Handbook on Opium : History and

Basis of Opioids in Therapeutics -

eBook PDF
Visit to download the full and correct content document:
https://ebooksecure.com/download/handbook-on-opium-history-and-basis-of-opioids-i
n-therapeutics-ebook-pdf/
Handbook on Opium
This page intentionally left blank
Handbook on Opium
History and Basis of Opioids in Therapeutics

Vasantha K. Kumar, MD
Delta Pain Consultants, Columbus, OH, United States
Academic Press is an imprint of Elsevier
125 London Wall, London EC2Y 5AS, United Kingdom
525 B Street, Suite 1650, San Diego, CA 92101, United States
50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States
The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom
Copyright © 2022 Elsevier Inc. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical,
including photocopying, recording, or any information storage and retrieval system, without permission in writing
from the publisher. Details on how to seek permission, further information about the Publisher’s permissions
policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright
Licensing Agency, can be found at our website: www.elsevier.com/permissions.
This book and the individual contributions contained in it are protected under copyright by the Publisher (other than
as may be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our
understanding, changes in research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any
information, methods, compounds, or experiments described herein. In using such information or methods they
should be mindful of their own safety and the safety of others, including parties for whom they have a professional
responsibility.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for
any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from
any use or operation of any methods, products, instructions, or ideas contained in the material herein.
Library of Congress Cataloging-in-Publication Data
A catalog record for this book is available from the Library of Congress
British Library Cataloguing-in-Publication Data
A catalogue record for this book is available from the British Library

ISBN: 978-0-323-90903-7

For information on all Academic Press publications

visit our website at https://www.elsevier.com/books-and-journals

Publisher: Stacy Masucci

Acquisitions Editor: Katie Chan
Editorial Project Manager: Sara Pianavilla
Production Project Manager: Punithavathy Govindaradjane
Cover Designer: Christian Bilbow
Typeset by STRAIVE, India
The illustration shows three legendary figures in medicine (from left to right): Apollo holding a bow, Aesculapius holding
a serpent-entwined staff, and Hippocrates holding a skull and all three examining a poppy plant. Putti at the steps hold
Materia Medica and a box of various chemicals, while the section on the right shows drugs being produced in the labora-
tory. Oil painting by Johannes Prey (c. 1791 CE) from Wellcome Collection. https://wellcomecollection.org/works/ju4rytva

v
This page intentionally left blank
 Dedication

To my parents, Sara and Kay, for the trail

To my wife Jo and son Barrett for the journey
This page intentionally left blank
Contents

About the Author xiii 3.2 Ancient Egypt 22

Preface xv 3.2.1 Cultivation of poppy 22
Acknowledgments xvii 3.2.2 Papyrus of Ebers 23
3.3 Classical history 24
3.3.1 Hippocrates of Cos 25
Part I 3.3.2 Theophrastus 27
3.3.3 Mithridates of Pontus 28
Plant 3.4 Dawn of common era 29
3.4.1 Scribonius 29
1. Botanical aspects 3.4.2 Celsus 29
1.1 Plant 3 3.4.3 Pliny the Elder 30
1.1.1 Overview 3 3.4.4 Dioscorides 32
1.1.2 Cultivation 3 3.4.5 Galenus 33
1.2 Latex 4 3.5 Synopsis 35
1.2.1 Laticifers 4 References 35
1.2.2 Capsule 5
1.2.3 Extraction of opium 7
4. Postclassical history
1.3 Opium alkaloids 8
1.3.1 Poppy sources 8 4.1 Late Antiquity 39
1.3.2 Nonpoppy sources 9 4.2 Islamic Renaissance 40
1.4 Synopsis 9 4.2.1 Medical glossators 40
References 9 4.2.2 Rhazes 42
4.2.3 Age of addiction 43
4.2.4 Avicenna 44
Part II 4.3 Eastern opium 46
History 4.4 Synopsis 46
References 47
2. Prehistory
2.1 Paleobotanical evidence 13 5. Modern history
2.2 Archaeological evidence 14
5.1 European Renaissance 49
2.2.1 Early humans 14
5.1.1 Paracelsus 49
2.2.2 Artifacts 14
5.1.2 Early theories on opium 50
2.3 Genetic evidence 14
5.2 Early modern 51
2.3.1 Origins of poppy 14
5.2.1 Thomas Sydenham 51
2.3.2 Spread of poppy 15
5.2.2 Opiologia 52
2.4 Evolutionary milestones 16
5.2.3 Thomas Dover 52
2.5 Synopsis 16
5.2.4 Opium experiments 53
References 17
5.3 Opium intemperance 54
5.3.1 Opium romantics 54
3. Ancient history 5.3.2 OTC opium 54
3.1 Opium in antiquity 19 5.4 Opium in the East 54
3.1.1 Mesopotamia 19 5.4.1 Opium in China 54
3.1.2 Clay tablets of Nineveh 21 5.4.2 Opium in India 55

ix
x Contents

5.5 Late modern 55 9. Opioids

5.6 First opioid epidemic 57
5.7 Chronology of opium 60 9.1 The family 99
5.8 Synopsis 60 9.1.1 Structure of morphinans 99
References 60 9.1.2 Chemical classes of opioids 99
9.2 Structure-activity relationships 99
9.2.1 Phenanthrenes 100
6. Contemporary history
9.2.2 Piperidines 102
6.1 Wars and anesthesia 63 9.2.3 Diphenylheptanes 102
6.1.1 Wars and opium 63 9.2.4 Benzomorphans 103
6.1.2 Opium and surgery 63 9.3 Common opioids 103
6.2 Second opioid epidemic 64 9.3.1 Diacetyl morphine 103
6.3 Synopsis 66 9.3.2 Codeine and hydrocodone 103
References 66 9.3.3 Oxycodone 103
9.3.4 Meperidine 103
9.3.5 Fentanyl 103
Part III 9.3.6 Methadone 104
9.3.7 Buprenorphine 104
Trade 9.3.8 Nalorphine 104
9.3.9 Naloxone 105
7. Business of opium 9.3.10 Naltrexone 105
7.1 Before Common Era 71 9.4 Unique formulations 105
7.2 Religion, free trade, and 9.4.1 Extended release 105
colonialism 71 9.4.2 Abuse deterrent 105
7.2.1 Indian opium 71 9.4.3 PAMORA 106
7.2.2 Chinese opium 74 9.4.4 Novel synthetics 106
7.2.3 Opium Wars 75 9.5 Milestones in opioid synthesis 106
7.2.4 Other opium 77 9.6 Synopsis 106
7.3 Commercialization 78 References 106
7.4 Licit trade 79
7.5 Illicit trade 80
7.6 Legislation 82 Part V
7.6.1 International efforts 83
7.6.2 Efforts in the United States 83
Molecular basics
7.6.3 Future perspectives 85
7.7 Synopsis 85
10. Receptors
References 85 10.1 Overview 111
10.1.1 Discovery 111
10.1.2 Receptor diversity 111
Part IV 10.1.3 Opioid genes 112
10.2 Endogenous opioid peptides 113
Alkaloids 10.3 Opioid receptor terminology 114
10.4 Ligand characteristics 114
8. Opiates 10.4.1 Message-address sequence 114
8.1 Discovery 91 10.4.2 Agonist/antagonist 115
8.2 Synthesis 93 10.5 Receptor structure 115
8.2.1 Extraction 93 10.5.1 Structural basics 116
8.2.2 Biosynthetic pathway 93 10.5.2 Binding pocket 116
8.3 Opium alkaloids 94 10.5.3 Orthosteric and allosteric sites 116
8.3.1 Major alkaloids 95 10.6 Kinetics of conformational changes 117
8.3.2 Minor alkaloids 96 10.7 Distribution of opioid receptors 119
8.4 Synopsis 96 10.7.1 Central distribution 119
References 96 10.7.2 Peripheral distribution 120
 Contents xi

10.8 Milestones 120 13.3 Transmission pathways 148

10.9 Synopsis 120 13.3.1 Peripheral nerves 148
References 121 13.3.2 Dorsal root ganglion 149
13.3.3 Dorsal horn 149
11. Effectors 13.3.4 Ascending fibers 151
13.3.5 Descending fibers 152
11.1 Overview 125
13.4 Perception and modulation 152
11.2 Heterotrimeric G proteins 125
13.4.1 Supraspinal mechanisms 152
11.2.1 Structure 125
13.4.2 Spinal modulation 153
11.2.2 Basal coupling with GPCR 126
13.5 Opioid analgesia 153
11.3 G protein/GPCR complex 126
13.5.1 Supraspinal and spinal
11.3.1 Activation 126
mechanisms 153
11.3.2 Termination of action 127
13.5.2 Molecular mechanisms 154
11.4 G protein-dependent pathways 127
13.6 Synopsis 154
11.4.1 Adenylyl cyclase and Gα
References 154
pathways 128
11.4.2 Effectors of Gβγ subunit 129
11.5 G protein-independent pathways 130 14. Adverse effects
11.5.1 Structure of arrestins 130 14.1 Overview 157
11.5.2 Arrestin-mediated pathways 131 14.2 Respiratory 157
11.5.3 Receptor trafficking 132 14.2.1 Respiratory control 157
11.6 Molecular mechanisms of opioid 14.2.2 Opioid-induced respiratory
effects 132 depression 158
11.6.1 Gα effects 133 14.3 Gastrointestinal 158
11.6.2 Gβγ effects 133 14.3.1 Opioid receptors and bowel
11.6.3 Arrestin effects 133 control 158
11.6.4 Heterologous sensitization 133 14.3.2 Opioid-induced bowel
11.6.5 Effector pathways database 134 dysfunction 158
11.7 Synopsis 134 14.3.3 Nausea and vomiting 159
References 134 14.4 Integumentary 159
14.4.1 Pruritus 159
14.5 Genitourinary 159
Part VI 14.5.1 Urinary retention 159
Benefits and harms 14.5.2 Sexual dysfunction 160
14.6 Neurological 160
12. Metabolism 14.6.1 Cognitive effects and
sedation 160
12.1 Overview 139 14.6.2 Myoclonus and seizures 160
12.1.1 Receptor-specific functions 139 14.6.3 Sleep disruption 161
12.1.2 Systemic effects 139 14.7 Cardiovascular 161
12.1.3 Supraspinal effects 139 14.7.1 Opioid receptors in
12.1.4 Spinal and peripheral effects 139 cardiovascular function 161
12.2 Opioid metabolism 141 14.7.2 Arrhythmogenesis 161
12.2.1 Absorption 141 14.7.3 Cardioprotective functions 161
12.2.2 Distribution 141 14.8 Endocrine and reproductive 162
12.2.3 Metabolism 142 14.8.1 Effects on HPG axis 162
12.2.4 Elimination 144 14.8.2 Effects on HPA axis 162
12.3 Synopsis 144 14.9 Mood disorders 163
References 145 14.10 Neuroinflammation 163
14.11 Angiogenesis and tumorigenesis 164
13. Analgesia 14.12 Tolerance 165
13.1 Overview of pain 147 14.12.1 Overview 165
13.2 Nociceptors 147 14.12.2 Mechanisms 166
xii Contents

