Brian E. McGeeney, MD, MPH, MBAAssistant Professor of Neurology

Pain Management Group, Neurology Department

Boston University School of Medicine

Disclosures

Consulting: Pernix,

Promius Pharma, Alder

Stock: Pfizer (small)

Psychedelic Medicine

May 13th 1957- Gordon Wasson, (a VP at

JP Morgan) describe spending last 4

summers in a remote mountain village in

Mexico (with his wife, a pediatrician)

consuming psilocybin mushrooms! Set off

US psychedelic cultural revolution

Psychedelic drugs exert profound effects on the brain and behavior, with minimal toxicity/adverse events

‘Psychedelic’ named by Humphrey Osmond 1957-mind-manifesting capability revealing useful properties

Between 1950-mid 1960’s more than 1000 clinical papers discussing 40,000 patients, several dozen books, 6 international conferences on psychedelic drug therapy

Perception that use associated with anti-war attitudes and rejection of conventional norms.

Clinical research slowed considerably after 1970, but in recent years has increased again

Grindspoon L, Bakalar JB. 1979. Psychedelic Drugs Reconsidered. Basic Books, New York p192 Osmond H. A review of the clinical effects of psychomimetic agents. 1957 Ann NY Acad Sci 66:418-434

Psychedelic Medicine

Ross, S et al. (2016) Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J. Psychopharmacol. 30, 1165–1180

Griffiths, RR. et al. (2016) Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer:a randomized double-blind trial. J. Psy- chopharmacol. 30, 1181–1197

Krebs, TS,Johansen,PO.(2012) Lysergic acid diethylamide (LSD) for alcoholism: meta-analysis of randomized controlled trials. J. Psychopharmacol. 26, 994–1002

Recently, 2 RCTs with psilocybin for anxiety and depression in subjects with life-threatening cancer were clearly positive and a favorable meta-analysis of data on LSD used to treat alcoholism (RCTs) was published

Extensive anecdotal use; used by cluster headache patients over the last 15 years+

Non-addictive, do not have direct effects on brain dopaminergic systems

Outcome related to set and setting like no other drug class

May 13th 1957- Gordon Wasson, (a VP at

JP Morgan) describe spending last 4

summers in a remote mountain village in

Mexico (with his wife, a pediatrician)

consuming psilocybin mushrooms! Set off

US psychedelic cultural revolution

Classical hallucinogens Indolamines ➢ Lysergic acid amide (LSA or ergine, in seeds)

➢ N,N-dimethyltryptamine DMT (in Ayahuasca)

➢ Psilocybin & psilocin (in ‘magic mushrooms’)

➢ lysergic acid diethylamide (LSD, synthetic)

➢ 5-Meo-DALT (synthetic)

Phenylalkylamines ➢ Mescaline (in peyote cactus)

➢ phenethylaines (‘amphetamines’)

➢ MDMA (Ecstacy)

Psychedelic Medicine

Preparing the brew ayahuasca, containing DMT plant other

alkaloids (MAOI effect) made in Peru & Brazil for ceremonies

In 1998 a 35 year old Scottish man with episodic cluster headache posted his personal observations on clusterheadache.com. One year he skipped his fall cycle and the only thing different was recreational use of LSD during summer and this started to be discussedPsilocybin cubensis growing in manure. Yum!

Personal communication, Bob Wold, cluster headache sufferer and founder of Clusterbusters

The Beginnings of Psychedelics for Cluster Headache

Psilocybin or LSD for Cluster Headache

➢ Survey of cluster headache (CH) patients who use one of these agents as an abortive and to induce a remission (21 chronic, 32 episodic)

➢ 10/20 chronic CH pts who used psilocybin reported a complete cessation of attacks- induced remission

➢ 2 chronic CH pts used LSD, at sub-hallucinogenic doses, both stopped attacks (10 days and 2 months)

Sewell RA, Halpern JH, Pope HG. Response of cluster headache to psilocybin and LSD. Neurology 2006;66:1920-1922

Psilocybin or LSD for Cluster Headache

Hallucinogens and Headache

Lysergic acid amide (LSA) containing seeds Psilocybin containing mushrooms Lysergic acid diethylamide (LSD) & other synthetic tryptamines

Indole ring, the primary structure of serotonin, tryptophan, and hallucinogenic compounds

Lysergic Acid Amide (LSA)3 natural sources available Rivea Corymbosa seeds Hawaiian Baby Wood Rose seeds Morning Glory seeds (certain

strains)

Rivea Corymbosa seeds analyzed by Dr Hofmann and found ergot alkaloids- d-Lysergic acid amide (ergine and epimer isoergine)

In the US it is LEGAL to buy, sell and cultivate these seeds. LSA however is schedule lll, so illegal to ingest

Rivea Corymbosa (Ololiuqui)

