Statement of the Problem - Headache Cooperative of New England

Marijuana and
Hallucinogens for Headache
Brian E. McGeeney, MD, MPH
Department of Neurology
Boston Medical Center
Boston University School of Medicine
Overview
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Historical overview of cannabis (marijuana)
Early use of cannabis in western medicine
Forms, benefits & harms of marijuana
Clinical trial data & medical marijuana
Types of hallucinogens
Hallucinogens in cluster headache
Federal Controlled Substance Schedules
Schedule
Accepted
medical
use?
Potential for Abuse,
addiction or physical
dependence
Examples
Schedule 1
No
High
Marijuana, LSD, Heroin,
Mescaline
Schedule 2
Yes
High
Morphine, oxycodone,
methadone, cocaine
hydrocodone/acetaminophen
Schedule 3
Yes
Less than schedule 1 &2 Opioids combined with a nonopioid; Codeine combinations
Schedule 4
Yes
Less than schedules 1-3
Benzodiazepines, chloral
hydrate
Schedule 5
Yes
Less than schedules 1-4
Antitussives with limited
amounts of codeine
Dependence Potential
Comparative Danger and Dependence
Active Dose/Lethal Dose
From Wikipedia, Adapted from Gable, R. S. (2006). Acute toxicity of drugs versus regulatory status. In J. M. Fish
(Ed.),Drugs and Society: U.S. Public Policy, pp.149-162, Lanham, MD: Rowman & Littlefield Publishers.
Early Historical Use of Cannabis
The first medicinal use is
recorded in a Chinese
document from the first 2
centuries AD, states passed
down from Emperor
Shen Nuang in the 3rd
millenium BC
Emperor Shen Nuang (2838-2698 B.C.)
Li, HL. An archaeological and historical account of cannabis in China. Econ. Bot. 1974;28:437-448
Hildegard of Bingen (1098-1179)
Hildegard was the first major German mystic; a proliferative writer,
philosopher, prophet, poet, dramatist and physician. From age 6
began having visions, which she said came straight from God. Her
visions were pivotal in directing her to a life of mysticism.
From Physica-“Whoever has an empty brain and head pains may eat
it [cannabis] and the head pains will be reduced”
Introducing Cannabis into Western Medicine
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Dr. O'Shaughnessy's 1839 paper caused a
sensation when it became widely
available in England. Physicians
throughout Europe and America tried
cannabis for a huge variety of illnesses.
Also introduced electrolyte
replacement for cholera and the
introduction of the telegraph to India
for which he was knighted by Queen
Victoria
W. B. O'Shaughnessy, MD (1809-1889)
O'Shaughnessy, W.B., 1839. On the Preparations of the Indian Hemp, or Gunjah, Transactions of the
Medical and Physical Society of Bengal, 8, 1838-40, 421-461. Reprinted in Mikuriya, 1973, 3-30.
Moon JB. Sir William Brook O’Shaughnessy-the foundations of fluid therapy and the Indian Telegraph Service. N Eng J Med
1967;276:283-4
First Cannabis use for Chronic Daily
Headache!
 “The headache to which I wish
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to draw attention is of a dull,
continuous or subcontinuous
character, attended sometimes
with paroxysmal exacerbations”
“..may last weeks, months or
even years”
Describes a regimen of
increasing doses of cannabis,
twice daily.
Mackenzie S. Remarks on The Value Of Indian Hemp in The Treatment of a
Certain Type of Headache. Br Med J. 1887 January 15; 1(1359): 97–98.
Belladonna & Cannabis Suppositories
(1889)
Farlow, JW. On the use of Belladonna and cannabis indica by the rectum in
gynecological practice. Boston Med. And Surg. Jour. 120;507-509: 1889
Cannabis for Headache
‘Reefer’ in Southern US Culture
‘Reefer Man’ Cab Calloway Orchestra 1933
Harry J. Anslinger
Director of the Federal Bureau of Narcotics (1930-1962)
“Colored students at the Univ.
of Minn, partying with female
students (white) smoking
[marijuana] and getting
sympathy with stories of racial
persecution. Result
pregnancy”
From The Protectors, Harry J Anslinger and the Federal Bureau of Narcotics 1930-1962,
By John C McWilliams, page 53. McWilliams cites “13. ‘Arrest and Conviction’ AP, box 8,
file 10.” Located in Anslinger personnel files donated to Penn State University
Medical Marijuana in the United States
1996: California
1998: Alaska, Oregon, Washington
1999: Maine
2000: Colorado, Hawaii, Nevada
2004: Montana
2006: Rhode Island
2007: New Mexico, Vermont
2008: Michigan
2010: Arizona, New Jersey
2011: Delaware, Washington, D.C.