14.13 Withdrawal 166 15.7 Other issues 195

14.13.1 Overview 166 15.7.1 Overdose 195
14.13.2 Mechanisms 167 15.7.2 Neonatal opioid withdrawal
14.14 Opioid-induced hyperalgesia 167 syndrome 196
14.14.1 Overview 167 15.7.3 Falls and crashes 196
14.14.2 Mechanisms 168 15.7.4 Infection 196
14.15 Dependence 170 15.8 Synopsis 196
14.15.1 Overview 170 References 197
14.15.2 Mechanisms 170
14.16 Other adverse effects 172 16. Advances and prospects
14.17 Synopsis 172
References 172 16.1 Opium production 205
16.1.1 Breeding techniques 205
16.1.2 Metabolic genetic engineering 205
Part VII 16.2 Overview of therapeutic advances 206
Therapeutic utility 16.3 Abuse-deterrent formulations 206
16.4 Peripheral selectivity 207
16.4.1 Peripheral receptors 207
15. Uses and issues
16.4.2 Nanocarrier delivery 208
15.1 Opioids in therapeutics 181 16.4.3 pH-dependent activation 208
15.2 Therapeutic principles 181 16.5 Molecular targets 208
15.2.1 Utility and safety 181 16.5.1 Overview 208
15.2.2 Relative potency and equivalence 182 16.5.2 Modification of endogenous
15.3 Therapeutic predicament 184 opioids 209
15.4 Acute pain 185 16.5.3 Multifunctional ligands 209
15.4.1 Perioperative use 185 16.5.4 Allosteric modulation 210
15.4.2 Nonsurgical use 186 16.5.5 Biased agonism 210
15.5 Chronic pain 187 16.5.6 Nonopioid receptor targets 211
15.5.1 Taxonomy 187 16.5.7 Receptor-independent selective
15.5.2 Chronic cancer pain 188 modulators 214
15.5.3 Chronic noncancer pain 189 16.6 Gene therapy 215
15.6 Opioid use disorder 192 16.7 Synopsis 215
15.6.1 Taxonomy 192 References 215
15.6.2 Medical use of opioids 193
15.6.3 Nonmedical use of opioids 193
15.6.4 Treatment of dependence 193
15.6.5 Guidelines 195 Index 221
About the Author
Vasantha K. Kumar, MD, completed medical school
at Madurai Medical College, Madurai, India, and served
for five years as Captain in Army Medical Corps. After
this tenure, he earned MD in Aerospace Medicine in
1986 from the Indian Air Force Institute of Aerospace
Medicine, Bangalore, India. He was National Research
Council Research Fellow at NASA Johnson Space Center,
Houston, Texas, from 1988 to 1990 and conducted human
trials on decompression sickness supporting extravehicu-
lar activities for the Space Shuttle program. He continued
this research as Supervisor of Environmental Physiology
Laboratory with a subcontractor at NASA Johnson Space
Center, Houston, Texas, until 1996. He later completed
an anesthesiology residency at the University of Texas,
Galveston, Texas, in 2000 and a pain medicine fellowship
at the University of Cincinnati, Cincinnati, Ohio, in 2001.
Since then, he has practiced comprehensive pain care in
various clinical settings.
Dr. Kumar has authored or presented more than 70 pa-
pers on topics such as decompression sickness, historical
perspectives, and chronic pain. He was awarded the “Silver
Snoopy” medal in 1996 by NASA astronauts for his con-
tribution to the Space Shuttle program. He also served on
the Editorial Board of the journal Aviation, Space, and
Environmental Medicine between 1996 and 1998. He is
Board Certified in Anesthesiology and Pain Medicine from
the American Board of Anesthesiology and a member of
several professional organizations. In addition to his profes-
sional activities, Dr. Kumar has a special interest in histori-
cal biographies and epistemology.
xiii
This page intentionally left blank
Preface
Those about to study medicine, and the younger Physicians,
should light their torches at the fires of the Ancients.
Carl von Rokitansky (c. 1846 CE)
Opium has always held a polysemic relationship and sig-
nificance in society. One of the earliest known drugs in the
history of humanity, its use has spanned contexts, cultures,
and continents across the globe. From the earliest find in
the funerary sites of Europe, it has proven to be a dominant
sociocultural factor in medicine, geopolitics, and economy.
Cautiously advocated by Hippocrates and ardently favored
by great minds such as Galen, Avicenna, and Paracelsus,
and commodified by colonial interests, opium has always
evoked dualistic attributes of remedy and poison in history.
After Serturner’s discovery of morphine almost
200 years ago, unbridled enthusiasm and use resulted in
the first opioid epidemic during the Industrial Age. Global
antiopium movement of this period assigned stricter con-
trols and limited use of opioids in medicine. Since then, a
quest for enhancing remedial effects of opium poppy has
thrust research on poppy and its products to a higher level,
unimagined by polymaths of the bygone era. Our compre-
hension of the plant and its potential has grown leaps and
bounds over the past century, and it is difficult to keep pace
with the flood of information. However, the use of opioids
for chronic pain in the 20th century, in its characteristic du-
alism, has either endorsed or queried its use during the cur-
rent opioid epidemic.
Aware of public health emergency during the current
opioid epidemic, I focused on doing the right thing by im-
plementing guidelines proffered by medical societies and
regulatory bodies that I only vaguely acknowledged histori-
cal events. About 5 years ago, I stumbled upon a book that
was tucked behind the counter in a dingy little bookstore
at the airport, where I was waiting for my flight home. The
book that piqued my interest, A Concise History of Hong
Kong by John Carroll (Rowman & Littlefield Publishers,
Inc., 2007), recounts the history of Hong Kong Island from
its tumultuous founding to its emergence as a major finan-
cial center of the East. I was thrilled with what the book had
to offer and sat wide-eyed through the long flight. I was fas-
cinated, but nescient, about the turn of events in the glorious
age of sail and the ignominious basis for this critical piece
of history—opium. It was a fortuitous moment, as it set me
on a quest to learn and retell the history of poppy as it was
scripted over the years.
Many therapeutic dilemmas posed by opioid use during
the current epidemic are not new, as these issues have chal-
lenged physicians for centuries. Ironically, several factors
that led to the first opioid epidemic of the Industrial Age
share common features with the second opioid epidemic of
modern times. However, we missed the opportunity to learn
from historical works and events while getting mired in de-
tails of the current opioid epidemic. As I waded through his-
torical documents on opium, I realized that history has the
answers to provide perspectives for research, therapeutics,
and policy-making for the future.
I must admit that I am neither a historian nor a linguist,
and my medical training stopped short of educating me on
drugs, “guidelines,” and how to use them in practice. This
book is an effort to bridge history and therapeutics. This book
trails poppy from prehistory to present history, as advocated,
analyzed, and advanced by the great minds in medicine. As
such, it is a synthesis of botany, chemistry, physiology, and
molecular biology interlaced with historical vignettes in the
spirit of great encyclopedists before me.
What started as a venture of self-education in history led
to a more complex palimpsest that poppy truly is. I have at-
tempted to present readers with a comprehensive knowledge
base on opium poppy, starting with the plant, its history, com-
merce, medical use, current status, and future perspectives.
It is my fervent hope that this endeavor serves as a resource
for anyone wishing to explore the world of opium poppy or at
least awakens interest in history as it has done for me.
Proceed then as you have begun.
Robert Brady (c. 1670 CE) in “Epistle to Thomas Sydenham”
Vasantha K. Kumar
Columbus, OH, United States
xv
This page intentionally left blank
Acknowledgments
This work is a tribute to the deliberations of numerous
protagonists and adversaries, struggles of transcribers and
glossators, and trials and labors of those researchers on
opium throughout history. Pictures tell stories better than
words, and I would like to acknowledge the contribution
by public domain figures and open source articles from
the United States National Library of Medicine, RCSB
Protein Data Bank, GPCRdb, Reactome, Wikimedia,
Wellcome Collection, and numerous other institutions.
All illustrations in this book are by the author, unless
otherwise indicated. This compilation is a work of
passion and personal endeavor, and the author received
no financial support for research, authorship, graphics,
drafting, and/or publication of this book. Particular
thanks are due to my team at Elsevier for bringing this
project to fruition.
xvii
This page intentionally left blank
Part I

Plant
This page intentionally left blank
Chapter 1
Botanical aspects
And he bowed his head to one side like a poppy that in a garden is
laden with its fruit and the rains of spring.
Homer in Iliad (c. 630 BCE)
1.1 Plant
1.1.1 Overview
Plants included in the family Papaveraceae are a group
of herbaceous flowering plants found primarily in the
Northern Hemisphere, which prefer a temperate climate
and have more than 100 subspecies. However, Papaver
(Latin: poppy) is also cultivated in some tropical areas
in the Southern Hemisphere. Many varieties grow in the
wild, including Poppy of Troy, Papaver setigerum (Latin:
bristly), some plants like Papaver rhoeas (Greek: red or
to fall) are grown for ornamental purposes, and Papaver
somniferum (Greek: to induce sleep) is the only species
acclaimed as a distinctive medicinal plant for pain relief
and maligned as the source of addictive drug all over the
world.
1.1.2 Cultivation
Papaver is a self-pollinating, multipurpose species. It is a
valuable food source for humans and also serves as animal
fodder (Bernath, 1998; Duke, 1983; Kapoor, 1995; Lim,
2013). It has a glaucous stem, sessile leaves with dentate
margins with peduncle, and drooping buds (Fig. 1.1). Poppy
flowers come in various shades of color, including white,
pink, violet, and red.
After poppy blooms, leaves fall within a week, and a
poppy pod or a capsule with its characteristic calyces forms
a prominent part of the plant (Fig. 1.2). The capsule size
may vary depending on the cultivar and geographical distri-
bution, from broad oval to cylindrical.
Poppy seeds are the most edible part of the plant and
kidney shaped and also vary in color from gray, white
to blue. They are usually harvested after the poppy cap-
sule has dried out, and they are used as a food additive to
Handbook on Opium. https://doi.org/10.1016/B978-0-323-90903-7.00018-1
Copyright © 2022 Elsevier Inc. All rights reserved.
provide texture, flavor, and caloric value (100 g of poppy
seeds provides approximately 500 cal). The seeds contain
linoleic acid (up to 60%) and are a great source of calcium,
niacin, thiamine, and tocopherols (Knutsen et al., 2018).
Poppy seed oil can be used without refining for cooking,
lubrication, or lamps, where they burn longer and cleaner
than olive oil. Poppy seed oil is expensive; its production
slowly reduced in the late 18th century, after which it was
completely stopped.
The vegetation period of cultivated poppy varies from
region to region, from 120 to 250 days, based on agrotech-
nical methods used and whether sown in spring or fall.
It is usually cultivated by the end of the rainy season in
Southeast Asia (Fig. 1.3). Usually, about a pound of poppy
seeds is required to sow one acre of land (Drug Enforcement
Administration (DEA), 1992).
Six distinct developmental stages are observed in the
growth of poppy (Bernath, 1998; Duke, 1983; Lim, 2013):
Phase 1: Embryo phase, when seeds are in the soil or
dormant (for up to 6 years).
Phase 2: Germination phase, when first leaves appear
(15–20 days).
Phase 3: Leaf rosette phase, the longest stage of leaf
formation (50–60 days for summer varieties and 180–
220 days for winter varieties).
Phase 4: Branching phase, lasts until blossoming
(20–30 days).
Phase 5: Blossoming and capsule formation phase, when
flowers bloom briefly for a day and green capsules take
another 10 days to mature (20–30 days).
Phase 6: Capsule ripening is the final phase when dry,
rattling poppy capsules are ready for seed harvesting
(15–25 days).
All phases of growth require careful tendering to en-
sure good capsule formation and may be adversely af-
fected at any stage by environmental factors such as light,
temperature, and moisture (Bernath, 1998). However, it
is labor-intensive once the capsule forms and is ready for
tapping.
3
4 PART | I Plant
FIG. 1.1 Poppy plant. Parts of Papaver somniferum by Otto Thome
(c. 1885 CE) including A, leaves; 1, longitudinal section of flower; 2,
­stamen; 3, pistil; 4, cross-section of ovary; 5, poppy capsule; 6, poppy
seeds. (Credit: Thome, O. W. (1885) from Wikimedia. https://commons.
wikimedia.org/wiki/File:Illustration_Papaver_somniferum0.jpg.)
FIG. 1.2 Green poppy capsule. Capsules may vary from oval to
cylindrical in shape. (Credit: Pixabay. https://pixabay.com/photos/
poppy-poppy-capsules-seeds-2502046/.)
1.2 Latex
1.2.1 Laticifers
Laticifers are an elongated, anastomosing network of cells
found in the cortex of the entire poppy plant from roots to
the capsule (Bird, Franceschi, & Facchini, 2003; Liscombe
& Facchini, 2008; Mahlberg, 1993). In the capsule, ­laticifers
are found within 2–4 cm of capsular surface (Fig. 1.4).
These laticifers are formed by resorption and coalescence
of cell walls, resulting in an elongated tubular system run-
ning throughout the plant.
It has been shown that biosynthetic enzymes are synthe-
sized in companion cells. They are then transported to sieve
elements where alkaloid biosynthesis occurs. Alkaloids of
poppy are stored as latex in vacuoles (Fig. 1.5), formed
from localized dilatation of endoplasmic reticulum within
the laticifer networks (Bercu, 2012; Lee, Hagel, & Facchini,
2013; Liscombe & Facchini, 2008). Latex particles of
opium alkaloids are suspended in these vacuoles (Fig. 1.6)
and located just below the capsular surface (Beaudoin &
Facchini, 2014; Griffing & Nessler, 1989; Nessler, Allen, &
Galewsky, 1985; Nessler & Mahlberg, 1976).
Modern techniques, such as immunofluorescent label-
ing, have enabled us to identify key enzymes in the bio-
synthesis of opium alkaloids. Furthermore, molecular
genetic techniques have aided in cell-specific localization
of alkaloid synthesis in Papaver somniferum (Beaudoin
& Facchini, 2014; Chalise, 2015; Liscombe & Facchini,
2008).
Results of these studies showed that synthesis of al-
kaloids of poppy occurs in the adjacent companion cells
and sieve elements and then they accumulate in latici-
fers (Bird et al., 2003; Harvest, 2011; Weid, Ziegler, &
Kutchan, 2004). It is difficult to produce morphine in
Papaver somniferum cell cultures, possibly due to the ab-
sence of a naturally occurring laticifer system in cultured
cells (Bird et al., 2003). Multiple levels of regulation ex-
ist in the synthesis of alkaloids from naturally occurring
amino acid l-tyrosine in the plant. Details of morphine
synthesis are dealt with in another section (please refer
to Section 8.3).
Box 1.1 Laticifer
Marcello Malpighi (1628–1694 CE), a renowned Italian
physician biologist (Fig. 1.7), called the milky latex exu-
date of plants “vasa propria.” His contemporary Nehemiah
Grew (1641–1712 CE), an English physician and the
“Father of Plant Anatomy” (Fig. 1.8), used a microscope to
describe the structure of the laticiferous system in plants,
which contain the milky sap, and also noted that this exu-
date coagulated (like blood) after extraction from the plant
(Arber, 1941).
 Botanical aspects Chapter | 1 5

RAINY SEASON COLD SEASON

Land
Prep Germination
15 days Leaf Rosette
60 days Branching
Flowering Capsule formation
30 days
30 days & ripening
30 days

FIG. 1.3 From cotyledons to capsules. Duration of each stage of growth varies depending on the subspecies, region, and environmental factors.

phloem
xylem

phloem

xylem

Current Opinion in Biotechnology

FIG. 1.4 Laticifers in poppy plant. Cross section of phloem shows pairing of laticifers (yellow), sieve elements, and companion cells (red) in aerial
parts, compared with roots of poppy. (With permission from Liscombe, D., & Facchini, P. (2008). Elsevier. https://doi.org/10.1016/j.copbio.2008.02.012.)

1.2.2 Capsule
Latex juice is found in all parts of the poppy plant, with
the highest concentration in the capsule, while its pres-
ence is negligible or absent in seeds (Knutsen et al.,
2018). Latex juice containing psychoactive alkaloids
increases in concentration as the capsule matures in the
final phase (Fig. 1.9). Final alkaloid concentration is in-
fluenced by a host of environmental factors, including
ambient light, water supply, temperature after flowering,
nutrients, infection by fungi, and enzymatic degradation
(Bernath, 1998).
6 PART | I Plant

FIG. 1.5 Cross section of laticifer in poppy. Enzymes are synthesized

in companion cells (cc), transported to sieve elements (se) for alkaloid
synthesis and stored in laticifers (la) in phloem parenchyma (pp). Other
structures shown include vascular cambium (vc) and xylem vessels (xy)
in xylem parenchyma (xp). (From Lee, E., Hagel, J. M., & Facchini, P. J.
(2013). https://doi.org/10.3389/fpls.2013.00182.)

FIG. 1.7 Marcello Malpighi. He was the first to describe the milky sap
of plants. (Credit: Wellcome Collection. https://wellcomecollection.org/
works/svekkc2e.)

FIG. 1.6 Electron micrograph of laticifer. Alkaloids of poppy are seen

suspended within vesicles (v) in the sieve (s) tubules. (With permission FIG. 1.8 Nehemiah Grew. He demonstrated the laticiferous system in
from Nessler, C. L., Allen, R. D., & Galewsky, S. (1985). https://doi. plants by microscopy. (Credit: Wellcome Collection. https://wellcomecol-
org/10.1104/pp.79.2.499.) lection.org/works/axt8asec.)
 Botanical aspects Chapter | 1 7

25

20

15
Percent

10

0
1
10
15
20
25
30
40
Number of Days after Flowering

FIG. 1.9 Alkaloid content in poppy capsule. With maturation, the al-
kaloid content of poppy increases after 3 weeks and starts to decrease
by 4 weeks. (Data from Bernath, J. (1998). Cultivation of poppy under
tropical conditions. In J. Bernath (Ed.), Poppy: The Genus Papaver (pp.
237–248). Harwood Academic Publishers.)
1.2.3 Extraction of opium
Opium alkaloids may be extracted from green poppy cap-
sules by excoriating superficially with a sharp and shallow
blade by hand, vertically or horizontally, so its milky white
sap is extruded (Fig. 1.10). The sap is allowed to dry for a
day or two, after which it is carefully scraped off the pods
and collected into wooden bowls (Fig. 1.11). Then, the
pod is ready for its next round of excoriation (Krikorian &
Ledbetter, 1975).
The green poppy pod secretes for about 10 days of
its annual cycle and may be tapped as much as six times
during this period. The concentration of opium reduces if
it is tapped more often. This process is labor-intensive, as
the poppy capsule is individually tapped repeatedly over
10 days. On average, the yield is approximately 80 mg
of raw opium per pod, and an acre of poppy provides
FIG. 1.11 Dried poppy latex. The dried milky sap contain-
ing opium is scrapped manually from each capsule. (With per-
mission from Couperfield@123rf.com. https://www.123rf.com/
photo_81603467_detail-of-harvesting-of-raw-opium-on-poppy-field.
html?downloaded=1.)
less than 6 kg of raw opium (DEA, 1992; Krikorian &
Ledbetter, 1975).
The raw opium may be “cooked” in boiling water to
remove all plant contaminants and then strained through
cheesecloth. This liquid opium may be re-heated in low
flame to yield a sticky brown paste (suitable for smoking or
eating). The collected opium is then air-dried before being
packaged into cubes or balls for shipment.
Another source of extracting opium is the naturally
dried pods of poppy capsules after harvesting their seeds
(Fig. 1.12). These dry capsules, called “poppy straw,” are
a common source for commercial production of opium,
which still contain opium alkaloids albeit at a lower
concentration.