Hofmann, A. Teonanacatl and Ololiuqui, two ancient magic drugs of mexico. Bull Narcotics. 1971;1:3-14

Ergot Alkaloids

Alkaloids are produced by diverse fungi, family Clavicipitaceae most well known

Alkaloids derived from L-tryptophan hold the indole nucleus in a ring system

Biologically, the alkaloid is any biologically active and heterocyclic chemical compound that contains nitrogen and may have some pharmacological activity and, in many cases, medicinal or ecological use

Chemical structures of ergot alkaloids

LSD

DHE

(Sansert)(Methergine)

Ergotamine

Ergot AlkaloidsMany species in the Claviceps family are endophytes, systemic symbionts that persist for the lifespan of the host plant and via seeds transmissible indefinitelyGrowth by endobiotic (growth is between plant cells within tissues) and epibiotic growth (on surface/between tissues)

Lysergic Acid Amide AlkaloidsErgonovine (ergometrine), commercially used to stimulate uterine contractionMethylergonovine and methysergide both synthetic examples

Peptide AlkaloidsErgotamine, partial agonist 5-HT types and alpha-adrenergic receptorsDihydroergotamine (synthetic) poor oral bioavailabilityBromocriptine (synthetic)Chemical structures of ergot alkaloids

LSD

DHE

(Sansert)(Methergine)

Psilocybin MushroomsPsilocybe cubensis, a tropical mushroom, has many ‘strains’ and can be grown from sporesOral bioavailability is high, ~50%, 1st pass metabolism converts psilocybin to the active psilocin appearing in the blood 30-50 minutes after ingestionPsilocybin 45 times less potent than LSD Psilocybin can cause headache!

Dry P. cubensis ~0.63% psilocybin 0.6% psilocin Cluster pts typically stop all medications before dosing0.5g-1g light dose, 5g ‘heroic dose’ dry weightClinical effect ~6 hours PO (iv only ~20 minutes)Generally dose on day 1,5,10Goal is to induce a remission or keep in remission

Johnson MW, Sewell RA, and Griffiths RR (2012) Psilocybin dose-dependently causes delayed, transient headaches in healthy volunteers. Drug Alcohol Depend 123: 132–140.

Psilocybin Mushrooms

Possession of psilocybin containing mushrooms is illegal (Schedule 1)Spores do not contain psilocybin and are not illegal in most US states. Spores are illegal in CA, Georgia and Idaho

Psilocybin Mushrooms

Psilocybin mushrooms featured in a series of stamps from the Republic of Benin (1996)

From National Geographic ChannelDrugs Inc. Hallucinogens (2012)

Pioneering psychiatrist Stanislov Grof

characterized LSD as a ‘nonspecific

amplifier of the unconscious’, based on

personal supervision of more than 1000

clinical administrations of LSD. He has

over 60 years of experience in research

on altered states of consciousness

➢ First synthesized in 1938, with psychedelic properties discovered in 1943 by Hoffman

➢ Relatively non selective serotonin and dopamine receptor ligand

➢ Clinical effects from about 25mcg orally

➢ Half life about 3 hours and clinical drug effect for about 12 hours or less

➢ Thought to be >50% protein bound ➢ Use for cluster much less than psilocybin,

for access/supply reasons

Lysergic Acid Diethylamide (LSD)

2-Bromo-LSD for Cluster Headache

➢ Brominated LSD (BOL or BOL-148) looses psychedelic effect but may still be useful for cluster headache

➢ Overlap pharmacology between BOL and LSD-when 1000mcg BOL TID PO for 5 days to 10 volunteers, the effect of 1mcg/kg LSD was significantly attenuated. (Isbell et al 1959)

➢ If a single dose of 2000-4000mcg BOL given along with LSD, there was no effect on the LSD response

➢ Further understanding of BOL requires more analysis of receptor binding and functional effects

Isbell H, Miner EJ, and Logan CR (1959) Cross tolerance between D-2-brom-lysergic acid diethylamide (BOL-148) and the D-diethylamide of lysergic acid (LSD-25). Psychopharmacology (Berl) 1:109–116.

2-Bromo-LSD for Cluster Headache

Karst M, et al. The non-hallucinogen 2-bromo-lysergic acid diethylamide as preventative treatment

for cluster headache: An open, non-randomized case series. Cephalalgia 2010;30(9):1140-1144

An open, non-randomized case series

of 5 Cluster headache patients (4

chronic 1 episodic who failed verapamil

and various other prophylactic agents

30µg/kg in water PO q 5 days X 3

Active at 10-12mg Shulgin dose 12-20mgDuration 2-4 hoursRapid onset and drop off

First synthesized by noted chemist Alexander Shulgin ~2004 (recreational) and became available online 2004 with no published scientific papers