2012: Connecticut, Massachusetts
2013: New Hampshire, Illinois
2014: Maryland, Minnesota, New York
2015: Georgia
www.wikipwdia.com Lokal_Profil - Vector map from Blank US Map.svg by User:Theshibboleth. Information and colours from Map-of-US-state-cannabis-laws.png by CL8 who credited www.norml.org in 11/06
Inhalation
Oral Ingestion
Baked Goods
Vaporizers
Marijuana oil
Cooking
Tincture of
Marijuana
Vaporizing Marijuana
From National Geographic Channel’s Drugs Inc. ‘Marijuana’ (2011)
Beneficial Effects of Marijuana
NERVOUS SYSTEM
Symptoms of Multiple Sclerosis
Pain of peripheral neuropathy
Migraine
Seizures
Anxiety & Depression
?Alzheimer’s disease
?Parkinson’s disease
RHEUMATOLOGY
Joint pains (arthritis)
CANCER PAIN
GASTROENTEROLOGY
Antiemetic
Appetite stimulant
?Treat inflammatory bowel
disease
OPHTHALMOLOGY
Reduces IOP, treating
glaucoma
Criticisms of Medical Marijuana
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Abuse potential and gateway drug
Patients want it recreationally
No dosing control
Federally illegal!
Backdoor legalization
Lack of scientific evidence
supporting benefit
Increased diversion to minors
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Brain maldevelopment or damage
Ill effects-  Memory and cognitive impairment
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Lung damage, cancer?
Psychosis/Schizophrenia?
Adverse Effects of Marijuana
CENTRAL NERVOUS
SYSTEM
Memory impairment
Anxiety, panic, paranoia
Addiction
?Schizophrenia
CEREBROVASCULAR
?TIA/Stroke
RCVS
PERIPHERAL VASCULAR
Raynauds
Thromboangitis obliterans
CARDIOVASCULAR
Increased angina frequency
Myocardial infarction
Cardiomyopathy
Arrhythmia
RESPIRATORY
Resp. symptoms
Bronchitis
?COPD
?cancer
GASTROENTEROLOGY
Cannabis hyperemesis syndrome
Pulmonary Effects of Marijuana Smoking
Increased risk of chronic bronchitis
No clear link to COPD
Smoke contains carcinogens
No demonstrable risk of cancer from
light or moderate use
Evidence mixed on carcinogenic risk
of long-term heavy use
Far lower risk of pulmonary
complications than tobacco
Tashkin DP. Effects of Marijuana Smoking on the Lung. Ann Am Thorac Soc 2013;10:239-247
Cardiovascular Effects of Marijuana
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Associations
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Myocardial infarction
Sudden cardiac death
Cardiomyopathy
Stroke/TIA
Arteritis
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Several reports note temporal
relation between marijuana use and
MI in the hour after dosing-many
normal coronary arteries
May also precipitate MI in those with
CAD
After MI, mortality rate significantly
higher in marijuana users
Enhances sympathetic tone
Marijuana increases heart rate and
blood pressure
Thomas G, et al. Adverse Cardiovascular, Cerebrovascular, and Peripheral Vascular Effects of Marijuana
Inhalation: What Cardiologists Need to Know. Am J Cardiol 2013
Marijuana and Brain Abnormalities?
The Journal of Neuroscience April 16th 2014
Marijuana and Brain Abnormalities?
40 people aged 18-25 years. Half
used marijuana at least once
weekly (starting 14-18 years old),
other half did not use.
For marijuana users, found
greater density values in the
nucleus accumbens and
amygdala.
Gilman JM, et al. Cannabis Use Is Quantitatively Associated with Nucleus Accumbens and Amygdala Abnormalities in
Young Adult Recreational Users. The Journal of Neuroscience April 16th 2014
Marijuana and Brain Abnormalities?
Limitations
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No measures of cognitive performance or any other
behaviors. Impossible to interpret meaning of any
brain measure differences
Marijuana group used multiple other substances;
impossible to disentangle the effects of marijuana
form those of other drugs
Association is not causation! Authors repeatedly and
explicitly state a causative relationship between
marijuana use and anatomic changes, only to state 2nd
last paragraph no causative relationship can be
concluded due to the cross-sectional design!
Impediments to Cannabis Research
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National Institute of Drug Abuse (NIDA) the sole
source of research grade cannabis for all US trials
NIDA contracts only with University of Mississippi
to grow the cannabis-dependent on their strains
DEA registration for a schedule 1 substance
IND application on file with the FDA
Privately funded marijuana studies must go through
Public Health Service review in addition to FDA—
an extra step that does not exist for research
concerning any other drug. That review is mandated
by the Department of Health and Human Services,
not DEA. REMOVED JUNE 2015
In the last year the Federal Government has
increased production from 46 pounds to 1400
pounds to ensure product for future trials!
