Brom-LSD in der Behandlung von Cluster-Kopfschmerz

Brom-LSD in der Behandlung von Cluster-Kopfschmerz

Bromo-LSD
in der
Behandlung von
Cluster-Kopfschmerz
Prof. Torsten Passie
Harvard Medical School, Boston
Hannover Medical School, Germany
Übersicht
Ø 
Cluster Kopfschmerz (CK)
Ø  LSD und Psilocybin bei CK
Ø  Bromo-LSD
Ø  Synopsis
Cluster-Kopfschmerz
Cluster Kopfschmerz
Ø  0,12 % der Bevölkerung
Ø  Männer/Frauen 6:1
Ø  Episodische und chronische Form
Ø  „Suicide headache“, typischer Beginn mit 20
Ø  Sehr starke Kopfschmerzen in Zyklen
Konventionelle Behandlung
Ø  Sauerstoff bei 70% effektiv
Ø  Triptane bei 70% effektiv
> Tank
> NW + Kosten
Ø  Verapamil Prophylaxe
> NW
Ø  Prednisone Prophylaxe
> NW
Ø  Neurostimulatoren
Ø 
> Komplikationen
Psilocybin + LSD bei CK
Harvard-Studie
Ø  Zufallsentdeckung 1993 (LSD)
Ø  Verbreitung von Infos über Internet
Ø  53 interviewt + medical records
Ø  32 episodische, 21 chronische CK-Patienten
Sewell et al. 2006
Harvard-Studie
Ø  Bei 52% Zyklus durchbrochen
Ø  Bei 41% teilweise effektiv
Ø  29 nutzten Psilo/LSD für Prophylaxe
Ø  5 von 6 LSD: Zyklus durchbrochen + Prävention
Ø  Psilocybin während Remission > CK-Prävention
Sewell et al. 2006
Begegnungen und Ideen
Ø  LSD
Ø  Serotonin
Ø  Gene
Ø  Psilocybin-Studie
Ø  LSD-Derivative
Bob Wold John Halpern
Internationale Kooperation
Laboratory for Integrative Psychiatry, Harvard Medical School
Bromo-LSD (BOL-148)
Bromo-LSD: Die Idee
Ø  Behinderung psychedelischer Forschung
Ø  Effektivität an halluzinogene Wirkung gebunden?
Ø  Sondierung von LSD-Derivaten
Ø  Von > 100 drei ausgewählt
Ø  BOL-148 getestet
BOL-148
Ø  2-Bromo-Lysergsäure-Diäthylamid
Ø  1955 synthetisiert von Troxler and Hofmann
Ø  ‚LSD-Placebo‘ für experimentelle Zwecke
Ø  Versuche an Tieren und Menschen (> 300)
Ø  Keine physiologische oder halluzinogene Aktivität
LSD
BOL-148
BOL-148 Nebenwirkungen
< 50 mcg/kg
Keine
60-100 mcg/kg
<10% Müdigkeitsempfinden Übelkeit Unruhe
<1%
Konzentrationsprobleme
BOL-148
Behandlung
Ø  Individuelle Heilversuche
Ø  Behandlungsresistente Patienten
Ø  Gründliche Untersuchung und Aufklärung
Ø  Behandlungsplan > Ethik-Kommission
Ø  Untersuchungen und Messungen
Behandlung
Ø  Hydrochlorid-Salz
Ø  30 mcg/Kg per os
Ø  3 Verabreichungen: Tag 1 - Tag 5 - Tag 10
Ø  Schmerztagebücher
Ø  Visits
VAS-Schmerzskala
CGI
Behandlungswirkungen
Number of
attacks/week
40
S5
35
N=5
30
25
S3
20
S4
15
10
S2
5
S1
1
2
3
4
30 mcg BOL every 5 days
for 3 doses total
5
6
7
8
9
10
11
12
13
14
15
16
Weeks
BOL-148 Resultate
Ø  Unterbrechung der akuten Attacke
Ø  Verminderung der Attackenfrequenz
Ø  Verbesserung der CK-Symptome
Ø  Ausweitung der Remissionsperiode
Ø  Keine signifikanten Nebenwirkungen
Wie weiter ?
