in the psychedelic field. It's also an interesting story about a discovery.

[You] will mainly hear here from me about bromo-LSD, which is a compound which [was]

originally synthesized by Hofmann in the mid-'50s, by Albert Hofmann,

the discoverer of LSD. So it seems that his LSD placebo will at last become a medication.

So that's quite interesting, but it's posthumous. He didn't know about that.

This is Albert Hofmann, as you may know. So...to give a short overview, I will tell you

very [briefly] about cluster headaches and what it means. I will also tell you

about the initial self-trials with LSD and psilocybin in cluster headaches.

Then I will talk some about bromo-LSD and the treatments [which] we have done

with bromo-LSD already and the future which may happen [with] bromo-LSD,

if everything works out well. What is [a] cluster headache?

One or 2 or 3 out of a thousand people have cluster headache[s], which [are] a very malign

form of migraine. There is a male-female...which is opposite to migraines, right?

It's called "suicide headache" because the people [who] have that disease are

so much [in] pain that they sometimes have these attacks a few times a day,

and...a lot of times in a row. Some people are even chronic that way. So they do [commit] suicide

to avoid the pain. It typically begins at the [age of] 20. There are episodic and chronic forms.

Some people have only these cycles, like having three months of cluster headaches,

then three months symptom-free, then another three months, or in a [slightly] different pattern,

they have these [attacks]. These are in fact very severe and repeated headaches,

which are occurring in cycles, so-called clusters. So it's a serious disease and we don't have

the real medication for it up to now. Here is a picture which may give you an idea

[of] how terrible that is, because you feel like a spear is in your head, going through it,

and you feel all that pain. It's really hard, and you also have lacrimation [crying]

and sometimes a [stuffy] nose and so on, but it's a really hard pain.

If you look up these videos [which] are on Youtube about this disease and how

the pain is going on, it's terrible. You wouldn't even believe it, if you can't see that.

So what are the conventional treatment[s]? We have treatments which are trying to

cope with acute headaches as well as giving prophylactic effects if taken on a daily basis.

That's the usual medications [which] we used up to now. But there may be

a new kind of treatment with bromo-LSD and maybe with LSD/psilocybin,

which may be called preventative, because you're doing the drug and then afterwards,

you have a kind of after-effect which is remission...so you don't have any cluster headaches,

even without taking the medication...additional times.

Breathing pure oxygen may help a lot of these people in acute attacks, around 70%.

But you always have to carry a tank with you. So it's hard to do sometimes.

[Triptans], which are used for treatment of migraines, are also effective in a lot of people,

but they have some side effects. Especially if you take them a few times a day,

you will get serious side effects which are really [dis]agreeable, and [there is]

also a cost factor. A lot of health insurance companies in the US don't pay

for that amount [which] you really need.

Verapamil is another medication, usually for cardiac purposes. It is used as

a prophylactic treatment, but that's off label, still. It also has a lot of side effects

which a lot of people can't tolerate. There's another medication, prednisone,

which is a cortisol preparation. That can have a lot of serious side effects,

immuno-modulatory effects, psychosis, osteoporosis, and so on. So you can't take that,

really, on a regular basis. Some new ideas are: because the illness is so severe in the pain

...some people even searched...for neurostimulators, where you put some wires

in the brain and stimulate [it] so that you have less pain. But it was found out recently,

because it's a [rival] approach to BOL in a way, it was recently found out

that they have a lot of complications, infections and everything. So everybody had complications,

in fact, every patient. So they're staying away from it right now.

Also it is the case [that] if you have the headaches on one side, for example,

and you put a neurostimulator in there, it may change to the other side.

So you've got one surgery after another, and it really doesn't work out that well.

The history is interesting, because a Scottish person with severe episodic cluster headaches

was having [them] for 18 years and then he wondered why he didn't get the attacks

[during] one year at a certain point. He always got it [then], at that point [in the year],

[but then] he didn't, for months. So he was looking up his diary and his memory, and said,

"what did I do [differently] than usual?" He found out that he took LSD in 1993,

two times that year. So he didn't get the cluster headaches [the] next year.

So he made that kind of causal [connection] about it.

This is what I already said.

So he was, on his own, taking LSD [on] a regular [schedule], [at] a hallucinogenic dose, to treat it.