First tried for cluster –late 2013Simple chemical, mild s/e, orally bioavailable, and was easy to obtain-unscheduled in US but likely falls under Analogues Act

5-MeO-DALT(N,N-diallyl-5-methoxytryptamine)

Active at 10-12mg Shulgin dose 12-20mgDuration 2-4 hoursRapid onset and drop off

Tryptamine class are normally unlikely to cause life-threatening changes in cardiovascular, renal or hepatic function

Safety unknown, with very low exposure numbers compared to psilocybin or other tryptamines

Last few years banned in a number of countries. Not in USA but may be illegal via banned analogue

5-MeO-DALT(N,N-diallyl-5-methoxytryptamine)

The Serotonin ConnectionIn 1954 suggested that LSD psychedelic effects were due to interference with serotonin in the brainAnden et al (1968) suggested LSD might be a direct serotonin agonist at serotonin receptors Serotonin (5-HT) performs its physiological functions by binding to specific cell membrane receptors

1998 the first clear evidence that the psychedelic effects were 5-HT2A mediated14 different serotonin receptors, classified into 7 subfamilies according to their primary structure and functional properties

Excluding 5-HT 3, which belongs to the ion channel receptor superfamily, the remainder of the 5-HT receptors are G protein-coupled receptors

Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Bäbler A, Vogel H, and Hell D (1998) Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport 9:3897–3902.

Biogenic monoamines including serotonin

are evolutionary old and important

modulators of long-lasting changes in cells.

They are found in many protozoans like

Tetrahymena pyriformis (above), a free

living ciliate common in freshwater ponds

López-Giménez JF, González-Maeso J.Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathways Curr Topics Behav Neurosci 2017 Jul 5

The Serotonin ConnectionPsychedelic agents are (partial)agonists at 5-HT2A, 5-HT2C and 5-HT1A receptors with downstream effects on glutamate, GABA, and dopamine among others

Psychedelic effects are due to action on 5-HT2A receptor, confirmed with clinical studies on specific 5-HT2A antagonist ketanserin, and 5-HT2A knockout mice (some 5-HT2A agonists do not cause psychedelic effects such as ergotamine)

➢ 5-HT 2A widely distributed in the brain- highest density in the neocortex, also seen in hippocampus, thalamus, hypothalamus and midbrain nuclei

➢ Substantial differences in distribution of 5-HT2A between different mammals (close in evolutionary terms)

➢ Rapid development of tolerance to psychedelic effects, thought to be due to 5-HT-2A downregulation. Daily use of LSD leads to a complete loss of sensitivity to drug by day 4 with cross tolerance to other psychedelics

➢ In contrast with most other GPCRs the 5-HT2A receptors undergoes downregulation in response to either agonist or antagonist

➢ Of other receptors, most consistent finding is involvement of 5-HT1A-tryptamines and LSD have significant affinity for, and 5-HT1A & 5-HT2A receptors co-localized on cortical pyramidal cells

➢ Psychedelics enhance glutamatergic transmission in the cortex

López-Giménez JF, González-Maeso J.Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathways Curr Topics Behav Neurosci 2017 Jul 5

The Serotonin Connection

Are Hallucinations an Essential part of the Purported Benefit for Cluster Headache? No!

➢ Many cluster patients treat at sub-hallucinogenic doses with effect

➢ 2-Bromo-LSD appears effective, small series

➢ Some patients have taken benzodiazepines to avoid hallucinogenic effects, but get benefit

Structurally similar to serotonin and act on serotonin receptors

Readily cross the blood-brain barrier (BBB), whereas the therapeutic serotonin agonists do not (at least not easily)

May have slower dissociation from serotonin receptors than typical medications, with particular significance across BBB

Biased agonism 5-HT2A (graphic on left)

Disrupt the Cluster Headache Circuit in a way that medications do not

Agonist A Agonist B

Pathway Pathway

1 2

Pathway Pathway

1 2

Old understanding of GPCRs having a linear spectrum of

efficacy. Recent discovery of multidimensionality of GPCR

signaling. Ligand specific activity in one pathway over another

Serotonin

receptor

Serotonin

receptor

Why Might Indolamine Hallucinogens Have Superior Outcomes to Standard Therapy?

Structurally similar to serotonin and act on serotonin receptors

Readily cross the blood-brain barrier (BBB), whereas the therapeutic serotonin agonists do not (at least not easily)

May have slower dissociation from serotonin receptors than typical medications, with particular significance across BBB

Biased agonism 5-HT2A (graphic on left)

Disrupt the Cluster Headache circuit in a way that medications do not

T

C

C

Amygdala

SPG

TG

Meningeal

vessels

Superchiasmic

nucleus

Lacrimal glands and

nasopharyngeal mucosa

Cluster Headache Circuit

Why Might Indolamine Hallucinogens Have Superior Outcomes to Standard Therapy?