Ø  Patent realisiert
Ø  Investoren gesucht
Ø  Keine Orphan drug
Ø  Minimierte Phase I + IIa Trials
Ø  Finanziert durch Konsortium Betroffener
Psychedelics für CK
Ø  Erheblich weniger Nebenwirkungen
Ø  Müssen nur wenige Male genommen werden
Ø  Erzielen Langzeit-Prävention
Ø  Nicht-halluzinogenes BOL-148 gut wirksam
Ø  mit minimierten Nebenwirkungen
Prof. Torsten Passie
Harvard Medical School, Boston
Hannover Medical School, Germany
Danke für Ihre
Aufmerksamkeit
Conclusions
Early studies
Ø  Comparing BOL to LSD in humans
Ø  5-1000 mcg/kg p.o., i.v.
Ø  Pretreatment for blocking of LSD effects
Ø  Psychic effects not blocked
Ø  BP increase + mydriasis blocked
LSA
LSD
BOL
Comparison
LSD
Visceral serotonin
Brain stem serotonin
Cerebrum serotonin
CNS arousal
Hallucinations
BOL
BOL Pharmacology
Ø  Effects last 2-3,5 hrs
Ø  Easy crossing of blood-brain barrier
Ø  No effect on BP, pulse, ECG, EEG
Ø  No effect on blood sugar + metabolic rate
Ø  No effect on sleep
Hannover Medical
School
Karst
Halpern
Synopsis
Ø  Some hallucinogens effective for CH
Ø  Acute and preventative effects
Ø  BOL-148 effective, but non-hallucinogenic
Ø  Virtually no side-effects
Ø  Patent valid
Phase II + III studies planned
Study outline
Ø  RCT, parallel group design
Ø  N = 40
Ø  Inclusion and exclusion criteria
Ø  Primary outcome measures
Ø  Headache frequency, vital signs, hormones etc.
BOL-148 Pharmacology
Ø  Turner/Merlis 1958: 5 mg/day in schizos: No effects on
psychoses
Ø  Isbell et al. 1959: 50 mcg = no psych effects
Ø  >70 mcg: mild psych effects
Ø  Effects last 4,5 hrs
B
Ø  2
B
Ø  2
BOL effects + sideeffects
Bertino et al. 1959
Ø  Double blind
Ø  Cross-over
Ø  N = 25
Ø  16, 32, 64, 128, 256 mcg/kg
BOL effects + sideeffects
32 / 64 mcg/kg p.o.
Ø  1 out of 6 subjects:
Ø  Numbness, tingling, salivation
Ø  Dizziness, tensions, restlessness, impaired concentration
Ø  Onset of symptoms 20-40 min.
Ø  Effects last for 1-3 hours
BOL effects + sideeffects
Ø  132/264 mcg/kg
6 out of 10:
Ø  Drunk feeling, tiredness, euphoria/anxiety impaired
concentration
Ø  No hallucinations or psychotic behaviour
Ø  Depressed feelings until 12 hrs post ingestion
Ø  No changes to BP, pulse, pupillary diameter
Vasodilatation
Ø Dilation of ophthalmic or carotid arteries
Ø Constriction of carotid siphon
Ø ↑blood flow to brain bilaterally
Ø Cold spots on the forehead
Ø Vasodilators precipitate attack
Ø  nitroglycerine, alcohol, histamine
Ø Vasoconstrictors bring relief
Ø  norepinephrine, DHE, ergotamine, exercise
Hypothalamic
dysfunction
F  Alterations in cortisol, prolactin, melatonin,
endorphins, testosterone
F  Periodicity
LSD and Psilocybin
F  93 cases of psilocybin
F 
F 
F 
F 
F 
100% effective in 37
partially effective in 46
ineffective in 5
abortive in 30/32
Subthreshold in 29/62
F  11 cases reported of LSD
F  100% effective in 10
F  >75% effective in 1
F  subthreshold in 5/10
Neurology, 66:1920-2, 2006
BOL
Pharmacodynamics
Ø  BOL (and LSD) increases serotonin in visceral tissues
Ø Heart + brain BOL, not LSD decreased serotonin
Ø LSD increased serotonin in all parts of the brain except
cerebrum
Ø BOL decreased serotonin in all parts of the brain, larger
decreases in the cerebrum
Treatments
F  Abortive
F  Oxygen--inconvenient
F  Intranasal lidocaine--adjunctive only
F  Triptans--can’t be used frequently
F  Prednisone--many side effects
F  Prophylactic
F  Verapamil--partially effective
F  Lithium--narrow therapeutic window
F  Ergotamine--risk of ergotism
F  Methysergide--retroperitoneal fibrosis
F  SOME PATIENTS DO NOT RESPOND TO ANYTHING!
