Cannabis Science 101Cannabis Science 101Palliative and Curative Relief Palliative and Curative Relief Through a Safe and Effective Through a Safe and Effective

Herbal MedicineHerbal Medicine

Paul ArmentanoPaul ArmentanoDeputy DirectorDeputy Director

NORML, NORML FoundationNORML, NORML Foundation

April 20, 2010April 20, 2010

San Jose State UniversitySan Jose State University

San Jose, CASan Jose, CA

#1 Rule of Medicine: “First, Do No Harm”#1 Rule of Medicine: “First, Do No Harm”

““Marijuana, in its natural form, is one of the safest therapeutically active Marijuana, in its natural form, is one of the safest therapeutically active substances known to man. By any measure of rational analysis marijuana can be substances known to man. By any measure of rational analysis marijuana can be safely used within a supervised routine of medical care.”safely used within a supervised routine of medical care.”

** (DEA Chief Administrative Law Judge Francis Young, 1988)** (DEA Chief Administrative Law Judge Francis Young, 1988)

““[E]xcept for the harms associated with smoking, the adverse effects of [E]xcept for the harms associated with smoking, the adverse effects of marijuana use are within the range of effects tolerated for other medications.”marijuana use are within the range of effects tolerated for other medications.”

** U.S. National Academy of Sciences, Institute of Medicine, 1999** U.S. National Academy of Sciences, Institute of Medicine, 1999

““Research … of cannabinoids and endocannbinoids has reached enormous Research … of cannabinoids and endocannbinoids has reached enormous proportions, with approximately 15,000 articles on cannabis sativa and proportions, with approximately 15,000 articles on cannabis sativa and cannabinoids and over 2,000 articles of endocannabinoids.” cannabinoids and over 2,000 articles of endocannabinoids.”

** (Medicinal Research Reviews, September 2008)** (Medicinal Research Reviews, September 2008)

#1 Rule of Medicine: “First, Do No Harm”#1 Rule of Medicine: “First, Do No Harm”

17,000 studies: What do we 17,000 studies: What do we knowknow? We know…? We know…

Cannabis is not an "intoxicant"Cannabis is not an "intoxicant""toxicum" = poison"toxicum" = poison

No known LD 50 rating (lethal dose in half)No known LD 50 rating (lethal dose in half)

Cannabis has an exceptional "safety ratio”Cannabis has an exceptional "safety ratio”

No “serious adverse effects associated with medical … use”No “serious adverse effects associated with medical … use”(Degenhardt et al., 2008, (Degenhardt et al., 2008, CMAJCMAJ))

Cannabis interacts with the limbic system, not the brain stem Cannabis interacts with the limbic system, not the brain stem --Cannabis is not a CNS depressant--Cannabis is not a CNS depressant

Yet cannabis is not FDA-approved… Why?Yet cannabis is not FDA-approved… Why?

Curative vs. Palliative ReliefCurative vs. Palliative Relief

Curative -- having the ability to cureCurative -- having the ability to cure Palliate -- to ease pain … without curingPalliate -- to ease pain … without curing

Cannabis and cannabinoids have the ability act as Cannabis and cannabinoids have the ability act as both a palliative or curative agents!both a palliative or curative agents!

Cannabis as a Palliative AgentCannabis as a Palliative Agent

AIDS/HIVAIDS/HIV Appetite stimulant, analgesic, anti-emetic, mood elevatorAppetite stimulant, analgesic, anti-emetic, mood elevator

CancerCancer anti-emetic, appetite stimulant, anxiolytic action, mood elevator, anti-emetic, appetite stimulant, anxiolytic action, mood elevator,

analgesicanalgesic

Chronic pain/Rheumatoid Arthritis/NeuropathyChronic pain/Rheumatoid Arthritis/Neuropathy Anti-inflammatory activityAnti-inflammatory activity

Crohn’s disease (aka inflammatory bowel disease) and other GI disordersCrohn’s disease (aka inflammatory bowel disease) and other GI disorders Anti-inflammatory activity, reduced acid reflux, reduced motilityAnti-inflammatory activity, reduced acid reflux, reduced motility

