Contents

Title Page and Notice		i
Committee		iii
Reviewers		v
Preface		vii
Acknowledgments		xi

EXECUTIVE SUMMARY		1

1	INTRODUCTION	13
	How This Study Was Conducted	15
	Marijuana Today	16
	Marijuana and Medicine	19
	Who Uses Medical Marijuana?	20
	Cannabis and the Cannabinoids	24
	Organization of the Report	30
2	CANNABINOIDS AND ANIMAL PHYSIOLOGY	33
	Introduction	33
	Cannabinoid Receptors	39
	The Endogenous Cannabinoid System	43
	Sites of Action	48
	Cannabinoid Receptors and Brain Functions	51
	Chronic Effects of THC	56
	Cannabinoids and the Immune System	59
	Conclusions and Recommendations	69
3	FIRST, DO NO HARM: CONSEQUENCES OF MARIJUANA USE AND ABUSE	83
	The Marijuana "High"	83
	Drug Dynamics	84
	Marijuana Use and Dependence	92
	Link Between Medical Use and Drug Abuse	101
	Psychological Harms	104
	Physiological Harms: Tissue and Organ Damage	109
	Summary and Conclusions	125
4	THE MEDICAL VALUE OF MARIJUANA AND RELATED SUBSTANCES	137
	Standards for Evaluating Clinical Trials	138
	Analgesia	139
	Nausea and Vomiting	145
	Wasting Syndrome and Appetite Stimulation	154
	Neurological Disorders	159
	Glaucoma	173
	Summary	177
	Other Reports on Marijuana as Medicine	180
5	DEVELOPMENT OF CANNABINOID DRUGS	193
	Federal Drug Development Policy	194
	Development and Marketing of Marinol	202
	Market Outlook for Cannabinoids	208
	Regulation of and Market Outlook for Marijuana	213
	Conclusions	218

APPENDIXES
A	Individuals and Organizations That Spoke or Wrote to the Institute of Medicine About Marijuana and Medicine	225
B	Workshop Agendas	232
C	Scheduling Definitions	240
D	Statement of Task	242
E	Recommendations Made in Recent Reports on the Medical Use of Marijuana	244
F	Rescheduling Criteria	256

INDEX		259



List of Tables and Figures
TABLES
1.1	Self-Reported Disorders Treated with Marijuana by Members of San Francisco Cannabis Cultivators Club	21
1.2	Self-Reported Disorders Treated with Marijuana by Members of Los Angeles Cannabis Resource Center (LACRC), According to Center Staff	22
1.3	Summary of Reports to IOM Study Team by 43 Individuals	23
1.4	Primary Symptoms of 43 Individuals Who Reported to IOM Study Team	24
1.5	Cannabinoids Identified in Marijuana	25
2.1	Landmark Discoveries Since the 1982 IOM Report	34
2.2	Compounds That Bind to Cannabinoid Receptors	44
2.3	Comparison of Cannabinoid Receptor Agonists	46
2.4	Cellular Processes That Can Be Targeted for Drug Development	48
2.5	Brain Regions in Which Cannabinoid Receptors Are Abundant	49
2.6	Cannabinoid Receptors	51
2.7	Effects of Cannabinoids on the Immune System	60
2.8	Historical Comparisons Between Cannabinoids and Opiates	69
3.1	Psychoactive Doses of THC in Humans	85
3.2	Drug Withdrawal Symptoms	90
3.3	Factors That Are Correlated with Drug Dependence	94
3.4	Prevalence of Drug Use and Dependence in the General Population	95
3.5	Relative Prevalence of Diagnoses of Psychiatric Disorders Associated with Drug Use Among Children	96
3.6	Effect of Decriminalization on Marijuana Use in Emergency Room (ER) Cases	103
4.1	Studies on the Effects of Marijuana and Cannabinoids in Multiple Sclerosis	163
4.2	Classes of Antispasticity Drugs	164
4.3	Drugs Used to Treat Movement Disorders	168
4.4	Clinical Trials of Cannabidiol (CBD) in Epileptics	171
4.5	Anticonvulsant Drugs for Various Types of Seizures	172
4.6	Classes of Drugs Used to Treat Glaucoma	176
5.1	Cannabinoids and Related Compounds Commonly Used in Research	201
5.2	Cannabinoids Under Development for Human Use	209

FIGURES
1.1	Cannabinoid biosynthesis	26
2.1	Diagram of neuron with synapse	38
2.2	Cannabinoid receptors	40
2.3	Cannabinoid agonists trigger a series of reactions within cells	41
2.4	Chemical structures of selected cannabinoid agonists	45
2.5	Locations of brain regions in which cannabinoid receptors are abundant	50
2.6	Diagrams showing motor regions of the brain	52
3.1	Age distribution of marijuana users among the general population	93
4.1	Emesis-stimulating pathways	146
4.2	Effect of nabilone on multiple sclerosis symptoms	162
5.1	Stages of clinical testing	196

List of Tables and Figures