He really prevented all [the] headaches. So no cluster headache was showing up

[during] this time. Then he tried to stay away from LSD to test if [there was] really a connection,

and the cluster headache showed up again. So this guy was posting these

very personal findings on the internet, and so, some other people became aware of that.

Some of them are also psychedelic aficionados, I guess, so they don't mind

taking such a medication, so it was tried on a larger basis.

They found out [that] it was very effective. So we have right now evidence

that three substances can treat cluster headaches in [a] way I will tell you about.

One is psilocybin; it was tried out too, and it works as well. The other is LSD,

not allowed in these preparations, right now. The next thing is bromo-LSD,

which I will talk about. Here are some batches from the '60s for analytical purposes.

What they have done, then, is, my colleagues from Harvard...had the idea, initiated by Bob Volt,

head of the organization Cluster Busters, [which] was founded around these findings,

and he's also announcing that he is preparing material here where you can

look up our studies as well as some brochures related to that kind of research.

In the year 2004-2005, Bob Volt was asking the Harvard guys, John Halpern, in fact,

to do a kind of survey about these cases. So these people were contacted by the internet,

and some of them, 53, were interviewed and gave their okay for getting their medical records,

[to show that] they [were] really diagnosed that way, so that we [were] really sure

they [had] that disease. Nearly 60% hadn't used any psychedelics recreationally,

but they took it because of the cluster headache, and it worked for them.

These were the participants. There was a use of psilocybin; out of 19 cases,

17 had success treating their cluster headaches with that. This study was done with

[R.] Andrew Sewell in cooperating with [John] Halpern and the [department] chief.

With the episodic cluster headaches, 29 of the 53 took the LSD for prophylactic purposes,

or the psilocybin. This is not a very good thing here.

In more than 50% it was effective... for breaking the cycle, but they didn't take it

on a daily basis. They only took it one time and then the cluster cycle was broken

in more [than] half of them. There is no medication out there which can do that.

I need to make that clear. [For] forty percent it was partially effective.

It diminished the pain, it diminished the frequency. So they may have at that point [in] time

not really figured out what the right treatment regime would be, and how often

you have to take it and at what doses and so on. This evaluation, this survey,

gave some ideas about that. The LSD users [also broke] the cycle and had some

preventative effect also. Twenty out of the psilocybin users [had] taken psilocybin

in between the cycles and had a preventative effect. It is still, by the way,

a miracle what the mechanism of that is. You may think about epigenetics or whatever,

but there is no idea about it as far as I know.

Here I will give you some numbers of the conventional things, like oxygen.

You see it's partially effective in the acute attacks, but it doesn't break the cycle.

Please understand that. So [with triptans], the same is going on. [They] can reduce

[the pain of an acute] attack, sometimes even eliminate it, but with all these side effects and stuff.

But psilocybin, with...not so much side effects, I would say, is giving

a much higher number, and it's only ineffective in a very few patients.

So now we're going to the prophylactic type of treatment, what they have tried

in these self-medication trials, if you [will]. Lithium is not very effective

in having these prophylactic effects. Verapamil is also not very effective,

but partially effective. Prednisone is much more effective, but it has these serious side effects,

so you can't take it on a longer basis; it's not allowed by the FDA.

Psilocybin is really effective in a way, [for] more than half of the patients, and with some...

it's partially effective, and you can see LSD is quite effective, maybe even more so

than psilocybin. We are not quite sure because there are no controlled trials out there

which compare these [two] medications. So how did we [come] up with that bromo-LSD idea?

At first, we were at McLean hospital, Harvard University, Harvard Medical School,

with Bob Volt who is here, and professor John Halpern from McLean hospital.

We were discussing LSD and how to do an LSD research project, how it may be

connected to serotonin and the activation of serotonin receptors. But the preventative

effect can't be explained that way, because the acute effects are over after a day,

so the material is out of the system. So we were talking about genes...We may apply

for a psilocybin study which was planned, and we were doing stuff on the research protocol

and so on. We were also thinking about LSD derivatives, and how did that come?

We [showed up] with Bob Volt as our sponsor from the Cluster Busters,

at the Harvard research administration, and we were sitting in a room with two fireplaces and

a big desk there, and these big chairs and stuff, and they were sitting in front of us.

We were talking with them, flexible at that moment, and then there was a pause

in the conversation, and the leading guy on the other side said, "You know what?"