Cannabis as a Palliative AgentCannabis as a Palliative Agent

GlaucomaGlaucoma Reduction in intraocular pressureReduction in intraocular pressure

Multiple Sclerosis and other movement disordersMultiple Sclerosis and other movement disorders Anti-spasmodic, antidystonic, sedative activity/sleep Anti-spasmodic, antidystonic, sedative activity/sleep

aid, reduces incontinenceaid, reduces incontinence

Tourette’s SyndromeTourette’s Syndrome

Reduction in tic severity, reduction in obsessive Reduction in tic severity, reduction in obsessive compulsive disorder (OCD)compulsive disorder (OCD)

Cannabis as a Curative AgentCannabis as a Curative Agent

Autoimmune disordersAutoimmune disorders Multiple Sclerosis, Diabetes, Crohn’s diseaseMultiple Sclerosis, Diabetes, Crohn’s disease

Neurodegenerative disordersNeurodegenerative disorders Alzheimer’s, ALS, MS, Parkinson’s disease, Huntington’s diseaseAlzheimer’s, ALS, MS, Parkinson’s disease, Huntington’s disease

CancerCancer Cannabinoids stimulate apoptosis and inhibit angiogenesisCannabinoids stimulate apoptosis and inhibit angiogenesis

MRSA MRSA Cannabinoids as anti-bacterial agentsCannabinoids as anti-bacterial agents

Neurotoxicity and NeurotraumaNeurotoxicity and Neurotrauma Stroke, TBIStroke, TBI

Autoimmune DisordersAutoimmune Disorders

Multiple SclerosisMultiple Sclerosis ““Cannabinoids may not only offer symptom control but Cannabinoids may not only offer symptom control but may also slow the may also slow the

neurodegenerative disease progressionneurodegenerative disease progression that ultimately leads to the that ultimately leads to the accumulation of disability.” (Baker et al., 2008, accumulation of disability.” (Baker et al., 2008, Current Pharmaceutical DesignCurrent Pharmaceutical Design))

Rog et al., 2007, Rog et al., 2007, Clinical TherapeuticsClinical Therapeutics: patients over a 2-year period reported : patients over a 2-year period reported requiring fewer daily doses of Sativex and reported lower median pain scores requiring fewer daily doses of Sativex and reported lower median pain scores the longer they took the drugthe longer they took the drug

Wade et al., 2006, Wade et al., 2006, Multiple SclerosisMultiple Sclerosis: 167 patients reported long-term use of : 167 patients reported long-term use of Sativex (mean duration: 434 days) relieved MS-associatd pain, spasticity, and Sativex (mean duration: 434 days) relieved MS-associatd pain, spasticity, and incontinence without requiring subjects to increase their doseincontinence without requiring subjects to increase their dose

Killestein et al., 2003, Killestein et al., 2003, Journal of NeuroimmunologyJournal of Neuroimmunology: administration of oral THC : administration of oral THC boosted immune function in MS patients; “These results suggest pro-boosted immune function in MS patients; “These results suggest pro-inflammatory disease modifying potential of cannabinoids [for] multiple inflammatory disease modifying potential of cannabinoids [for] multiple sclerosis”sclerosis”

““Cannabis may also slow the neurodegenerative processes that Cannabis may also slow the neurodegenerative processes that ultimately lead to chronic disability in multiple sclerosis and probably ultimately lead to chronic disability in multiple sclerosis and probably other diseasesother diseases.” (Pryce et al., 2003, .” (Pryce et al., 2003, BrainBrain))

Autoimmune DisordersAutoimmune Disorders

DiabetesDiabetes Lu et al. 2006, Lu et al. 2006, AutoimmunityAutoimmunity: rats administered CBD protected against : rats administered CBD protected against

diabetes; at a median of 17 weeks all untreated controls had diabetes diabetes; at a median of 17 weeks all untreated controls had diabetes versus only 40% of rats administered CBDversus only 40% of rats administered CBD