FIG. 1.10 Excoriation of poppy capsule. Each excoriation re-
sults in milky exudate over 1–2 days. (With permission from
Couperfield@123rf.com. https://www.123rf.com/photo_81603489_
detail-of-cutting-poppy-heads-with-knife-to-harvest-opium-latex.
html?downloaded=1.)
FIG. 1.12 Poppy straw. Dry poppy capsules with seeds consti-
tute the “straw.” (Credit: Pixabay.com. https://pixabay.com/photos/
seeds-dried-poppy-poppies-flower-4461737/.)
8 PART | I Plant

1.3 Opium alkaloids

1.3.1 Poppy sources
The word “opium” is used to define latex juice of the
poppy and is most likely derived from the Greek word
“opos” (c. 100 CE). Natural opium is blackish brown
in color with a characteristic bitter taste. It contains as
much as 80 ­alkaloids (10%–30% of content), sugars
(20%), water (20%), and meconic acid (5%) (Chalise,
2015). The alkaloids belong to several groups: phen-
anthrene derivatives, which include the morphinan
alkaloids (morphine, codeine, thebaine, oripavine),
benzylisoquinolines (papaverine, reticuline, laudanine),
phthalideisoquinolines (noscapine or narcotine, narcoto-
line, narceine), protoberberines (berberine), and ben- FIG. 1.13 Maker of dreams. Morpheus with poppy in hand. Oil painting
zophenanthridines (sanguinarine) (Lim, 2013; Mishra by Jean-Bernard Restout (c. 1771 CE). (Credit: https://www.clevelandart.
et al., 2013; Schiff, 2002). org/art/1963.502.)
Psychoactive morphinan alkaloids (morphine, co-
deine, thebaine, oripavine) are the predominant reason
for its cultivation (Gupta, 2016). Many plants in Papaver
species have minimal quantities of opium and of no com-
mercial value. Morphinan alkaloid concentration may
range from 20% to 30% in Papaver somniferum, 10%
to 15% in Papaver setigerum, and minimal or none in
other Papaver species. In Papaver orientale, primary al-
kaloids are oripavine (20%) and thebaine (9%), while in
Papaver bracteatum, 90% of alkaloid content is thebaine
(Hosztafi, 2014; Khanna & Shukla, 1986). The alkaloid
sanguinarine, widely used for its antibacterial and antiin-
flammatory effects, especially in toothpaste, is found in
the root, stem, and leaves, but not in the poppy capsule.
A new variety of poppy developed in Australia called
top1 specifically accumulates thebaine and oripavine, in-
stead of morphine (Beaudoin & Facchini, 2014; Hosztafi,
2014).

Box 1.2 Hypnos and Morpheus

In Greek mythology, Hypnos (Somnus in Roman mythol-
ogy—hence Papaver somniferum) was the God of sleep
(Fig. 1.14), who tricked Zeus into sleep twice at the be-
hest of Hera during the Trojan War to favor Greek vic-
tory. His parents were Nyx (Goddess of night) and Erebus
(God of darkness), his twin brother was Thanatos (God
of death), and his wife was Pasithea (Goddess of relax-
ation). Dreams were created by the children of Somnus
and Pasithea, called “Oneiroi” comprising of four broth-
ers. Morpheus (Greek morphe = to form) was the most
powerful and in charge of dreams (Fig. 1.13), with the
assistance of his brothers Phobetor (who created pho-
bic nightmares), Phantasus (who created illusions), and
Ikelos (who created prophecy). Morpheus had wings to
take him into anyone’s dreams, including those of other
Gods, and slept in a cave surrounded by poppy fields
(Gottler, 2018).
FIG. 1.14 God of sleep. Greeks called him Hypnos (sculpture in the British
Museum), and Romans called him Somnus. (Credit: Wikimedia. https://com-
mons.wikimedia.org/wiki/File:Hypnos,_British_Museum_No._267.JPG.)
Naturally occurring opioids from Papaver somniferum
are morphine (from the Greek God “Morpheus”), codeine
(Greek: “kodeia” or poppy head), thebaine (Greek: “Thebai,”
city in Egypt where it was grown), and minor alkaloid of
importance oripavine. The major alkaloid of opium, mor-
phine, was identified in 1804 CE (Schmitz, 1985), codeine
in 1832 CE, thebaine in 1835 CE (Wisniak, 2013), and al-
most 100 years later, oripavine in 1935 CE (Hosztafi, 2014).

1.3.2 Nonpoppy sources
Interestingly, some of the naturally occurring peptides are
found related to opioids—alkaloid mitragynine from south
Asian plant Mitragyna speciosa or kratom, terpenoid sal-
vinorin A from central American plant Salvia divinorum
used in Shamanistic rituals, and dermorphin and deltorphin
from the skin of certain South American frogs. Mitragynine
also has psychoactive properties, salvinorin A is a potent
hallucinogen, and dermorphin has low therapeutic potential
(Ivanovic, 2017; Zjawiony et al., 2019).
Box 1.3 Entheogen
Salvinorin A is a natural hallucinogen found in Salvia divi-
norum, used by Mazatec shamans of Mexico as an entheo-
gen (Greek: entheos, root for enthusiasm) in rituals. Salvia
was first recorded by anthropologist Jean Basset Johnson
(1915–1944 CE), while studying native Mazatecs in 1939 CE
as a graduate student from California. Along with his wife
Irmgard Weitlaner, he made numerous field trips to study the
Mazatecs. His research was interrupted by World War II, and
he died at the age of 29 while serving in Tunisia. His father-
in-law, Roberto Weitlaner (1883–1968 CE), was an Austrian
engineer, who worked in several US steel companies before
turning to anthropology while residing in Mexico. He is well
known for the re-discovery of psilocybin mushrooms in 1936
CE and also wrote extensively on ethnic and linguistic as-
pects of indigenous Americans of the region.
Incidentally, Finnish chemist Adolf Arppe discovered a
product in 1845 CE that “turned from white to green on stand-
ing” by heating morphine with sulfuric acid. Later in 1869
CE, Augustus Matthiessen and Charles Alder Wright named
it “apomorphia” (Auffret, Drapier, & Vérin, 2018). Although
pharmacological similarities were noted with morphine, it
was found to be “no more like morphine than sawdust is like
sugar” (Dent, 1934). In addition to its emetic and sedative
effects, it has dopaminergic excitatory properties and is used
as an anti-Parkinsonian drug to treat hypomotility.
1.4 Synopsis
The Papaveraceae family has numerous plants, but Papaver
somniferum is the major medicinal plant of interest. Poppy
is grown in tropical as well as temperate climates over a
period of 6–7 months. It is a multipurpose plant with leaves
and seeds that serve as an edible food source, while the la-
tex of poppy capsule is of great medicinal value. Alkaloids
of poppy (numbering 80) are synthesized in the laticiferous
system of the plant and found abundantly in capsules, com-
pared with the rest of the plant. Morphinan alkaloid con-
centration varies from 20% to 30% in Papaver somniferum,
while thebaine is a major alkaloid in Papaver bracteatum.
Extraction of opium by an excoriation of capsules is known
for centuries and labor-intensive. Some peptides from
Botanical aspects Chapter | 1 9
n­ onpoppy sources (kratom, salvia) are also chemically re-
lated to opium. Dry poppy capsules (poppy straw) are now
a major commercial source for opium globally.
References
Arber, A. (1941). Nehemiah Grew and Marello Malpighi. Proceedings
of the Linnean Society of London, 153(2), 218–238. https://doi.
org/10.1111/j.1095-8312.1941.tb00282.x.
Auffret, M., Drapier, S., & Vérin, M. (2018). The many faces of apomor-
phine: Lessons from the past and challenges for the future. Drugs in
R and D, 18(2), 91–107. https://doi.org/10.1007/s40268-018-0230-3.
Beaudoin, G. A. W., & Facchini, P. J. (2014). Benzylisoquinoline alka-
loid biosynthesis in opium poppy. Planta, 240(1), 19–32. https://doi.
org/10.1007/s00425-014-2056-8.
Bercu, R. (2012). Histoanatomical aspects of the vegetative organs of Papaver
Rhoeas L. Annals of the Romanian Society for Cell Biology, 17(2), 186–
191. http://www.analelesnbc.ro/arhivapdfvol17issue2/28.pdf.
Bernath, J. (1998). Cultivation of poppy under tropical conditions. In J.
Bernath (Ed.), Poppy: The genus Papaver (pp. 237–248). Harwood
Academic Publishers.
Bird, D. A., Franceschi, V. R., & Facchini, P. J. (2003). A tale of three cell
types: Alkaloid biosynthesis is localized to sieve elements in opium pop-
py. Plant Cell, 15(11), 2626–2635. https://doi.org/10.1105/tpc.015396.
Chalise, U. (2015). The poppy plant: Phytochemistry & pharmacology.
Indo Global Journal of Pharmacological Sciences, 5(1), 58–65.
Dent, J. (1934). Apomorphine in the treatment of anxiety states, with
special reference to alcoholism. British Journal of Inebriety, 32(2),
65–88. https://doi.org/10.1111/j.1360-0443.1934.tb05016.x.
Drug Enforcement Administration (DEA). (1992). Opium poppy cultiva-
tion and heroin processing in Southeast Asia. U.S. Drug Enforcement
Administration, Intelligence Division, Strategic Intelligence Section.
DEA-92004 (NCJ Number 141189). https://www.ojp.gov/pdffiles1/
Digitization/141189NCJRS.pdf.
Duke, J. (1983). Papaver somniferum. In Handbook of energy crops.
Unpublished. https://hort.purdue.edu/newcrop/duke_energy/Papaver_
somniferum.html.
Gottler, C. (2018). Imagination in the chamber of sleep: Karel van Mander
on Somnus and Morpheus. In P. Bakker, C. Luthy, C. Swan, & C.
Zitterl (Eds.), Image, imagination and cognition (pp. 147–176). Brill.
https://doi.org/10.1163/9789004365742_008.
Griffing, L. R., & Nessler, C. L. (1989). Immunolocalization of the major
latex proteins in developing laticifers of opium poppy (Papaver som-
niferum). Journal of Plant Physiology, 134(3), 357–363. https://doi.
org/10.1016/S0176-1617(89)80256-1.
Gupta, P. (2016). Fundamentals of toxicology. Academic Press.
Harvest, T. (2011). Laticifers and latex in Papaver somniferum L.:
Capacity, development and translocation. Ph.D. Thesis University of
Tasmania. https://eprints.utas.edu.au/12463/.
Hosztafi, S. (2014). Recent advances in the chemistry of oripavine and
its derivatives. Advances in Bioscience & Biotechnology, 5, 704–717.
https://doi.org/10.4236/abb.2014.58084.
Ivanovic, M. (2017). Opioids – Structure and synthesis. https://www.chem.
bg.ac.rs/fakultet/izdavastvo/Opioids- -Structure_and_Synthesis.pdf.
Kapoor, L. D. (1995). Opium poppy – Botany, chemistry, and pharmacol-
ogy (pp. 1–17). The Haworth Press.
Khanna, K. R., & Shukla, S. (1986). HPLC investigation of the inheri-
tance of major opium alkaloids. Planta Medica, 2, 157–158. https://
doi.org/10.1055/s-2007-969106.
10 PART | I Plant
Knutsen, H. K., Alexander, J., Barregård, L., Bignami, M., Brüschweiler,
B., Ceccatelli, S., … Vollmer, G. (2018). Update of the Scientific
Opinion on opium alkaloids in poppy seeds. EFSA Journal, 16(5).
https://doi.org/10.2903/j.efsa.2018.5243.
Krikorian, A. D., & Ledbetter, M. C. (1975). Some observations on the culti-
vation of opium poppy (Papaver Somniferum L.) for its latex. Botanical
Review, 41(1), 30–103. https://doi.org/10.1007/BF02860836.
Lee, E. J., Hagel, J. M., & Facchini, P. J. (2013). Role of the phloem in
the biochemistry and ecophysiology of benzylisoquinoline alkaloid
metabolism. Frontiers in Plant Science, 4. https://doi.org/10.3389/
fpls.2013.00182.
Lim, T. (2013). Papaver somniferum. In T. Lim (Ed.), Edible medicinal
and non-medicinal plants (pp. 201–217). Springer Science Business
Media. https://doi.org/10.1007/978-94-007-5653-3_12.
Liscombe, D. K., & Facchini, P. J. (2008). Evolutionary and cellu-
lar webs in benzylisoquinoline alkaloid biosynthesis. Current
Opinion in Biotechnology, 19(2), 173–180. https://doi.org/10.1016/j.
copbio.2008.02.012.
Mahlberg, P. G. (1993). Laticifers: An historical perspective. Botanical
Review, 59(1), 1–23. https://doi.org/10.1007/BF02856611.
Mishra, S., Triptahi, V., Singh, S., Phukan, U. J., Gupta, M. M., Shanker,
K., & Shukla, R. K. (2013). Wound induced tanscriptional regulation
of benzylisoquinoline pathway and characterization of wound induc-
ible PsWRKY transcription factor from Papaver somniferum. PLoS
One, 8(1). https://doi.org/10.1371/journal.pone.0052784.
Nessler, C., Allen, R., & Galewsky, S. (1985). Identification and charac-
terization of latex-specific proteins in opium poppy. Plant Physiology,
79(2), 499–504. https://doi.org/10.1104/pp.79.2.499.
Nessler, C. L., & Mahlberg, P. G. (1976). Laticifers in stamens of Papaver som-
niferum L. Planta, 129(1), 83–85. https://doi.org/10.1007/BF00390918.
Schiff, P. L. (2002). Opium and its alkaloids. American Journal of
Pharmaceutical Education, 66(2), 186–194. http://www.ajpe.org/
legacy/pdfs/aj660217.pdf.
Schmitz, R. (1985). Friedrich Wilhelm Sertürner and the discovery of mor-
phine. Pharmacy in History, 27(2), 61–74.
Weid, M., Ziegler, J., & Kutchan, T. (2004). The roles of latex and the
vascular bundle in morphine biosynthesis in the opium poppy, Papaver
somniferum. Proceedings of the National Academy of Sciences,
13957–13962. https://doi.org/10.1073/pnas.0405704101.
Wisniak, J. (2013). Pierre-Jean Robiquet. Educacion Quimica, 24(1), 139–
149. https://doi.org/10.1016/S0187-893X(13)72507-2.
Zjawiony, J. K., Machado, A. S., Menegatti, P. C., Ghedini, P. C., Costa,
E. A., Pedrino, G. R., … Fajemiroye, J.O. (2019). Cutting-edge search
for safer opioid pain relief: Retrospective review of salvinorin A and
its analogs. Frontiers in Psychiatry, 10. https://doi.org/10.3389/fps
yt.2019.00157.
Part II