Subject 1
Ø  44 yrs
83 kg
Ø  CH since about 3 yrs 1-6 episodes weekly
Ø  Typical CH symptoms
VAS 8-10
Ø  Therapy: Sumatriptan nasally
Ø  Prophylactic verapamil with some success
Subject 1 Preassessment
February
14
VAS 4.3
15
10
16
10
17
7.2
18
8.5
19
8.0
21
10
Subject 1 Acute
effects
Ø  February 22
9.00 2.5 mg p.o.
Ø  + February 27 and March 3
Ø  Vital signs unchanged
Ø  Flabby feeling, little bit nausea
Subject 1 Follow-up
General effects
Ø  CH attacks still there
Ø  Less neck pain
for weeks
Ø  Frequency reduction
10 instead of 15-20
Ø  Pain reduction
30 % for 2 months
Subject 2
Ø  27 yrs
68 kg
Ø  Chronic CH for 10 yrs
Ø  Typical CH symptoms
Ø  Therapy so far: good response for O2
Ø  Prophylactic verapamil with no success
Subject 2 Preassessment
March
4
VAS
9.2
5
10
6
7.7
7
9.7
8
7.0
9
6.8
10
8.0
Subject 2 Acute
effects
Ø  March 11 9.00
9.45 coincidentally CH
Ø  but only VAS 4 and at 10 a.m. VAS <1
Ø  At 11.15 no pain
Ø  Vital signs unchanged
Ø  Funny feeling, sweating hands, face warm, muscles tense
Subject 2 Follow-up
Ø  Additional BOL at March 16 + 21
Ø  March 23
VAS 4.4
Ø  March 31 VAS 2.2
Ø  Visits
May 9
September 23
Ø  No further attacks reported
International
research
USA
Psilocybin
Germany
Psilocybin
Harvard Medical School
LSD
Hannover Medical School
LSD
BOL
Pharmacodynamics
Ø  BOL is displacing bound 3-H-LSD
Ø  No reduction in turnover of central 5-HT + NA
Ø  Highest binding in frontal + temporal cortex
Ø  Less in parietal + motor cortex
Ø  More less in basal ganglia + thalamus
Side-effects with 20 mg
i.v.
Ø  Drowsiness
Ø  Depression
Ø  Vital signs unchanged
Ø  Irritation + restlessness
Ø  Derealization + depersonalization
Ø  No hallucinations or psychedelic effects
BOL
Ø  Synthetic production
Ø  Certification
Ø 
Scottish men with episodic CH since 18 yrs
Ø 
CH every seven month for 4 weeks with 6 attacks per dayH
Ø 
In 1993 LSD recreationally
Ø 
Next expected attack did not occur
Ø 
Next two years LSD 3-4 times and missed all clusters
Ø 
After 12 month abstinence from lsd his attacks came back
Ø 
He then took psilocybin every 3 month
Ø 
Hethen consumed only sub-threshold doses of psilocybin (qurter of effective dose)
Ø 
And did not experience any CH attacks
Ø 
He then discontinued psilocybinfor testimg purposes and in january 1998 his next ch peroid began
Ø 
First pst on this in the internet was on july 28, 1998
Ø 
He from then on ingested psilocybi mushrooms every six months
History
Planned psilocybin
study
Ø  Harvard study
Ø  Research protocol written
Ø  Days 1, 5 and 10 psilocybin 10-20 mg p.o.
Ø  Headache diaries
Ø  Frequency and ... As outcome parameters
Conventional
treatment
Ø Lithium less effective > thyroid and kidney damage
Ø Methysergide less effective > retroperitoneal fibrosis
Ø Ergotamine less effective > not in heart conditions
Ø For 10% of patients no medication works
Ø New implantable neurostimulators > complications
History
Ø  Early use of Mutterkron (ergot) in headaches
Ø  A. Hofmanns ergot derivatives used in headaches
Harvard survey chronics
Ø  21 participated
Ø  5 of 7 psilo aborted CH attack
Ø  10 of 20 complete terminatio of attacks
Ø  8 partial efficacy
Ø  period delayed or prevented
Ø  Subhallucinogenic doses some efficacy in 42%
Sewell et al. 2006
Outcome measures
Ø  Frequency of headaches
Ø  Intensity of headaches
Ø  Symptom constellation
Ø  Side-effects
Ø  Time to next cluster attack
Sample
data