Prof. Torsten Passie Harvard Medical School, Boston Hannover Medical School, Germany

Bromo-LSD

Behandlung von Cluster-Kopfschmerz

in der

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 > Tank

Ø  Triptane bei 70% effektiv > NW + Kosten

Ø  Verapamil Prophylaxe > NW

Ø  Prednisone Prophylaxe > NW

Ø  Neurostimulatoren > Komplikationen

Ø 

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

BOL-148 LSD

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 VAS-Schmerzskala CGI

Ø  Visits

Number of attacks/week

10

5

Weeks

35

15

20

25

30

40

4 1 2 3 5 6 7 8 9 10 11 12

30 mcg BOL every 5 days for 3 doses total

S1

S2

S3

S4

S5

16 14 15 13

Behandlungswirkungen

N = 5

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

Danke für Ihre Aufmerksamkeit

Prof. Torsten Passie Harvard Medical School, Boston Hannover Medical School, Germany

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

Visceral serotonin Brain stem serotonin Cerebrum serotonin CNS arousal Hallucinations

BOL LSD

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 + side-effects

Bertino et al. 1959

Ø  Double blind

Ø  Cross-over

Ø  N = 25

Ø  16, 32, 64, 128, 256 mcg/kg

BOL effects + side-effects

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 + side-effects

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

  Alterations in cortisol, prolactin, melatonin, endorphins, testosterone

  Periodicity

LSD and Psilocybin   93 cases of psilocybin   100% effective in 37   partially effective in 46   ineffective in 5   abortive in 30/32   Subthreshold in 29/62

  11 cases reported of LSD   100% effective in 10   >75% effective in 1   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

  Abortive   Oxygen--inconvenient   Intranasal lidocaine--adjunctive only   Triptans--can’t be used frequently   Prednisone--many side effects

  Prophylactic   Verapamil--partially effective   Lithium--narrow therapeutic window   Ergotamine--risk of ergotism   Methysergide--retroperitoneal fibrosis

  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 Pre-assessment

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 Pre-assessment

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 Harvard Medical School

Psilocybin LSD

Germany Hannover Medical School

Psilocybin 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  Irritation + restlessness

Ø  Derealization + depersonalization

Ø  No hallucinations or psychedelic effects

Ø  Vital signs unchanged

BOL

Ø  Synthetic production

Ø  Certification

History 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

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