History
This page intentionally left blank
Chapter 2
Prehistory
Soul-soothing plant! that can such blessings give,
By thee the mourner bears to live!
By thee the hopeless die!
Charlotte Smith in Ode to the Poppy (c. 1795 CE)
For most part of their existence (almost 95%), modern
humans survived by “foraging” or “hunting and gather-
ing.” Although preagricultural diet consisted of meat, fruits,
nuts, and roots, early farming of cereals developed approxi-
mately 10 thousand years ago or KYA (Greek: chilioi or
kilo, meaning thousand) (i.e., around 8000 BCE) (Nielsen
et al., 2017; Trinkaus, 2005). When humans began to ex-
periment with the domestication of plants, mostly out of
necessity, they would have naturally used plants found in
surroundings with beneficial properties. It is entirely pos-
sible that humans knew about poppy even before the era of
farming. The story of origin and spread of poppy around the
world makes an interesting inquiry. In this short review, we
look at palaeobotanical and archaeological clues, followed
by recent interpretation using genomic analysis (Nielsen
et al., 2017).
2.1 Paleobotanical evidence
Poppy is considered indigenous to Asia Minor in the
Mediterranean region (Carod-Artal, 2013; Duke, 1983;
Gabra, 1956). It is generally accepted that Papaver se-
tigerum is phylogenetically earlier than Papaver som-
niferum (Gabra, 1956). The “dump-heap theory” of Edgar
Anderson proposes an interesting line of reasoning for the
advent of farming in general (Stebbins, 1978). It proposes
that dump or rubbish heaps of prehistoric human camp sites
enabled vigorous growth of plants and that humans used
this observation to grow specific plants they found useful.
This concept also offers an attractive explanation for the
origin of poppy cultivation by humans.
Handbook on Opium. https://doi.org/10.1016/B978-0-323-90903-7.00010-7
Copyright © 2022 Elsevier Inc. All rights reserved.
Box 2.1 Edgar Anderson
Edgar Anderson (1897–1969 CE), a great American bota-
nist who recognized genetic variation in plants, said that
“if we are to learn anything … we must reduce the prob-
lem to the simplest terms.” His popular book “Plants,
Man and Life” published in 1952 CE is an exploit of his
research laced with philosophical and historical views
on plants. Incidentally, he briefly worked with two great
­geneticist-statisticians in Britain: R.A. Fisher, a distinguished
mathematician-­ geneticist who founded modern statisti-
cal science, and J.B.S. Haldane, an illustrious evolutionary
biologist-geneticist-statistician, who, among numerous
other contributions, also proposed that sickle cell disease
offered immunity to malaria.
Palaeobotanical evidence indicates that opium poppies
were cultivated in the Near East region and then spread into
Europe along the Mediterranean coast into Spain. Seeds of
Papaver somniferum were discovered in a submerged vil-
lage called La Marmotta at the bottom of volcanic Lake
Bracciano near Rome, Italy, in the early 1990s (Merlin,
2003). This site is considered to be a farming community,
dating back to the early Neolithic (c. 5700 BCE) period
(Fig. 2.3). Poppy seeds were found stored in utensils, along
with cereals, indicating possible cultivation of poppy dur-
ing this period. It is the earliest known association of poppy
with humans (Harris, 2015; Merlin, 1984, 2003).
Poppy seeds were found in several funerary sites and settle-
ments dating to the middle Neolithic (c. 4200 BCE) and late
Neolithic (c. 3000 BCE) periods. Fossilized poppy seeds were
discovered in several human settlements in Central Europe and
Swiss Foreland during this period as well (Fig. 2.3). Although
poppy seeds were frequently found in early Neolithic sites,
find of poppy capsules in a funeral site at Cueva de los
Murcielagos (Spain) dated much later (c. 2500 BCE). These
sites were reviewed at great length by ethnobotanist Mark
Merlin (University of Hawaii at Manoa) (Merlin, 1984).
13
14 PART | II History
Based on palaeobotanical evidence, it appears that
poppy had a significant place in daily life with seeds as
a food source and possibly used for its oil (Merrillees,
1979). However, poppy capsules were not a common find,
and evidence for processing of poppy capsules or their use
as a mind-altering drug during Neolithic period is lacking
(Boekhoud, 2003; Lillios, 2010; Merlin, 2003; Merrillees,
1989).
2.2 Archaeological evidence
2.2.1 Early humans
Archaic humans existed since two million years ago (MYA)
in various forms, including Neandertals and Desovians, un-
til Homo sapiens evolved around 200 thousand years ago
or KYA (kilo or thousand years ago). It is presumed that
modern humans interacted with archaic humans during this
period (Trinkaus, 2005). Modern humans then emerged
from Africa in two waves: one around 60 KYA via Arabia,
southeast Asia to Australia, and another around 45 KYA
via the Levant to Europe. The last major wave of migration
was around 15 KYA from Siberia across Beringia into the
Americas (Manco, 2013; Nielsen et al., 2017; Pääbo, 2014).
Chimpanzees and bonobos share high similarity with
the human genome (Seaman & Buggs, 2020) and are our
closest relatives along with archaic humans. Chimpanzees
are omnivores; fruits and seeds consist almost 60% of their
food source. They are also known to preferentially eat cer-
tain plants of value that are not part of their staple. Their
knowledge would have passed onto archaic and later mod-
ern humans. We could only surmise that after migration out
of Africa, poppy (indigenous to Asia Minor) was carried by
early migrants into other areas in Europe.
2.2.2 Artifacts
The earliest poppy artifacts discovered include late Bronze
age necklaces with poppy capsule pendants (c. 1550 BCE)
and paintings with poppy gardens in the tombs of Egyptian
Kings in Thebes, including that of Tutankhamun (Rosso,
2010; Veiga, 2016). In one of these paintings, Meritaton,
daughter of Pharaoh Akhenaton and Queen Nefertiti, was de-
picted offering poppy to her husband Pharaoh Semenkhare
(c. 1400 BCE) (Rosso, 2010). Gold poppy-shaped earrings
were found in the tomb of Queen Tausret, the last Pharaoh
of the Nineteenth Dynasty, in whose time it is believed that
Troy was taken (Veiga, 2016). These paintings, offerings, and
ornaments suggest that poppy was an object fit for Egyptian
Royals or used by them for their psychedelic effects.
In the Aegean, Minoan (c. 2100 BCE), Mother Earth
Goddess, and her descendent Demeter, Greek Goddess of
Agriculture, are often depicted in various reliefs holding
grains and poppy capsules (Carod-Artal, 2013; Merrillees,
1962). Artifacts with poppy capsule engraved gold pins and
pendants dating to the Mycenaen period (c. 1500 BCE)
were unearthed in Crete. Other finds included terracotta
idols of “Poppy Goddess” and hairpins resembling opium
poppy in Crete and multiple items of daily use such as jars,
ivory pipe for smoke, and numerous clay jugs shaped like
opium poppy in Cyprus (c. 1200 BCE) (Gabra, 1956; Guo
et al., 2018). Numerous artifacts excavated in this region
showed widespread use and trading of poppy in the Aegean
(Boekhoud, 2003; Lillios, 2010; Merlin, 1984). Poppy was
probably a valuable commodity with medicinal and recre-
ational values during this period.
The first evidence for the presence of opium (morphine,
codeine, noscapine) and poppy oil from Papaver som-
niferum was found in a juglet (c. 1550 BCE) from Egypt
in the British Museum (Gabra, 1956; Merrillees, 1962).
The chemical presence of other opium alkaloids (papaver-
ine and thebaine) was recently confirmed in a Cypriot ju-
glet from this period as well (Smith, Stacey, Bergström, &
Thomas-Oates, 2018). These findings suggest that opium
was possibly known and extracted from poppy during this
period.
Based on archaeological evidence, Kritikos et al. pos-
tulated that the Minoans in Crete (c. 2100 BCE) and
later Mycenaeans in Greek mainland (c. 1400 BCE) used
poppy for “oil, healing powers, euphoria, sleep and death”
(Askitopoulou, Ramoutsaki, & Konsolaki, 2002; Kritikos
& Papadaki, 1967). These findings are also suggestive of
religious use of opium poppy dating up to the Common Era
(Veiga, 2016).
2.3 Genetic evidence
The advent of molecular genetic techniques and whole-­
genome analysis has provided us with innovative techniques
to evaluate existing evidence. Genetic studies on poppy are
a recent effort, and immense advances have been made over
the past couple of years.
2.3.1 Origins of poppy
Opium poppy belongs to the Papaveraceae family of flow-
ering eudicot plants of the ancient order Ranunculales. The
taxonomy of Papaveraceae has changed over the years, and
it was included in the order Ranunculales around 1993 CE.
The Papaveraceae family represents a higher evolutionary
level in this order based on the evolution of benzylisoquino-
line alkaloids (BIA) (Mihalik, 1999). Phylogenomic analy-
sis of Papaver origin has only recently been accomplished
using whole-genome sequence assemblies (Guo et al.,
2018; Li, Winzer, He, & Graham, 2020).
Phylogenetically, S-norcoclaurine (1-benzylisoquinoline)
is the earliest alkaloid, estimated to be present in the
­order Ranunculales around 122 MYA, and protoberberine

FIG. 2.1 Phylogenetic clade of Papaver alkaloids. Alkaloid S-norcoclaurine is the earliest phylogenetically, while morphinans recent in evolution.
a­ lkaloids appearing between 122 MYA and 110 MYA. It is
estimated that the next group of benzophenanthridine alka-
loids appeared before the Papaveraceae family split in the
order Ranunculales around 77 MYA. It was followed by the
evolution of phthalideisoquinoline alkaloids noscapine and
thebaine. Morphinan alkaloids, to which morphine belongs,
evolved around 18 MYA after a major whole-genome du-
plication (WGDa) event in Papaver during the evolutionary
process (Fig. 2.1). Thus, morphinans represent the highest
order of alkaloid evolution in Papaver (Li et al., 2020).
2.3.2 Spread of poppy
Tracing the origin and migration of humans through vast
continents is a monumental task since 99% of human devel-
opment occurred in “prehistory” before any form of written
documents were kept. Our understanding of evolution was
mainly dependent on archaeological and paleontological
information in the past. Data acquired from mitochondrial
DNA since the 1980s was limited in scope, as it represented
only female inheritance and not the whole genome. A ­major
a. WGD is the process of spontaneous doubling of all chromosomes,
whereby a duplicated gene is allowed to mutate, while the original gene
remains unchanged. This major event in evolution enables us to trace phy-
logenetic origin and changes.
Prehistory Chapter | 2 15
breakthrough occurred when the full human genome was
decoded in 2003 CE. Advances in sequencing and other
techniques are helping us to understand and reevaluate
earlier data (Stewart & Chinnery, 2015). Thus, the shift
from artifact-based archaeology (“pots are not people”) to
­technology-based archaeology has been valuable in tracing
human stories.
With the advent of farming around 10 KYA, poppy was
probably cultivated for its nutritional value. This is borne
out by bowls containing poppy seeds (along with other
grains) found in La Mormotta site in Italy (Harris, 2015;
Merlin, 2003), which dates closer to 8 KYA—earliest evi-
dence of poppy use by modern humans (Fig. 2.2). Recent
genetic studies confirmed a common source for two pat-
terns of spread of agriculture (including poppy) into Europe
during the Neolithic period. One spread in southern Europe
called Cardial Pottery Culture along the Mediterranean
coastline into Iberia, and another called Linearbandkeramik
(LBK or Linear Pottery Ceramic) Culture along the Danube
into Central Europe (Olalde et al., 2015; Salavert, 2017).
Opium poppy seeds were found along with ancient cereals
(wheat, barley), pulses (chickpeas), and oleaginous plants
(flax, poppy) in several of these cultural sites (Merlin,
1984; Salavert, 2017). Thus, there is considerable ­evidence
to ­support the concept that poppy was cultivated in the
Neolithic period in Europe, probably one of the earliest
16 PART | II History
FIG. 2.2 Possible routes of poppy spread. Patterns of poppy spread possibly follow the same line of the spread of agriculture into Europe.
crops to be cultivated by humans, and followed the spread
of farming into Western Europe (Salavert et al., 2020).
2.4 Evolutionary milestones
The evolution and spread of poppy from the Near East to
other parts of the world followed, mostly along human mi-
gration lines, and these main events are depicted in Fig. 2.3.
In summary, evolutionary milestones in history started
with mammals (200 MYA) to Homo sapiens who evolved
almost 100 million years after poppy and the earliest find-
ing of poppy in a human settlement around 7500 years ago.
Genetic studies have shown that morphinan alkaloids were
present in poppy for at least 18 million years before mod-
ern humans, with higher-order morphinans being the last to
evolve.
For an interesting description of human migration in
general and specifically European migration, based on an
interdisciplinary mix of history, archaeology, genetics,
and linguistics, we recommend Jean Manco’s Ancestral
Journeys (2013). For key discussions on the spread of
a­griculture, refer to Olalde et al. (2015), regarding the
spread of poppy, refer to Salavert et al. (2020), and for ge-
netic studies on poppy, refer to Li et al. (2020).
2.5 Synopsis
Tracing the use of poppy by early humans is a difficult
endeavor. Palaeobotanical and archaeological evidence
(as early as 8 KYA) points to its use in diet, its popularity
as jewelry, and its use as an artifact in funeral sites and
possibly a recreational drug. Recent phylogenetic evalu-
ations, using new tools such as whole-genome analysis,
indicate that poppy as a plant existed at least 100 MYA,
and morphinans evolved approximately 18 MYA before
modern humans. Evidence also indicates that the poppy
plant is indigenous to the Near East region. It probably
spread along the Mediterranean coastline and Swiss
Forelands into Europe during human migration in the
Neolithic period. New tools such as genome analysis,
hopefully, will bring new vistas on opium use by early
humans.