Nelson B. Medical Marijuana: Hints of Headway? Cytosource 2015;123:67-68
Whiting PF et al. Cannabinoids for Medical Use. A Systematic Review and Meta-analysis. JAMA 2015;313:2456-2473
Conclusions
Moderate-quality evidence to
support the use of cannabinoids
for the treatment of chronic pain
and spasticity.
There was low-quality evidence associated with improvements in
nausea and vomiting due to
chemotherapy, weight gain in HIV
infection, sleep disorders, and
Tourette syndrome.
Whiting PF et al. Cannabinoids for Medical Use. A Systematic Review and Meta-analysis. JAMA 2015;313:2456-2473
AAN Guideline On Cannabis in Multiple Sclerosis
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May offer oral cannabis extract (OCE)
for MS related symptoms of spasticity
and pain (excluding central neuropathic
pain) Level A and THC (Level B)
OCE probably ineffective for improving
objective spasticity measured (short
term) or tremor (Level B)
Might offer Sativex oromucosal
cannabinoid spray to reduce symptoms
of spasticity, pain and urinary frequency
(Level B)
Yadav V et al. Summary of evidence-based guideline: Complementary and alternative medicine in multiple sclerosis. Report of the
Guideline Development Subcommittee of the American Academy of Neurology. Neurology 2014;82:1083-1092
Conclusions
Moderate-quality evidence to
support the use of cannabinoids
for the treatment of chronic pain
and spasticity.
There was low-quality evidence associated with improvements in
nausea and vomiting due to
chemotherapy, weight gain in HIV
infection, sleep disorders, and
Tourette syndrome.
Whiting PF et al. Cannabinoids for Medical Use. A Systematic Review and Meta-analysis. JAMA 2015;313:2456-2473
FDA Approved Cannabinoids
Dronabinol
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Schedule 3
Trans isomer of synthetic THC
FDA indicationsChemo induced n/vomiting
Anorexia associated weight loss with AIDS
Limitation is oral
admin &
absorption from
stomach
Nabilone
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Schedule 2
Synthetic THC mimic
FDA indication
-Chemotherapy induced n/vomiting
Sativex (Nabiximols)
Features in American Academy of Neurology Guideline On Cannabis in MS
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Not approved
in the US
www.gwpharm.com
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Each spray- fixed dose of THC 2.7mg and
CBD 2.5mg, derived from plants (not
synthetic)- a tincture
Launched in 27 countries (incl. UK and
Canada) for MS spasticity
In development for cancer pain and
neuropathic pain
Side effects- dizziness (25%),
drowsiness(8.2%) and disorientation (4%)
Otsuka Pharmaceuticals has exclusive license
to develop and market Sativex in the US
Oral CBD only product in trials
Cannabinoids in Epilepsy
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Despite >20 anti-seizure meds, 30% of people with
epilepsy still have seizures
Preliminary studies identified defects in
endocannabinoid system in those with epilepsy
(lower levels of CSF anandamide)
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Historically only 4 placebo-controlled studies
using cannabinoids and epilepsy- problems with
methodology, poor power and lack of blinding
Cannabidiol (CBD) -anti-seizure- independent of
endocannabinoid system
THC and synthetic THCs can provoke seizures
Friedman D, Devinsky O. Cannabinoids in the Treatment of Epliepsy. N Engl J Med 2015;373:1048-58
GlossD, Vickrey B. Cannabinoids for epilepsy. Cochrane Database Syst Rev 2014;3:CD009270
Epidiolex from GW Pharmaceuticals
Clinical evidence with
Cannabinoids & Headache
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Studies on the use of
cannabinoids for pain started
in the 1970’s
There are no blinded studies
on the use of cannabinoids
for headache
Russo E. Cannabis for migraine treatment: the once and future prescription? An
historical and scientific review. Pain 1998;76:3-8
Experimental evidence with
Cannabinoids & Headache
Goadsby et al demonstrated
that an endogenous
cannabinoid receptor ligandanandamide was able to
inhibit dural blood vessel
dilation from electrical stim,
CGRP, nitrous oxide and
capsaicin and this was reversed
by a cannabinoid antagonist
Akerman S, Kaube H, Goadsby PJ. Anandmide Is Able to Inhibit Trigeminal Neurons Using an in Vivo
Model of Trigeminovascular-Mediated Nociception. J Pharm Exp Therapeutics. 2003;309:56-63
Retrospective observational
study- Medical Marijuana clinic
Identified 262 pts between
1/2010-9/2014 with migraine
121 had a follow up visit- included
68% previous or current marijuana
use on first visit
Primary outcome: number of
migraines/month
Headaches/month
reduced 10.4-4.6 (p<0.01)
 85% pts decrease in
frequency, 15% same and
3% increase in freq.
