] only in these
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desperate cases, treatment-resistant cases. So we have done a thorough examination of them.
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We have done a treatment protocol. We were going through the IRB [Institutional Review Board]
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asking for that, if that is allowed and stuff, and we made these examinations
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and assessments afterwards. Okay, we were giving the hydrochloride salt...
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[The] important [thing] is, we had three administrations 5 days apart,
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which was found out by that initial survey study, that it may work on the preventative
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effect more than other modes of applications. We were looking for the pain diary, obviously,
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and the clinical global impression, and had some personal visits with the patients afterwards.
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Here you can see the treatment effects. Below is these little arrows, in the beginning,
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at the number 3 there. They show when we have given the Bromo-LSD three times,
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so people were under clinical supervision at that point [in] time. Then you can see how it goes down,
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and here you can see the weeks. It goes 16 weeks and nothing happen[ed] anymore.
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So there is a solid preventative effect, and we even had some of the patients,
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[who] were severely ill patients, [who] didn't have an attack for years.
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Funny how that happened. We also had one patient who had an attack when we applied the substance.
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There was a diminuition of that pain, during the attack in that patient, and there was
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obviously a decrease in frequency, and [improvement] even in the first time when they
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[still had] attacks after the first application. Then their symptoms [got] better [from] the medication,
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and we had this remission extension, [as] it was called. We now speak about
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preventative effects. There were no serious side effects seen...virtually nothing.
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What will be the next step? ...You have to go into all these investors' meetings,
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and with these financial guys, [who have] paranoia that something may not be right
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with that project and all that. You have to find somebody who is willing to invest