FIG. 2.3 Milestones in human and poppy evolution. Evolution of morphinan alkaloids preceded human evolution.
References
Askitopoulou, H., Ramoutsaki, I. A., & Konsolaki, E. (2002).
Archaeological evidence on the use of opium in the Minoan
world. International Congress Series, 1242(C), 23–29. https://doi.
org/10.1016/S0531-5131(02)00769-0.
Boekhoud, J. J. (2003). Alkaloids & artifacts: Opium in the Bronze Age
Aegean (pp. 288–300). University of Calgary. https://doi.org/10.1016/
S0531-5131(02)00769-0.
Carod-Artal, F. J. (2013). Psychoactive plants in ancient Greece.
Neurosciences and History, 1(1), 28–38. https://nah.sen.es/vmfiles/
abstract/NAHV1N1201328_38EN.pdf.
Duke, J. (1983). Papaver somniferum. In J. Duke (Ed.), Handbook of en-
ergy crops Purdue University. https://hort.purdue.edu/newcrop/duke_
energy/Papaver_somniferum.html.
Gabra, S. (1956). Papaver species and opium through the ages. Bulletin de
l’Institut d’Egypte, 37, 39–56.
Guo, L., Winzer, T., Yang, X., Li, Y., Ning, Z., He, Z., et al. (2018). The
opium poppy genome and morphinan production. Science, 362(6412),
343–347. https://doi.org/10.1126/science.aat4096.
Harris, J. (2015). La Marmotta: A Neolithic settlement beneath the wa-
ters of Lake Bracciano. Current World Archaeology, 71, 40–42. http://
www.world-archaeology.com.
Kritikos, P. G., & Papadaki, S. P. (1967). The history of the poppy and of
opium and their expansion in antiquity in the eastern Mediterranean
area. UNODC Bulletin on Narcotics, 4–002, 17–38. https://www.uno-
dc.org/unodc/en/data-and-analysis/bulletin/bulletin_1967-01-01_3_
page004.html.
Li, Y., Winzer, T., He, Z., & Graham, I. (2020). Over 100 million years
of enzyme evolution underpinning the production of morphine in the
Papaveraceae family of flowering plants. Plant Communications,
1(100029), 1–16. https://doi.org/10.1016/j.xplc.2020.100029.
Lillios, K. T. (2010). Heraldry for the dead. University of Texas Press.
Manco, J. (2013). Ancestral journeys. Thames & Hudson.
Merlin, M. (1984). On the trail of the ancient opium poppy. Associated
University Press.
Prehistory Chapter | 2 17
Merlin, M. (2003). Archaeological evidence for the tradition of psychoac-
tive plant use in the old world. Economic Botany, 57(3), 295–323.
https://www.jstor.org/stable/4256701.
Merrillees, R. S. (1962). Opium trade in the Bronze Age Levant. Antiquity,
36(144), 287–292. https://doi.org/10.1017/S0003598X00036814.
Merrillees, R. S. (1979). II: Opium again in antiquity. Levant, 11(1), 167–
170. https://doi.org/10.1179/lev.1979.11.1.167.
Merrillees, R. S. (1989). Highs and lows in the Holy Land: Opium
in biblical times. In Vol. 5. Eretz-Israel: Archaeological, histori-
cal and geographical studies (pp. 148–154). https://www.jstor.org/
stable/23621938.
Mihalik, E. (1999). Biology of poppy. In J. Bernath (Ed.), Medicinal plants
of the world (pp. 7–45). CRC Press.
Nielsen, R., Akey, J. M., Jakobsson, M., Pritchard, J. K., Tishkoff, S., &
Willerslev, E. (2017). Tracing the peopling of the world through genom-
ics. Nature, 541(7637), 302–310. https://doi.org/10.1038/nature21347.
Olalde, I., Schroeder, H., Sandoval-Velasco, M., Vinner, L., Lobón, I.,
Ramirez, O., et al. (2015). A common genetic origin for early farm-
ers from Mediterranean Cardial and Central European LBK cultures.
Molecular Biology and Evolution, 32(12), 3132–3142. https://doi.
org/10.1093/molbev/msv181.
Pääbo, S. (2014). The human condition – A molecular approach. Cell,
157(1), 216–226. https://doi.org/10.1016/j.cell.2013.12.036.
Rosso, A. M. (2010). Poppy and opium in ancient times: Remedy or nar-
cotic. Biomedicine International, 1(2), 81–87.
Salavert, A. (2017). Agricultural dispersals in Mediterranean and
Temperate Europe. In H. Shugart (Ed.), Environmental sciences:
Oxford research encyclopedia (pp. 1–43). Oxford University Press.
https://doi.org/10.1093/acrefore/9780199389414.013.307.
Salavert, A., Zazzo, A., Martin, L., Antolin, F., Gauthier, C., Thil, F.,
et al. (2020). Direct dating reveals the early history of opium poppy
in Western Europe. Nature Scientific Reports, 10, 20263. https://doi.
org/10.1038/s41598-020-76924-3.
Seaman, J., & Buggs, R. J. A. (2020). FluentDNA: Nucleotide visualiza-
tion of whole genomes, annotations, and alignments. Frontiers in
Genetics, 11. https://doi.org/10.3389/fgene.2020.00292.
18 PART | II History
Smith, R. K., Stacey, R. J., Bergström, E., & Thomas-Oates, J. (2018).
Detection of opium alkaloids in a Cypriot base-ring juglet. Analyst,
143(21), 5127–5136. https://doi.org/10.1039/c8an01040d.
Stebbins, L. G. (1978). Edgar Anderson 1897–1969. National Academy of
Sciences. http://www.nasonline.org/publications/biographical-mem-
oirs/memoir-pdfs/anderson-edgar.pdf.
Stewart, J. B., & Chinnery, P. F. (2015). The dynamics of mitochondrial
DNA heteroplasmy: Implications for human health and disease. Nature
Reviews Genetics, 16(9), 530–542. https://doi.org/10.1038/nrg3966.
Trinkaus, E. (2005). Early modern humans. Annual Review of
Anthropology, 34, 207–230. https://doi.org/10.1146/annurev.
anthro.34.030905.154913.
Veiga, P. (2016). Opium: Was it used as a recreational drug in Ancient
Egypt? In I. Micheli (Ed.), Cultural and linguistic transition explored
(pp. 199–215). EUT Edizioni Università di Trieste. http://hdl.handle.
net/10077/14300.
Chapter 3

Ancient history

she cast into the wine of which they were drinking a drug,
to quiet all pain and strife, and bring forgetfulness of every ill.
Homer in Odyssey (c. 8th century BCE)

3.1 Opium in antiquity

3.1.1 Mesopotamia
The story of opium in recorded history (c. 4000 BCE)
starts in Egypt and the Fertile Crescent of the Middle
East. It is generally assumed that Assyrian and Egyptian
cultures co-existed in recorded history dating as early as
4000 BCE (Langdon, 1921). The people of Mesopotamia
included Sumerians in the south, Akkadians in the middle,
and Assyrians in the north. Egyptian Dynasties were a con-
stant threat to the Levant during this period. Campaigns of
Assyrian Kings Esarhaddon (c. 673 BCE–671 BCE) and
his son Ashurbanipal (c. 667 BCE–663 BCE) leading to
the sack of Thebes and plunder of its riches are well docu-
mented (Kahn, 2006). It could therefore be assumed that
Assyrians probably knew about the cultural and medical use
of poppy by Egyptians.
The history of Mesopotamian civilization was largely
unknown until recent times. The earliest recognition of
Babylonian ruins by Pietro della Valle in 1616 CE (Fig. 3.1) FIG. 3.1 Pietro della Valle. Pietro journeyed from Italy to India between
led to excavations by the vicar Abbe Beauchamp more than 1614 CE and 1626 CE and also brought back cuneiform writings from
a century later (Ben-Zaken, 2009; Blunt, 1953; Gurney, Mesopotamia to Europe. (Portrait by Gilliam van der Gouwen (n.d.) in
2011; Stone, 2014). This was followed by British East India Wikimedia. https://commons.wikimedia.org/wiki/File:Portret_van_Pietro_
Company’s Claudius James Rich in 1811 CE and numerous della_Valla,_RP-P-1909-4464.jpg.)
others (Budge, 1920).
archeology, he was also an ethnographer and composer and
wrote theoretical dissertations on music. His journey makes
Box 3.1 Pietro’s journey interesting reading for anyone interested in history.
The yearnings of biblical hermeneutics took the Italian
Nobleman Pietro della Valle from Rome all the way through However, a big breakthrough on Babylonian civiliza-
Levant, Mesopotamia, Iran to India and back. During his visit tion occurred in 1847 CE, more than 200 years after Pietro,
to the city of Hillah, Iraq in 1616 CE, he identified ruins of with the discovery of clay tablets in King Ashurbanipal’s
Babylon from his knowledge of the scriptures and also brought Library by Austen Layard (Fig. 3.2) and Hormuzd Rassam
back the first inscribed bricks with cuneiform writings. Besides (Fig. 3.3).

Handbook on Opium. https://doi.org/10.1016/B978-0-323-90903-7.00015-6

Copyright © 2022 Elsevier Inc. All rights reserved. 19
20 PART | II History
FIG. 3.2 Sir Austen Henry Layard. Layard discovered clay tablets in the
Library of Ashurbanipal containing Sumerian inscriptions. (Photography
by Caldesi Blandford & Co. (n.d.) in Wellcome Collection. https://­
wellcomecollection.org/works/e29pdsr7.)
FIG. 3.3 Hormuzd Rassam. Rassam was an archeologist and co-­
discoverer of Assyrian clay tablets. (Portrait by Philip Henry Delamotte
(c. 1854 CE) in Wikimedia. https://commons.wikimedia.org/wiki/
File:Hormuzd.Rassam.reclined.jpg.)
Box 3.2 Assyrian archeologists
On his way to Sri Lanka looking for a British Civil Service
job, Austen Henry Layard (1817 CE–1894 CE) explored
ruins of Assyria in 1847 CE and 1849 CE and discovered
several monuments including Ashurbanipal’s Library (c. 700
BCE) in the city of Assur. Layard and his assistant Hormuzd
Rassam (1826 CE–1910 CE) unearthed thousands of clay
tablets in ruins of Kouyunjik mounds of Nineveh on the out-
skirts of Mosul in modern Iraq. The drawings on the ruins by
Layard are as fascinating as his excavations (Layard, 1867).
He later turned to politics, investigated the Indian Mutiny of
1857 CE, and was British Under-Secretary for Foreign Affairs
for years.
Rassam had an illustrious career as well and discovered
numerous cylinders and clay tablets with inscriptions, in-
cluding the Epic of Gilgamesh. He also served briefly as
a British diplomat before resuming his archeological work
with numerous other discoveries throughout the rest of his
career (Reade, 1993).
The clay tablets were written in Sumerian or Akkadian
on numerous topics, including the earliest known story
of the region “Poor Man of Nippur” and the earliest liter-
ary work “Epic of Gilgamesh.” Most of these clay tablets
were fragmented and partially baked from fire and de-
struction by invading forces. These epics were later trans-
lated by the printer-turned-archeologist George Smith in
1872 CE.
Clay tablets found in the Ashurbanipal’s Library
(c. 600 BCE) consisted of several Babylonian texts includ-
ing approximately 1594 literary and scientific texts, other
religious, historical, and medical topics, and archival texts
totaling more than 3500 tablets dating as early as 1500 BCE
(Reade, 1993). Of these, approximately 81 tablets are de-
voted to plants and medicine (Fincke, 2003).
Furthermore, ancient bas reliefs excavated in Nimrud
(near Nineveh) showed figures holding a plant with a cap-
sular head. It was argued by some that this plant ­represented
poppy, while other researchers considered it to be pome-
granate (Krikorian, 1975). Based on these figures and other
cuneiform writings, the view that Sumerian culture knew
about the medicinal use of poppy was proposed and propa-
gated by earlier experts on this subject (Kramer, 1963;
Kritikos & Papadaki, 1967; Thompson, 1924). However,
this idea was challenged by other Sumerian experts
subsequently.
The change in views on poppy in Sumerian culture
arises primarily from early difficulties in reading and inter-
preting ancient Sumerian writings. Sumerian is a “language
isolate” with no relationship to other languages, includ-
ing Akkad (the earliest Semitic language) and its dialects
(Assyrian, Babylonian) (Jastrow, 1915). Translation of
these writings was complex and attempted by many, but
credit for early breakthrough goes to British Army Officer
Sir Henry Rawlinson (Fig. 3.4).

FIG. 3.4 Sir Henry Rawlinson. As a young captain in British East India
Company, Rawlinson copied trilingual inscriptions on Mount Behistun in
1837 CE. (Photograph by Lock & Whitfield (n.d.) in Wikimedia. https://
commons.wikimedia.org/wiki/File:Sir_Henry_Rawlinson.jpg.)
Box 3.3 Holy trinity of cuneiform
Cuneiform script, originally developed by Sumerians,
was used in Mesopotamia until about 100 BCE when it
was replaced by an alphabetic script. Major contribution
for deciphering cuneiform script was provided by British
East India Company Army officer Sir Henry Creswicke
Rawlinson (1810 CE–1895 CE). While stationed in Persia,
Rawlinson found trilingual (old Persian, Elamite, and
Babylonian) cuneiform inscriptions on a cliff 300 feet
above ground level in Mount Behistun. He diligently
copied these, by hanging from a ladder often held pre-
cariously on the hill by an aide or using a telescope, inter-
preted and published the old Persian part of inscriptions in
1837 CE (Rawlinson, 1898).
Rawlinson’s early transcription, along with scholarly
work by Rev Edward Hincks and Franco-German Jules
Oppert, often called “holy trinity of cuneiform,” paved the
way for deciphering complex Babylonian scripts by 1857
CE. An online dictionary of the Akkadian language was
completed in 2010 CE by the University of Chicago.
3.1.2 Clay tablets of Nineveh
Clay tablets from Nineveh (dating to 1500 BCE) con-
taining the first ever recorded “Pharma” were found
Ancient history Chapter | 3 21
in two Sumerian tablets, one with a single prescrip-
tion and the other with 15 prescriptions. In his tran-
scription on plants and herbals “The Assyrian Herbal,”
Campbell Thompson interpreted the words “HUL GIL”
and “PA-PA” to connote poppy plant (Thompson, 1924).
As these words were found numerous times in the tab-
lets, poppy was advanced as a popular Assyrian medici-
nal plant. In an extension of his translation, Thompson
again identified “poppy” in at least three prescriptions
(Thompson, 1924, pp. 12–13 and 23), which helped to
propagate the concept that poppy was known and used
in Sumerian Pharma.
Box 3.4 Transcribing Assyrian
Reginald Campbell Thompson (1876 CE–1941 CE), a British
Assyriologist, in addition to being involved in the excava-
tions in Nineveh (in 1904 CE and later in 1923 CE), was
Assistant Professor of Semitic Languages in the University
of Chicago (1907–1909 CE), served as Intelligence Officer
in First World War, wrote fiction and books on Assyriology,
and often performed trapeze as a hobby.
Samuel Noah Kramer (1897 CE–1990 CE), whose fam-
ily emigrated from Ukraine region to the United States in
1905 CE, took interest in Assyriology when he was 30 years
old, participated in excavations in Iraq, worked on Assyrian
Dictionary at University of Chicago, and spent most of his
career transcribing Sumerian tablets until his death (Kramer,
1988).
However, in later transcriptions of these tablets, no
word in Sumerian or Akkadian was definitely identified as
poppy by etymologists (Kramer, 1963; Krikorian, 1975;
Merrillees, 1979). In his authoritative treatise, Samuel
Noah Kramer goes over layers of confusion to clarify the
archeological history of Sumerians. The prescriptions from
Sumerian Pharma contained materials from plants such as
thyme, mustard, figs, plum, pear, willow, fir, pine, processed
with vegetable oil, beer, and wine. He concluded that there
is no definitive mention of pain or poppy in these prescrip-
tions (Kramer, 1963).
The Chicago Assyrian Dictionary (CAD) now reads
“HUL GIL” as “UKUS”, interpreted as a cucumber;
“PA-PA” or “ARARU” or “IRRU,” now read as “TIGILLU”
and interpreted as melon (Krikorian, 1975). Many of the
words interpreted in “The Assyrian Herbal” by Campbell
Thompson are now considered either obsolete or inter-
preted differently.
In a review of these works, it is concluded by Krikorian
that there is no evidence that poppy was cultivated or used
by Sumerians, Babylonians, or Assyrians (Krikorian,
1975). Thus, contrary to popular writings, it appears that
the medicinal use of poppy was largely unknown in ancient
Mesopotamia.
22 PART | II History