A Cautious Tale of Serotonin

Carcinoid tumors, rare neuroendocrine tumors (1-2/100K PA), demonstrated to produce serotonin in 1953

Association with heart valvular disease (1950’s)- non-rheumatic, pathophysiology unknown

From 1960’s methysergide and ergotamine associated with similar valvular disease

Exact target mediating the valvulopathyremained unknown

Connolly H et al. Surgical Management of Left-Sided Carcinoid Heart Disease. Circulation. 2001;104:I-36-I-40

Anterior mitral valve leaflet removed at

surgery for severe mitral valve regurgitation

secondary to carcinoid syndrome. Leaflet

and chordal thickening are present. B,

Microscopic examination demonstrates

proliferation of myofibroblast in loose

myxoid matrix

A Cautious Tale of Serotonin Fen-Phen [Fenfluromine and phentermine], 1996 >18M scripts

1997 NEJM 24 subjects recorded on routine evaluation, were taking fen/Phen for average 12 months, all had abnormal valves and regurgitation on echo, 8 had new pulmonary hypertension and 5 needed surgical valve replacement. Abnormalities histopathologically identical to changes seen with carcinoid or ergotamine. Fen-Phen removed from market 1997

Fen/Phen episode renewed interest in identifying the specific 5-HT receptor subtype involved in drug induced valvular disease

The 5HT2B receptor is widely expressed in cardiac valves and its activity results in fibroblast proliferation and structural abnormalities, as demonstrated in heart disease promoted by carcinoid tumors which produce excessive serotonin

Fitzgerald LW et al. Possible Role of Valvular Serotonin 5-HT2B Receptors in the Cardiopathy Associated with Fenfluramine

Mol Pharmacol. 2000 Jan;57(1):75-81

A Cautious Tale of Serotonin

Pergolide and Cabergoline Non-specific dopamine agonists were used in Parkinson’s Disease First report of pergolide and valvular disease 2002, and 5-HT2B activity of both high Pergolide taken off market 2007 and cabergoine not used in PD now but still used at lower doses

for hyper-prolactinemia Multiple cross-sectional studies on those using cabergoline for prolactinomas (smaller dose) did

not identify a valvular problem

R. De Vecchis, C. Esposito, C. Ariano, Cabergoline use and risk of fibrosis and insufficiency of cardiac valves. Meta-analysis of observational studies. Herz 38(8), 868–880 (2013)

Vroonen L et al. Prospective, long-term study of the effect of cabergoline onvalvular status in patients with prolactinoma and idiopathic hyperprolactinemia. Endocrine (2016)

Drug 5-HT2A 5-HT2B 5-HT2C

Serotonin 614 4 12.2

+Norfenfluramine 187 56 27

-Norfenfluramine 267 99 65

Cabergoline 7.8 2.6 190

Pergolide 1.6 14 45

Ergotamine 9.0 3.0 12

Methysergide 15.0 9.1 1.8

Methylergonovine 12.6 0.49 12.4

2013 meta-analysis (De Vecchis) cabergoline and the risk of developing cardiac valve disease in endocrinology. Trend to develop mild to moderate valve regurgitation. Included 7 studies comparing data of 444 treated cases V 954 controls. They conclude that although globally safe, a periodic ultrasound assessment should not be avoided even if cabergoline dose is low. Recent long term prospective study (Vroonen et al) reassuringly negative

So Do Psychedelics Tickle 5-HT-2B?

Receptor Psilocin LSD

5-HT-1A 567.4 1.1

5-HT-1B 219.6 3.9

5-HT-1D 36.4 14

5-HT-1E 93

5-HT-2A 107.2 2.7

5-HT-2B 4.6 30

5-HT-2C 97.3 5.5

5-HT-5A 9

5-HT-5B 3.23

5-HT-6 57.0 2.3

5-HT-7 3.5 6.6

Doctor-Patient Communication and First Amendment Rights

California- medical marijuana in 1996. After DEA threats, physicians brought suit to prohibit the Government from taking action against them for communicating with patients about the medical use of marijuana.

Trial court-DEA action only permissible if Feds had substantial evidence that the physician ‘aided and abetted the purchase, cultivation, or possession of marijuana’.

In 2002- 9th Circuit Court of Appeals affirmed the injunction, ruling that First Amendment prohibits the government from punishing physicians “on the basis of the content [potential usefulness of marijuana] of doctor-patient communications.

Little doubt the US Supreme Court would follow it today

Annas GJ. Medical Marijuana, Physicians, and State Law. NEJM 2014;Sept 11th

A Final Example

Tom went chronic (cluster) July 25th 2005. Failed occipital nerve stimulation and TWO deep brain stimulators.I met him Sept 2014 (left picture)- attack free for~ 43 days after psilocybin. Remains practically free of attacks with psilocybin q 2 months

THE END!