"We had Leary here." So it seems like there's a wall you have to go over, and that

may [not be] easy. So what we did is we came up with the idea, "maybe we should"

"look...for the derivatives," but mainly for the purpose [of proving]

that the most appropriate thing you can figure out in respect to the derivatives,

the most appropriate derivative may not work. Because there was some evidence that

only a hallucinogenic effect will give you the full treatment effect. It seems it is [dependent],

maybe, on that. So we had the idea to prove that the other medication, the non-hallucinogenic one,

is not working. Therefore we could go on with the LSD study, right?

So we came up with that. We [had] already cooperated for some years.

The idea was, first, what I told you. The hindrance of psychedelic research at Harvard

may be a big deal. There may be some dependence on the hallucinogenic effect.

We have looked for more than 100 derivatives, so I have looked for that before, anyway,

for no reason. We figured out 3 derivatives which may be appropriate from these few data

which were generated during the '60s, and we came up with BOL-148, which is bromo-LSD.

Here you will be okay. So it is LSD, in fact, with one atom done in another fashion, so

it's a little difference. It was synthesized, I'm not quite sure if it was '55 or '57. I think it was '55.

They synthesized that as a kind of placebo to compare that with LSD's effect.

They [did] a lot of trials in animals and human[s] [during] that time. During the '60s, there [was] a lot

of stuff going on because they [wanted] to know...At that point [in] time they were

of the opinion that the anti-serotonergic activity, which they [had] measured in a very crude

[manner] with some tissues...was giving LSD its effects. But they figured out

that bromo-LSD was doing the same in respect to this crude anti-serotonergic testing,

but it is not giving you any hallucinogenic effects. So that thing was excluded in a way

by bromo-LSD in these trials. So what they also found was that there was virtually no

physiological activity, even in the higher dose range, like 10-20 mg intravenous,

which they [had] also tried. There was also no hallucinogenic activity, but some kind of

curious side effects which we will come [to] later in this talk.

So here we see these [two] molecules, and you can see on the right side, I marked that

with this orange thing, so you can see [that] there's only one hydrogen changed

into a bromo. But what is not shown here, as far as I know, [is that] the bromo is much bigger.

That means it doesn't fit into the receptor anymore that much. There are some receptor

interactions, but very slightly. They have compared LSD and BOL in humans (you may know that)

up to really big doses. They also looked...for, partially for military purposes, I guess,

how they can pre-treat soldiers with BOL, making them resistant to LSD.

But what they found is [that] the psychic effects were not blocked, but some of the physiological

effects were blocked. So it may be that it hooked up to the receptor but it [was] not

pushing the button. I will not go into that because of time reasons.

But...you can see some differences, mainly in the cerebrum serotonin, BOL is bringing it down,

LSD is neutral in that respect, and the CNS arousal is even going down with BOL,

also in animals. You don't have any hallucinations with BOL.

What we found is it has a much shorter time of action, and it seems that from some evidence...

it's easily crossing the blood-brain barrier, as LSD does too, as far as I know.

It has no effect on blood pressure, pulse, ECG, EEG, [or] blood sugar, [or] metabolic rate,

and so on, and also not on sleep. So it's a kind of side-effect-free material, in a way.

There were some side effects found, but not in the dose range up to 550 micrograms per kilogram.

There were virtually no side effects. Some of our patients [who] have gotten

30 micrograms per kilogram, they told us something. It's like a half-glass of wine;

you feel tipsy, whatever that means. But in the higher dose range you get this kind of tiredness,

because you get low arousal, and restlessness, and sometimes, in some patients,

difficulty [in concentrating]. I myself have [taken] 5 mg, which is a double dose

[compared with] what we gave to the patients, and one marked effect was a kind of

dysphoria. It's not euphoria, like most people [get] from LSD; it's dysphoria.

[It] may be an inverse agonist; I don't know. But that was a marked effect and it's also

sometimes described, but it wasn't that [bad]. Okay, I hope I can go through these slides.

We had some people synthesizing BOL. That was quite a big deal, because it's not easy

to synthesize that much. We also got an analytical certificate for that stuff.

We used that in a few patients together with my friend and colleague, Professor Karst,

who is a pain professor [at] Hanover Medical School. We have a specific law

in Germany, that in treatment-resistant patients, if you take complete responsibility