3.2 Ancient Egypt

3.2.1 Cultivation of poppy
Ancient Egypt, dating back to its predynastic period (5000
BCE), was a land of a great civilization and known for its
sciences including architecture, religion, and medicine.
There is evidence for cultivation and use of poppy during
the XVIII Dynasty (c. 1500 BCE) of the Pharaonic civiliza-
tion of Egypt. Poppy was cultivated in Thebes during this
period and inspired the name “thebaine” to one of the major
alkaloids of poppy (Bryan, 1930). Poppies were shown fre-
quently in bouquets along with mandrake and cornflowers
in Egyptian paintings, including the tomb of Tutankhamun
(Rosso, 2010).
Several Egyptian papyri in Hieretic script (Greek:
Hieros = sacred; Hieretic is a cursive and shorthand form
of Hieroglyphics), such as Edwin Smith and Ebers papyri
(both dating to 1500 BCE), were discovered in the 18th
century. However, their interpretation remained an onerous
task until the discovery of the Rosetta Stone (Fig. 3.5) and
subsequent transcription by Thomas Young (Fig. 3.6) and
Jean-Francois Champollion (Fig. 3.7).

FIG. 3.6 Thomas Young. Physician polymath who deciphered Rosetta

Stone, credited as the “last man who knew everything.” (Mezzotint by G.R.
Ward (c. 1855 CE) in Wellcome Collection. https://wellcomecollection.org/
works/xv69yyrp.)

FIG. 3.7 Jean-Francois Champollion. Champollion, an accomplished

FIG. 3.5 The Rosetta Stone. Trilingual inscriptions on the Rosetta philologist who completed the decipherment of Rosetta Stone, is known
Stone with Hieroglyphics in the upper third panel. (Unknown author as “Father of Egyptology.” (Painting by Leon Cogniet (1831 CE) in
(n.d.) in Wikimedia Commons. https://commons.wikimedia.org/wiki/ Wikimedia. https://commons.wikimedia.org/wiki/File:Jean-Francois_
File:Rosetta_Stone_BW.jpeg.) Champollion,_by_Leon_Cogniet.jpg.)
 Ancient history Chapter | 3 23

Box 3.5 Hieroglyphics

Egyptian Hieroglyph (Greek for “holy word”) was a system
of pictorial writings dating to 3000 BCE, until its decline by
the third century CE, when the Coptic (based on Greek al-
phabet) language was adapted in Egypt. Hieroglyphics was
lost in time, and the earliest work to interpret Hieroglyphics
was published, almost six centuries after its disuse, by
Arabian Egyptologist Ibn Wahshiyya (Kitab al-Mustaham)
in 982 CE.
However, complete interpretation of Hieroglyphics re-
mained difficult until the discovery of the Rosetta Stone.
This inscription (c. 196 BCE) was discovered in 1799 CE by
Pierre Francois Xavier Bouchard, an officer of Napoleon’s
army in the city of Rashid. The stone contained trilingual
inscriptions (Hieroglyphic, Demotic, and Greek) of the
same message; it was seized by the British in 1801 CE af-
ter Napoleon’s defeat and currently resides at the British
Museum in London.

Box 3.6 Race for Rosetta

The Rosetta Stone was deciphered by two great minds
with fierce competition. It was initially cross-interpreted
FIG. 3.8 Page from Ebers Papyrus. Poppy was mentioned in Ebers
from Demotic script by English physician Thomas Young. It
Papyrus as a component of several remedies. (U.S. National Library of
was later fully deciphered in 1820 CE by the charismatic Medicine (c. 1500 BCE). http://resource.nlm.nih.gov/101436767.)
Frenchman Jean-Francois Champollion.
Thomas Young (1773–1829 CE) was a physician poly-
math who mastered ancient languages by 14 years of age,
established wave theory of light, worked on physiology
of optics, formulated several biophysical characteristics
(Young’s modulus of elasticity, Young-Laplace equation of
capillary pressure, Young’s rule for calculating drug dose
for children), and laid foundation for interpreting Rosetta
Stone. He was called “the last man who knew everything”
(Robinson, 2005).
Champollion (1790–1832 CE), youngest of seven chil-
dren in his family, mastered ancient oriental languages,
Latin and Greek, by 16 years of age, became a professor
of history by age 20, served as a curator of Egyptian collec-
tion in Louvre Museum by 36 years of age, and took part in
Franco-Tuscan expedition to Egypt. He died early by age 41
of stroke; he is hailed as “Father of Egyptology” (Robinson,
2012).

3.2.2 Papyrus of Ebers

Papyrus of Ebers (c. 1500 BCE) listed multiple preparations
along with spells and incantations for dealing with ailments, in
accordance with the theory of diseases of the times (Fig. 3.8).
It is a medical compendium in Hieratic with 811 prescrip-
tions and lists multiple diseases and several plant remedies,
including parts of poppy plant, berries, and seeds as constit-
uents in several prescriptions (Bryan, 1930; Nunn, 1996). FIG. 3.9 Georg Moritz Ebers. Ebers was a German novelist who came
Ebers Papyrus is a historic discovery and landmark in the across a set of medical papyrus in Egypt (1874 CE),which now bears his name.
(Wikimedia (n.d.). https://commons.wikimedia.org/wiki/File:Georg_Ebers.jpg.)
history of medicine.
24 PART | II History
Box 3.7 Egyptian papyri
Edwin Smith (1822–1906 CE) from Connecticut was an
Egyptologist and dealer of antiquities. He lived for almost
two decades in Egypt, and in 1862 CE, came across two sets
of papyri in Luxor. He kept the first set of papyrus, while
the second set was temporarily in his possession until 1869
CE, after which its whereabouts unknown. The first set of
papyrus was donated by his daughter (after his death) to
New York Historical Society. Its significance was not real-
ized until analyzed by historian James Breasted in 1930 CE.
Edwin Smith Papyrus is the oldest known treatise on cranial
and spinal cord injuries (Hughes, 1988; Van Middendorp,
Sanchez, & Burridge, 2010).
Georg Mortiz Ebers (1837–1898 CE) was a German
novelist (Fig. 3.9), who popularized Egyptian folklore
through historical romantic novels in Germany. The sec-
ond set of papyrus was purchased by Ebers, when it sur-
faced again in Luxor in the winter of 1874 CE. It was
wrapped in old mummy clothes and perfectly preserved,
and consisted of a scroll 20 meters long containing 108
columns of text, dated at the reign of Amenophis I (1536
BCE) (Bryan, 1930). Ebers Papyrus is a compendium of
medical knowledge of the day written in Hieratic, trans-
lated into German with great devotion by physician
Egyptologist Hans Joachim, and into English (1930 CE) by
physician Cyril Bryan.
Opium poppy is mentioned in the Ebers Papyrus as “Spn”
(Rosso, 2010) and is the earliest known record on opium. There
is frequent mention of poppy in Ebers Papyrus as a compo-
nent of several remedies used for headache to stop crying in
children and abdominal discomfort (Fig 3.10). Treatment of
headache in the medical papyri was analyzed by Karenberg
and Leitz (2001), including a few prescriptions that in-
cluded poppy as a component (Karenberg & Leitz, 2001).
FIG. 3.10 Poppy prescriptions in papyri. Examples of prescriptions in papyri containing poppy as one of the ingredients.
However, poppy was not the only ingredient for the treat-
ment of pain or any other ailments in the papyri (Bryan,
1930; Hobbs, 1998; Rosso, 2010). These findings indicate
that although soporific and analgesic effects of poppy were
known, other medicinal or addictive potentials were prob-
ably unrecognized during this time.
3.3 Classical history
Pharmacopeia of ancient Egypt was eagerly studied
by Greek physicians and formed the basis of several
therapeutics in Greek medicine. The earliest reference
­
to poppy in Greek writings is attributed to Linear B
Mycenaean tablets of Pylos (c. 1400 BCE), discovered by
British Archeologist Arthur Evans in 1939 CE. Several ref-
erences to the Greek Goddess Demeter were found in these
tablets (Janke & Solca, 2018). Linear B equivalent of the
word “I-DA-MA-TE” in the Minoan A tablets is often con-
sidered equivalent to “DAMATE” in the Mycenean B tab-
lets and interpreted as Demeter in classic Greek. Demeter
was usually depicted as the Goddess of Harvest, with cere-
als and poppy in her hand in ancient Greece. It was inferred
from this depiction that poppy was known and used during
those times in ancient Greece.
Box 3.8 Linear B script
Sir Arthur John Evans (1851–1941 CE), a British journalist-
archeologist and adventurer-statesman, unearthed the
Palace of Knossos on Crete. He was instrumental in delin-
eating Minoan civilization (c. 2700–1600 BCE) that pre-
dated Mycenaean (c. 1600–1100 BCE) based on artifacts.
In addition, he also found 3000 clay tablets in two different
scripts—Linear A and Linear B dating to the Minoan period
that gave insight into their civilization (Evans, 1950). One of

his school friends was Francis Maitland Balfour, a renowned
biologist and Darwinian. For a general description and cata-
log of ancient languages of Levant and Mediterranean, refer
to website Mnamon (www.mnamon.sns.it).
The first reference to poppy in the literature is attributed
to early Greek poets (c. seventh century BCE), Hesiod and
Homer. Hesiod in “Theogony” described a banquet scene at
the city of Mekone near Corinth. Homer described “droop-
ing head” of poppy in “Iliad,” and a drug “to lull all pain
and anger” called nepenthe in “Odyssey” that Helen of
Troy obtained from an Egyptian noble. It is postulated that
Mekone was named after the field of poppies, and nepenthe
may have been opium (Kritikos & Papadaki, 1967).
No further information on poppy is available until the
start of the classical Greek period around fifth century
BCE. Eminent writings of Hippocrates, Aristotle, and
Theophrastus at the dawn of Greek medicine renewed inter-
est in the medical use of opium poppy.
3.3.1 Hippocrates of Cos
Hippocrates of Cos (c. 460 BCE–370 BCE), known as “Father
of Clinical Medicine” was a great influence on Medicine
(Craik, 2014; Jones, 1923; Jouanna, 1999; Fig. 3.11), and
FIG. 3.11 Hippocrates of Cos. Poppy was mentioned in Hippocratic
Corpus multiple times but was not the primary component of these reme-
dies. (Lithograph by Lanta, J. (c. 1835 CE) in Wellcome Collection. https://
wellcomecollection.org/works/uhdx4jrn.)
Ancient history Chapter | 3 25
collection of his works is known as “Hippocratic Corpus.”
Remedies described by Hippocrates for diseases included
parts of several plants (numbering 200, including poppy),
mostly mixed with other ingredients (such as old wine,
cumin, honey, pepper, silphium or asafetida, celery, fen-
nel, goat cheese, castor oil, black hellebore, bark of pome-
granate, acacia, and anise, among others) (Elliott, 1914;
Prioreschi, Heaney, & Brehm, 1988). Poppy is referred to
as “mekon” in various texts of Hippocratic Corpus (Cilliers
& Retief, 2000; Coxe, 1846; Retief & Cilliers, 2010). In
Fistulae, Hippocrates recommends “white meconium”
(white poppy) for anal inflammation and protrusion when
other measures fail. Poppy extracts and seeds (in mixtures
with several other substances) were prescribed by him for
gynecological ailments including leukorrhea (Astyrakaki,
Papaioannou, & Askitopoulou, 2010).
Box 3.9 Corpus Hippocraticum
The works of Hippocrates II of Cos (460–357 BCE), written
in Ancient Greek and numbering 60, are collectively known
as “Corpus Hippocraticum” (these works are listed in Craik,
2014). English translation of complete works of Hippocrates
is not available—most are taken from Latin translations of
Foesius (1624 CE), Haller (1775 CE), Gardeil (1801 CE), or
Kuhn (1825 CE).
Hippocrates is a descendent of Hippolochus, son of
Podalirius Esculapius, grandson of Apollo—line of great phy-
sicians of their times. Similar to the Pythagorean philosophy
of four elements (water, earth, wind, and fire), Hippocrates
believed that the body consisted of four humors (black bile,
yellow bile, phlegm, and blood) and four elements (cold,
hot, dry, and moist). In the case of diseases, healing is done
by restoring the balance of these humors and elements by
using four methods such as bleeding, emetics, purgatives,
and surgery. Hippocratic Oath has a Pythagorean influence
of four fundamentals including duty, justice, respect, and se-
crecy (Jouanna, 1999). Pythagorean philosophy, propagated
by Empedocles (493–433 BC) who believed in reincarna-
tion, was founded by the legendary Pythagoras.
In an extensive review of the Hippocratic Corpus from the
compendium by Maloney and Frohn (1986), Prioreschi et al.
found direct reference to poppy for relief of pain in only three
passages (Maloney & Frohn, 1986; Prioreschi, 1993). These
passages are quoted below, where page numbers refer to the
work by Maloney & Frohn (1986):
For the pain of the uterus … a soup of white poppy seeds and
nettle seeds.
(On Women’s Diseases, II, ccvi, Littre, VIII, p. 400)
hypochondria are also painful, an enema is to be given and, on
an empty stomach, a drink of birthwort, hyssop, cumin, laser
wort, white poppy, flowers of copper, honey, vinegar, and Water.
(On Diseases, III, xvi, Littre, VII, pp. 146–148)
26 PART | II History