Forms- Vaporized 42pts,
edible 66 pts, smoked 65 pts,
topical 15 pts
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Rhyne DN et al. Effects of Medical Marijuana on Migraine Headache Frequency in an Adult Population.
Pharmacotherapy 2016 Jan 9. doi: 10.1002/phar.1673. [Epub ahead of print]
Cannabinoid Receptor Evolution
Cannabinoid Receptor Evolution
Cannabinoid receptors occur
throughout the vertebrates- hence are
evolutionarily ancient.
Genes for such a receptor were found
in the deuterostomian invertebrate
Ciona intestinalis, but not in
protostomian invertebrates (e.g.
Drosophila).
Ciona intestinalis
(transparent sea squirt)
Likely that cannabinoid receptors
developed first in deuterostomian
invertebrates
Hallucinogens and Headache
The Beginings of Hallucinogen use
for Cluster Headache
Psilocybin cubensis growing in manure. Yum!
In 1998 a 35 year old
Scottish man wrote on
clusterheadache.com. He
had episodic cluster for
many years. One year he
skipped his fall cycle and the
only thing different was
recreational use of LSD
during summer and this
started to be discussed
Personal communication, Bob Wold, cluster headache sufferer and founder of a cluster headache website
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.
21/53-chronic CH and 10/20 who used psilocybin reported a
complete cessation of attacks
2 chronic CH pts used LSD, at sub-hallucinogenic doses, both
stopped attacks
Sewell RA, Halpern JH, Pope HG. Response of cluster headache to psilocybin and LSD. Neurology 2006;66:1920-1922
From National Geographic Channel
Drugs Inc. Hallucinogens (2012)
Hallucinogens and Headache
Indole ring, the primary structure of serotonin,
tryptophan, and hallucinogenic compounds
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Lysergic acid amide containing seeds
Psilocybin containing mushrooms
Lysergic acid diethylamide or other synthetic tryptamines
Lysergic Acid Amide (LSA)
3 natural sources available
 Rivea Corymbosa seeds
 Hawaiian Baby Wood
Rose seeds
 Morning Glory seeds
(certain strains)
Rivea Corymbosa (Ololiuqui)
In the US it is LEGAL to buy,
sell and cultivate these seeds.
LSA however is schedule lll
Lysergic Acid Amide (LSA)
Rivea Corymbosa seeds
analyzed by Dr Hofmann
and found ergot
alkaloidsd-Lysergic acid amide
(ergine and epimer
isoergine)
Rivea Corymbosa (Ololiuqui)
Hofmann, A. Teonanacatl and Ololiuqui, two ancient magic drugs of mexico. Bull Narcotics. 1971;1:3-14
Legal Issues with Psilocybin Mushrooms
Possession of psilocybin
containing mushrooms is
illegal (Schedule 1).
What can happen!
Spores do not contain
psilocybin and are not
illegal in most US states.
Spores are illegal in CA,
Georgia and Idaho.
LSD and Migraine
Thoth Press 2003
Otto snow outlines his use of LSD
(pub. 2003) to treat migraine
attacks and with periodic use keep
attacks away.
He references Ling & Buckman
(1963) who detail the clinical use of
LSD for cases of anxiety, frigidity,
migraine, psoriasis, etc., based on
their treatment of over 350 patients
at Marlborough Day Hospital (in
London).
Thomas M. Ling and John Buckman, Lysergic Acid (LSD-25) & Ritalin in the Treatment of Neurosis. The Lambarde
Press (London), 1963
Sicuteri F. Prophylactic treatment of migraine by means of lysergic acid derivatives. Triangle 1963;6(3):116-125
Really bad Places to Dose
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At a HCNE meeting
Dinnertime at your girlfriends
parent’s house
In line for driver’s license
renewal
Your Boss’s wedding
Your sanity hearing
Your probation and parole
office
The employment office
In your physicians waiting room
2-Bromo-LSD for Cluster Headache
A Case Series
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
X3
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
2-Bromo-LSD for Cluster Headache
A Case Series
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
5-MeO-DALT
(N,N-diallyl-%-methoxytryptamine)
Active at 10-12mg
Shulgin dose 12-20mg
Duration 2-4 hours
Rapid 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 2013
Simple chemical, mild s/e, orally
bioavailable, and easy to obtain
(not banned)
5-MeO-DALT
(N,N-diallyl-%-methoxytryptamine)
Tryptamine class are normally
unlikely to cause life-threatening
changes in cardiovascular, renal or
hepatic function
Active at 10-12mg
Shulgin dose 12-20mg
Duration 2-4 hours
Rapid onset and drop off
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
Doctor-Patient Communication and First
Amendment Rights
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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
THE END!