If sudden, intense pain develops and there is faintness, make Box 3.10 Vivisectionists
pills of one drachma with rose leaves, cinnamon, pure myrrh,
Erasistratus served briefly as a court physician of Seleucus
oil of bitter almonds, and poppy sap. Put them on a pitcher
Nikator of Syria and later practiced in Alexandria and
shard and, when it is red, use for fumigation. Antioch. Famed story of Erasistratus diagnosing the son
(On Women’s Diseases, II, ccvi, Littre, VIII, p. 400) of Seleucus, Antiochus, as love sick with his young step-
mother Stratonice, was later immortalized by several artists.
They also found that poppy was used (with other ingredi- Seleucus was gracious to offer his young wife to his son,
ents) in 13 other passages to treat symptoms associated with which healed future King Antiochus’ sickness.
pain, but in the majority of conditions with pain (at least 81 Erasistratus, along with the great Anatomist Herophilus
different painful conditions discussed by Hippocrates), poppy (330–260 BCE), studied anatomy by human vivisection
was not at all prescribed. Overall, poppy was included in ap- on (alive) criminals (Bay & Bay, 2010). Both distinguished
proximately 20% of these remedial mixtures for pain in the separate neural pathways for sensory and motor function.
Hippocratic Corpus (Prioreschi et al., 1988). Given these Herophilus, often called “Father of Anatomy,” made great
findings, it may be inferred that there was no separation of contributions to the anatomy of the brain and vascular
system and was a major influence on Galen. Human vivi-
treatment of pain from general treatment of diseases in the
section was abandoned after them until the 16th century
Hippocratic Corpus. Forever a cautious physician, Hippocrates (Dobson, 1925; Pearce, 2013; von Staden, 1992).
said in the Oath, “I will give no deadly medicine to anyone if
asked, nor suggest such counsel” (Jouanna, 1999). It is widely held that Alexander the Great (356–323
The first herbal “Rhizotomika” was written by Greek BCE), a pupil of Aristotle (384–322 BCE), introduced
physician Diocles of Carystus (c. 350 BCE), known as opium to the people of Persia and India (Holt, 2003)
“younger Hippocrates.” Most of his work is fragmen- (Fig. 3.12). Aristotle himself was interested in medicine and
tary and deduced from quotes of later physicians such as
Galen, Celsus, and Oribasius. In description of medici-
nal plants, Diocles included poppy and its effects on the
body. His work is also considered to be the first to include
pictures of plants in prescriptions (van der Eijk, 2000).
There is some indication that Diagoras of Cyprus
(c. 300 BCE), “skilled at sorting the medicinal herbs”
(quoted in De materia medica, 4.64.5–6), disapproved
the use of opium (Osbaldeston & Wood, 2000). He is fre-
quently mentioned in writings of later physicians (such as
Dioscorides, Erasistratus, and Oribasius) as a prominent
­oculist and is credited with preparation of the “rose col-
lyrium” for severe pain in the eye:
“Fresh roses without the white part of the petals 72 drach-
mas (weight), kadmeía 25 drachmas, krókos (saffron) 6
drachmas, opium 3 drachmas, … myrrh 3 drachmas, …”
(quoted by Oribasius, 3.141).

Grant (1997) and Tsoucalas et al. (2018)

Diagoras was concerned with adulteration of poppy in

his preparation, which was harmful to the eye. It is also
claimed that Diagoras said that it was “better to suffer pain
than to become dependent on opium” (Booth, 1996).
It is mentioned that Erasistratus of Ceos (c. 325–250
BCE) treated snake bites with a mixture of opium and cas-
toreum (Billinger, 1876). However, Erasistratus did not
recommend poppy juice for other illnesses or pain (Tibi,
2005). Most of his works are quoted by Galen, and it is al-
leged that Erasistratus may have killed himself using opium FIG. 3.12 King Porus and Alexander the Great. Alexander vanquished
Porus in Western Punjab and then made him a satrap of his empire. This
(Pearce, 2013). It is unclear if Diagoras and Erasistratus encounter may have introduced opium poppy to India. (Engraving by
were concerned about opium due to adulterants in the prep- Alonzo Chappel (1865 CE) in Wikimedia. https://commons.wikimedia.org/
aration, or due to consideration as a poison or both. wiki/File:Surrender_of_Porus_to_the_Emperor_Alexander.jpg.)
Another random document with
no related content on Scribd:
have been sufficiently described above (p. 55), and it remains only to
be mentioned that the bones of the palatine arch are but rarely
absent, as for instance in Murænophis; and that the symplectic does
not extend to the articulary of the mandible, as in Amia and
Lepidosteus, though its suspensory relation to the Meckelian
cartilage is still indicated by a ligament which connects the two
pieces. Of the mandibulary bones the articulary (35) is distinctly part
of Meckel’s cartilage. Frequently another portion of cartilage below
the articulary remains persistent, or is replaced by a separate
membrane-bone, the angular.
4. Membrane-bones of the alimentary portion of the visceral
skeleton of the skull.—The suspensorium has one tegumentary bone
attached to it, viz. the præoperculum (30); it is but rarely absent, for
instance in Murænophis. The premaxillary (17) and maxillary (18) of
the Teleostei appear to be also membrane-bones, although they are
clearly analogous to the upper labial cartilages of the Sharks. The
premaxillaries sometimes coalesce into a single piece (as in Diodon,
Mormyrus), or they are firmly united with the maxillaries (as in all
Gymnodonts, Serrasalmo, etc.) The relative position and connection
of these two bones differs much, and is a valuable character in the
discrimination of the various families. In some, the front margin of the
jaw is formed by the premaxillary only, the two bones having a
parallel position, as it has been described in the Perch (p. 53); in
others, the premaxillary is shortened, allowing the maxillary to enter,
and to complete, the margin of the upper jaw; and finally, in many no
part of the maxillary is situated behind the premaxillary, but the entire
bone is attached to the end of the premaxillary, forming its
continuation. In the last case the maxillary may be quite abortive.
The mobility of the upper jaw is greatest in those fishes in which the
premaxillary alone forms its margin. The form of the premaxillary is
subject to great variation: the beak of Belone, Xiphias is formed by
the prolonged and coalesced premaxillaries. The maxillary consists
sometimes of one piece, sometimes of two or three. The principal
membrane-bone of the mandible is the dentary (34), to which is
added the angular (36) and rarely a smaller one, the splenial or os
operculare, which is situated at the inside of the articulary.
 5. Cartilage-bones of the respiratory portion of the visceral
skeleton of the skull.—With few exceptions all the ossifications of the
hyoid and branchial arches, as described above (p. 58), belong to
this group.
6. Membrane-bones of the respiratory portion of the visceral
skeleton of the skull.—They are the following: the opercular pieces,
viz. operculum (28), sub-operculum (32), and interoperculum (33).
The last of these is the least constant; it may be entirely absent, and
represented by a ligament extending from the mandible to the hyoid.
The urohyal (42) which separates the musculi sternohyoidei, and
serves for an increased surface of their insertion; and finally the
branchiostegals (43), which vary greatly in number, but are always
fixed to the cerato- and epi-hyals.
7. Dermal bones of the skull.—To this category are referred some
bones which are ossifications of, and belong to, the cutis. They are
the turbinals (20), the suborbitals (19), and the supratemporals. They
vary much with regard to the degree in which they are developed,
and are rarely entirely absent. Nearly always they are wholly or
partly transformed into tubes or hollows, in which the muciferous
canals with their numerous nerves are lodged. Those in the temporal
and scapulary regions are not always developed; on the other hand,
the series of those ossicles may be continued on to the trunk,
accompanying the lateral line. In many fishes those of the infraorbital
ring are much dilated, protecting the entire space between the orbit
and the rim of the præoperculum; in others, especially those which
have the angle of the præoperculum armed with a powerful spine,
the infraorbital ring emits a process towards the spine, which thus
serves as a stay or support of this weapon (Scorpænidæ, Cottidæ).
The pectoral arch of the Teleosteous fishes exhibits but a
remnant of a primordial cartilage, which is replaced by two
ossifications,[10] the coracoid (51) and scapula (52); they offer
posteriorly attachment to two series of short rods, of which the
proximal are nearly always ossified, whilst the distal frequently
remain small cartilaginous nodules hidden in the base of the pectoral
rays. The bones, by which this portion is connected with the skull,
are membrane-bones, viz. the clavicle (49), with the postclavicle (49
+ 50), the supraclavicle (47), and post-temporal (46). The order of
their arrangement in the Perch has been described above (p. 59).
However, many Teleosteous fish lack pectoral fins, and in them the
pectoral arch is frequently more or less reduced or rudimentary, as in
many species of Murænidæ. In others the membrane-bones are
exceedingly strong, contributing to the outer protective armour of the
fish, and then the clavicles are generally suturally connected in the
median line. The postclavicula and the supraclavicula may be
absent. Only exceptionally the shoulder-girdle is not suspended from
the skull, but from the anterior portion of the spinous column
(Symbranchidæ, Murænidæ, Notacanthidæ). The number of basal
elements of each of the two series never exceeds five, but may be
less; and the distal series is absent in Siluroids.
The pubic bones of the Teleosteous fishes undergo many
modifications of form in the various families, but they are essentially
of the same simple type as in the Perch.
 CHAPTER V.

MYOLOGY.

In the lowest vertebrate, Branchiostoma, the whole of the

muscular mass is arranged in a longitudinal band running along each
side of the body; it is vertically divided into a number of flakes or
segments (myocommas) by aponeurotic septa, which serve as the
surfaces of insertion to the muscular fibres. But this muscular band
has no connection with the notochord except in its foremost portion,
where some relation has been formed to the visceral skeleton. A
very thin muscular layer covers the abdomen.
Also in the Cyclostomes the greatest portion of the muscular
system is without direct relation to the skeleton, and, again, it is only
on the skull and visceral skeleton where distinct muscles have been
differentiated for special functions.
To the development of the skeleton in the more highly organised
fishes corresponds a similar development of the muscles; and the
maxillary and branchial apparatus, the pectoral and ventral fins, the
vertical fins, and especially the caudal, possess a separate system
of muscles. But the most noteworthy is the muscle covering the
sides of the trunk and tail (already noticed in Branchiostoma), which
Cuvier described as the “great lateral muscle,” and which, in the
higher fishes, is a compound of many smaller segments,
corresponding in number with the vertebræ. Each lateral muscle is
divided by a median longitudinal groove into a dorsal and ventral
half; the depression in its middle is filled by an embryonal muscular
substance which contains a large quantity of fat and blood-vessels,
and therefore differs from ordinary muscle by its softer consistency,
and by its colour which is reddish or grayish. Superficially the lateral
muscle appears crossed by a number of white parallel tendinous zig-
zag stripes, forming generally three angles, of which the upper and
lower point backwards, the middle one forwards. These are the outer
edges of the aponeurotic septa between the myocommas. Each
septum is attached to the middle and the apophyses of a vertebra,
and, in the abdominal region, to its rib; frequently the septa receive
additional support by the existence of epipleural spines. The fibres of
each myocomma run straight and nearly horizontally from one
septum to the next; they are grouped so as to form semiconical
masses, of which the upper and lower have their apices turned
backwards, whilst the middle cone, formed by the contiguous parts
of the preceding, has its apex directed forward; this fits into the
interspace between the antecedent upper and lower cones, the
apices of which reciprocally enter the depressions in the succeeding
segment, whereby all the segments are firmly locked together
(Owen).
In connection with the muscles reference has to be made to the
Electric organs with which certain fishes are provided, as it is more
than probable, not only from the examination of peculiar muscular
organs occurring in the Rays, Mormyrus, and Gymnarchus (the
function of which is still conjectural), but especially from the
researches into the development of the electric organ of Torpedo,
that the electric organs have been developed out of muscular
substance. The fishes possessing fully developed electric organs,
with the power of accumulating electric force and communicating it in
the form of shocks to other animals, are the electric Rays
(Torpedinidæ), the electric Sheath-fish of tropical Africa
(Malapterurus), and the electric Eel of tropical America (Gymnotus).
The structure and arrangement of the electric organ is very different
in these fishes, and will be subsequently described in the special
account of the several species.
The phenomena attending the exercise of this extraordinary
faculty also closely resemble muscular action. The time and strength
of the discharge are entirely under the control of the fish. The power
is exhausted after some time, and it needs repose and nourishment
to restore it. If the electric nerves are cut and divided from the brain
the cerebral action is interrupted, and no irritant to the body has any
effect to excite electric discharge; but if their ends be irritated the
discharge takes place, just as a muscle is excited to contraction
under similar circumstances. And, singularly enough, the application
of strychnine causes simultaneously a tetanic state of the muscles
and a rapid succession of involuntary electric discharges. The
strength of the discharges depends entirely on the size, health, and
energy of the fish: an observation entirely agreeing with that made
on the efficacy of snake-poison. Like this latter, the property of the
electric force serves two ends in the economy of the animals which
are endowed with it; it is essential and necessary to them for
overpowering, stunning, or killing the creatures on which they feed,
whilst incidentally they use it as the means of defending themselves
from their enemies.
 CHAPTER VI.

NEUROLOGY.

The most simple condition of the nervous central organ known in

Vertebrates is found in Branchiostoma. In this fish the spinal chord
tapers at both ends, an anterior cerebral swelling, or anything
approaching a brain, being absent. It is band-like along its middle
third, and groups of darker cells mark the origins of the fifty or sixty
pairs of nerves which accompany the intermuscular septa, and
divide into a dorsal and ventral branch, as in other fishes. The two
anterior pairs pass to the membranous parts above the mouth, and
supply with nerve filaments a ciliated depression near the extremity
of the fish, which is considered to be an olfactory organ, and two
pigment spots, the rudiments of eyes. An auditory organ is absent.
The spinal chord of the Cyclostomes is flattened in its whole
extent, band-like, and elastic; also in Chimæra it is elastic, but
flattened in its posterior portion only. In all other fishes it is
cylindrical, non-ductile, and generally extending along the whole
length of the spinal canal. The Plectognaths offer a singular
exception in this respect that the spinal chord is much shortened, the
posterior portion of the canal being occupied by a long cauda
equina; this shortening of the spinal chord has become extreme in
the Sun-fish (Orthagoriscus), in which it has shrunk into a short and
conical appendage of the brain. Also in the Devil-fish (Lophius) a
long cauda equina partly conceals the chord which terminates on the
level of about the twelfth vertebra.
The brain of fishes is relatively small; in the Burbot (Lota) it has
been estimated to be 1/720th part of the weight of the entire fish, in
the Pike the 1/1305th part, and in the large Sharks it is relatively still
smaller. It never fills the entire cavity of the cranium; between the
dura mater which adheres to the inner surface of the cranial cavity,
and the arachnoidea which envelops the brain, a more or less
considerable space remains, which is filled with a soft gelatinous
mass generally containing a large quantity of fat. It has been
observed that this space is much less in young specimens than in
adult, which proves that the brain of fishes does not grow in the
same proportion as the rest of the body; and, indeed, its size is
nearly the same in individuals of which one is double the bulk of the
other.

Fig. 41.—Brain of Perch.

I. Upper aspect. II. Lower aspect.
a, cerebellum; b, optic lobes; c, hemispheres; e, lobi inferiores; f, hypophysis; g,
lobi posteriores; i, Olfactory lobes; n, N. opticus; o, N. olfactorius; p, N. oculo-
motorius; q, N. trochlearis; r, N. trigeminus; s, N. acusticus; t, N. vagus; u, N.
abducens; v, Fourth ventricle.
The brain of Osseous fishes (Fig. 41) viewed from above shows
three protuberances, respectively termed prosencephalon,
mesencephalon, and metencephalon, the two anterior of which are
paired, the hindmost being single. The foremost pair are the
hemispheres, which are solid in their interior, and provided with two
swellings in front, the olfactory lobes. The second pair are the optic
lobes, which generally are larger than the hemispheres, and
succeeded by the third single portion, the cerebellum. In the fresh
state the hemispheres are of a grayish colour, and often show some
shallow depressions on their surface; a narrow commissure of white
colour connects them with each other. The optic lobes possess a
cavity (ventriculus lobioptici), at the bottom of which some
protuberances of variable development represent the corpora
quadrigemina of higher animals. On the lower surface of the base of
the optic lobes, behind the crura cerebri, two swellings are observed,
the lobi inferiores, which slightly diverge in front for the passage of
the infundibulum, from which a generally large hypophysis or
pituitary gland is suspended. The relative size of the cerebellum
varies greatly in the different osseous fishes: in the Tunny and
Silurus it is so large as nearly to cover the optic lobes; sometimes
distinct transverse grooves and a median longitudinal groove are
visible. The cerebellum possesses in its interior a cavity which
communicates with the anterior part of the fourth ventricle. The
medulla oblongata is broader than the spinal chord, and contains the
fourth ventricle, which forms the continuation of the central canal of
the spinal chord. In most fishes a perfect roof is formed over the
fourth ventricle by two longitudinal pads, which meet each other in
the median line (lobi posteriores), and but rarely it remains open
along its upper surface.
The brain of Ganoid fishes shows great similarity to that of the
Teleostei; however, there is considerable diversity of the
arrangement of its various portions in the different types. In the
Sturgeons and Polypterus (Fig. 42) the hemispheres are more or
less remote from the mesencephalon, so that in an upper view the
crura cerebri, with the intermediate entrance into the third ventricle
(fissura cerebri magna), may be seen. A vascular membranous sac,
containing lymphatic fluid (epiphysis), takes its origin from the third
ventricle, its base being expanded over the anterior interspace of the
optic lobes, and the apex being fixed to the cartilaginous roof of the
cranium. This structure is not peculiar to the Ganoids, but found in
various stages of development in Teleosteans, marking, when
present, the boundary between prosencephalon and
mesencephalon. The lobi optici are essentially as in Teleosteans.
The cerebellum penetrates into the ventriculus lobi optici, and
extends thence into the open sinus rhomboidalis. At its upper
surface it is crossed by a commissure formed by the corpora
restiformia of the medulla.
 Fig. 42.—Brain of Polypterus. (After Müller.)
I., Upper; II., Lateral; III., Lower aspect.
a, Medulla; b, corpora restiformia; c, cerebellum; d, lobi optici; e, hypophysis; f,
fissura cerebri magna; g, nervus opticus; g’, chiasma; h, hemispheres; i, lobus
olfactorius; k, sinus rhomboidalis (fourth ventricle).
As regards external configuration, the brain of Lepidosteus and
Amia approach still more the Teleosteous type. The prosencephalon,
mesencephalon, and metencephalon are contiguous, and the
cerebellum lacks the prominent transverse commissure at its upper
surface. The sinus rhomboidalis is open.
The brain of the Dipnoi shows characters reminding us of that of
the Ganoids as well as the Chondropterygians, Ceratodus agreeing
with Protopterus in this respect, as in most other points of its
organisation. The hemispheres form the largest part of the brain;
they are coalescent, as in Sharks, but possess two lateral ventricles,
the separation being externally indicated by a shallow median
groove on the upper surface. The olfactory lobes take their origin
from the upper anterior end of the hemispheres. Epiphysis and
hypophysis well developed. The lobi optici are very small, and
remote from the prosencephalon, their division into the lateral halves
being indicated by a median groove only. The cerebellum is very
small, overlying the front part of the sinus rhomboidalis.

Fig. 43.—Brain of Carcharias. (After Owen.)

ac, Nerv. acusticus; b, corpus restiforme; c, cerebellum; d, lobus opticus; e,
hypophysis; g, nervus opticus; h, hemisphere; i, lobus olfactorius; i’, olfactory
pedicle; k, nerv. olfactorius; l, epiphysis; m, nerv. oculo-motorius; tr, nerv.
trigeminus; v, nerv. vagus.
The brain of Chondropterygians (Fig. 43) is more developed than
that of all other fishes, and distinguished by well-marked characters.
These are, first, the prolongation of the olfactory lobes into more or
less long pedicles, which dilate into great ganglionic masses, where
they come into contact with the olfactory sacs; secondly, the space
which generally intervenes between prosencephalon and
mesencephalon, as in some Ganoids; thirdly, the large development
of the metencephalon.
The hemispheres are generally large, coalescent, but with a
median, longitudinal, dividing groove. Frequently their surface shows
traces of gyrations, and when they are provided with lateral
ventricles, tubercles representing corpora striata may be observed.
The olfactory pedicles take their origin from the side of the
hemispheres, and are frequently hollow, and if so, their cavity
communicates with the ventricle of the hemisphere. The optic lobes
are generally smaller than the hemispheres, coalescent, and
provided with an upper median groove like the prosencephalon. At
their base a pair of lobi inferiores are constant, with the hypophysis
and sacsus vasculosus (a conglomeration of vascular loops without
medullary substance) between them.
The cerebellum is very large, overlying a portion of the optic
lobes and of the sinus rhomboidalis, and is frequently transversely
grooved. The side-walls of the fourth ventricle, which are formed by
the corpora restiformia, are singularly folded, and appear as two
pads, one on each side of the cerebellum (lobi posteriores s. lobi
nervi trigemini).
 Fig. 44.—Brain of Bdellostoma. (Enlarged, after
Müller.)
I., Upper; II., Lower aspect. Letters as in Fig. 45.
 Fig. 45.—Brain of Petromyzon. (Enlarged,
after Müller.)
I., Upper; II., Lower aspect.
a, Medulla oblongata; ac, nerv. acusticus; b,
corpus restiforme or rudimentary
cerebellum; d, lobus ventriculi tertii; d’,
entrance into the third ventricle; c,
hypophysis; fa, nerv. facialis; g, nerv.
opticus; h, hemisphere; hy, nerv.
hypoglossus (so named by Müller); i, lobus
olfactorius; k, sinus rhomboidalis; l,
 epiphysis; m, nerv. oculo-motorius; q,
corpora quadrigemina; tr, nerv. trigeminus;
tro, nerv. trochlearis; v, nerv. vagus.
The brain of the Cyclostomes (Figs. 44, 45) represents a type
different from that of other fishes, showing at its upper surface three
pairs of protuberances in front of the cerebellum; they are all solid.
Their homologies are not yet satisfactorily determined, parts of the
Myxinoid brain having received by the same observers
determinations very different from those given to the corresponding
parts of the brain of the Lampreys. The foremost pair are the large
olfactory tubercles, which are exceedingly large in Petromyzon. They
are followed by the hemispheres, with a single body wedged in
between their posterior half; in Petromyzon, at least, the vascular
tissue leading to an epiphysis seems to be connected with this body.
Then follows the lobus ventriculi tertii, distinctly paired in Myxinoids,
less so in Petromyzon. The last pair are the corpora quadrigemina.
According to this interpretation the cerebellum would be absent in
Myxinoids, and represented in Petromyzon by a narrow commissure
only (Fig. 45, b), stretching over the foremost part of the sinus
rhomboidalis. In the Myxinoids the medulla oblongata ends in two
divergent swellings, free and obtuse at their extremity, from which
most of the cerebral nerves take their origin.
The Nerves which supply the organs of the head are either
merely continuations or diverticula of the brain-substance, or proper
nerves taking their origin from the brain, or receiving their constituent
parts from the foremost part of the spinal chord. The number of
these spino-cerebral nerves is always less than in the higher
vertebrates, and their arrangement varies considerably.
A. Nerves which are diverticula of the brain (Figs. 41–45).
The olfactory nerves (first pair) always retain their intimate
relation to the hemispheres, the ventricles of which are not rarely
continued into the tubercle or even pedicle of the nerves. The
different position of the olfactory tubercle has been already
described as characteristic of some of the orders of fishes. In those
fishes in which the tubercle is remote from the brain, the nerve which
has entered the tubercle as a single stem leaves it split up into
several or numerous branches, which are distributed in the nasal
organ. In the other fishes it breaks up into branchlets spread into a
fan-like expansion at the point, where it enters the nasal cavity. The
nerve always passes out of the skull through the ethmoid.
The optic nerves (second pair) vary in size, their strength
corresponding to the size of the eye; they take their origin from the
lobi optici, the development of which again is proportionate to that of
the nerves. The mutual relation of the two nerves immediately after
their origin is very characteristic of the sub-classes of fishes. In the
Cyclostomes they have no further connection with each other, each
going to the eye of its own side.[11] In the Teleostei they simply cross
each other (decussate), so that the one starting from the right half of
the brain goes to the left eye and vice versa. Finally, in Palæichthyes
the two nerves are fused together, immediately after their origin, into
a chiasma. The nerve is cylindrical for some portion of its course, but
in most fishes gradually changes this form into that of a plaited band,
which is capable of separation and expansion. It enters the bulbus
generally behind and above its axis. The foramen through which it
leaves the skull of Teleostei is generally in a membranous portion of
its anterior wall, or, where ossification has taken place, in the orbito-
sphenoid.
B. Nerves proper taking their origin from the brain
(Figs. 41–45).
The Nervus oculorum motorius (third pair) takes its origin from
the Pedunculus cerebri, close behind the lobi inferiores; it escapes
through the orbito-sphenoid, or the membrane replacing it, and is
distributed to the musculi rectus superior, rectus internus, obliquus
inferior, and rectus inferior. Its size corresponds to the development
of the muscles of the eye. Consequently it is absent in the blind
Amblyopsis, and the Myxinoids. In Lepidosiren the nerves supplying
the muscles of the eye have no independent origin, but are part of
the ophthalmic division of the Trigeminus. In Petromyzon these
muscles are supplied partly from the Trigeminus, partly by a nerve
representing the Oculo-motor and Trochlearis, which are fused into a
common trunk.
 The Nervus trochlearis (fourth pair), if present with an
independent origin, is always thin, taking its origin on the upper
surface of the brain from the groove between lobus opticus and
cerebellum; it goes to the Musculus obliquus superior of the eye.
C. Nerves taking their origin from the Medulla oblongata (Figs.
41–45).
The Nervus abducens (sixth pair) issues on the lower surface of
the brain, taking its origin from the anterior pyramids of the Medulla
oblongata, and supplies the Musculus rectus externus of the eye,
and the muscle of the nictitating membrane of Sharks.
The Nervus trigeminus (fifth pair) and the Nervus facialis
(seventh pair) have their origins close together, and enter into
intimate connection with each other. In the Chondropterygians and
most Teleostei the number of their roots is four, in the Sturgeons five,
and in a few Teleostei three. When there are four, the first issues
immediately below the cerebellum from the side of the Medulla
oblongata; it contains motory and sensory elements for the maxillary
and suspensorial muscles, and belongs exclusively to the trigeminal
nerve. The second root, which generally becomes free a little above
the first, supplies especially the elements for the Ramus palatinus,
which sometimes unites with parts of the Trigeminal, sometimes with
the Facial nerve. The third root, if present, is very small, and issues
immediately in front of the acustic nerve, and supplies part of the
motor elements of the facial nerve. The fourth root is much stronger,
sometimes double, and its elements pass again partly into the
Trigeminal, partly into the Facial nerve. On the passage of these
stems through the skull (through a foramen or foramina in the
alisphenoid) they form a ganglionic plexus, in which the palatine
ramus and the first stem of the Trigeminus generally possess
discrete ganglia. The branches which issue from the plexus and
belong exclusively to the Trigeminus, supply the organs and
integuments of the frontal, ophthalmic, and nasal regions, and the
upper and lower jaws with their soft parts. The Facial nerve supplies
the muscles of the gill-cover and suspensorium, and emits a strong
branch accompanying the Meckelian cartilage to the symphysis, and
another for the hyoid apparatus.
 The Nervus acusticus (eighth pair) is strong, and takes its origin
immediately behind, and in contact with, the last root of the seventh
pair.
The Nervus glossopharyngeus (ninth pair)[12] takes its origin
between the roots of the eighth and tenth nerves, and issues in
Teleostei from the cranial cavity by a foramen of the exoccipital. In
the Cyclostomes and Lepidosiren it is part of the Nervus vagus. It is
distributed in the pharyngeal and lingual regions, one branch
supplying the first branchial arch. After having left the cranial cavity it
swells into a ganglion, which in Teleostei is always in communication
with the sympathic nerve.
The Nervus vagus or pneumogastricus (tenth pair) rises in all
Teleostei and Palæichthyes with two discrete strong roots: the first
constantly from the swellings of the corpora restiformia, be they
thinner or thicker and overlying the sinus rhomboidalis, or be they
developed into lateral plaited pads, as in Acipenser and
Chondropterygians. The second much thicker root rises from the
lower tracts of the medulla oblongata. Both stems leave the cranial
cavity by a common foramen, situated in Teleosteous fishes in the
exoccipital; and form ganglionic swellings, of which those of the
lower stem are the more conspicuous. The lower stem has mixed
elements, motory as well as sensory, and is distributed to the
muscles of the branchial arches and pharynx, the œsophagus and
stomach; it sends filaments to the heart and to the air-bladder where
it exists. The first (upper) stem forms the Nervus lateralis. This
nerve, which accompanies the lateral mucous system of the trunk
and tail, is either a single longitudinal stem, gradually becoming
thinner behind, running superficially below the skin (Salmonidæ,
Cyclopterus), or deeply between the muscles (Sharks, Chimæra), or
divided into two parallel branches (most Teleostei): thus in the Perch
there are two branches on each side, the superficial of which
supplies the lateral line, whilst the deep-seated branch
communicates with the spinal nerves and supplies the septa
between the myocommas and the skin. In fishes which lack the
lateral muciferous system and possess hard integuments, as the
Ostracions, the lateral nerve is more or less rudimentary. It is entirely