El-Remessy et al, 2006, El-Remessy et al, 2006, American Journal of PathologyAmerican Journal of Pathology: rats treated : rats treated with CBD were protected against diabetic neuropathywith CBD were protected against diabetic neuropathy

Autoimmune DisordersAutoimmune Disorders

Crohn’s/inflammatory bowel diseaseCrohn’s/inflammatory bowel disease Wright et al. 2005, Wright et al. 2005, GastroenterologyGastroenterology: “Cannabinoids enhanced epithelial : “Cannabinoids enhanced epithelial

wound closure” in the inflamed lining (membrane) of the GI tract in wound closure” in the inflamed lining (membrane) of the GI tract in human tissue human tissue

Sanger. 2007, Sanger. 2007, British Journal of PharmacologyBritish Journal of Pharmacology: activation of the : activation of the cannabinoid receptors reduce gastric secretions, GI motility cannabinoid receptors reduce gastric secretions, GI motility (spontaneous moving), and promotes sphincter relaxation. (spontaneous moving), and promotes sphincter relaxation.

Neurodegenerative DisordersNeurodegenerative Disorders Alzheimer’s diseaseAlzheimer’s disease

Marchalant et al., 2007, Marchalant et al., 2007, NeuroscienceNeuroscience: rats administered a cannabis agonist : rats administered a cannabis agonist possessed a possessed a 50%50% improvement in memory compared to controls in a water improvement in memory compared to controls in a water maze memory test.maze memory test.

““[C]annabinoids offer a multi-faceted approach for the treatment of Alzheimer's [C]annabinoids offer a multi-faceted approach for the treatment of Alzheimer's disease by providing disease by providing neuroprotection and reducing neuroinflammationneuroprotection and reducing neuroinflammation, , whilst simultaneously supporting the brain's intrinsic repair mechanisms by … whilst simultaneously supporting the brain's intrinsic repair mechanisms by … enhancing neurogenesisenhancing neurogenesis. ... [This] offers a pharmacological approach for the . ... [This] offers a pharmacological approach for the treatment of AD that treatment of AD that may be more efficacious than current treatment may be more efficacious than current treatment regimensregimens." (Campbell et al., 2007, ." (Campbell et al., 2007, British Journal of PharmacologyBritish Journal of Pharmacology))

Eubanks et al., 2006, Eubanks et al., 2006, Molecular PharmaceuticsMolecular Pharmaceutics: THC inhibits the enzyme : THC inhibits the enzyme responsible for the aggregation of amyloidal plaque -- the primary marker for responsible for the aggregation of amyloidal plaque -- the primary marker for Alzheimer's disease -- in a manner “Alzheimer's disease -- in a manner “considerably superiorconsiderably superior” to approved ” to approved Alzheimer's drugs such as donepezil and tacrine. “Our results provide a Alzheimer's drugs such as donepezil and tacrine. “Our results provide a mechanism whereby the THC molecule can mechanism whereby the THC molecule can directly impact Alzheimer's directly impact Alzheimer's disease pathologydisease pathology. … THC and its analogues may provide an improved . … THC and its analogues may provide an improved therapeutic [option] for Alzheimer's disease [by]... therapeutic [option] for Alzheimer's disease [by]... simultaneously treating simultaneously treating both the symptoms and the progression of [the] diseaseboth the symptoms and the progression of [the] disease.”.”

Neurodegenerative DisordersNeurodegenerative Disorders

Amyotrophic Lateral Sclerosis (aka Lou Gehrig’s Disease)Amyotrophic Lateral Sclerosis (aka Lou Gehrig’s Disease) Raman et al, 2004, Raman et al, 2004, Amyotrophic Lateral Sclerosis & Other Motor Neuron Amyotrophic Lateral Sclerosis & Other Motor Neuron

DisordersDisorders: administration of THC in mice both before and after the onset of : administration of THC in mice both before and after the onset of ALS symptoms ALS symptoms staved disease progression and increased survivalstaved disease progression and increased survival compared to controls.compared to controls.

““Marijuana is a substance with many properties that may be applicable to the Marijuana is a substance with many properties that may be applicable to the management of amyotrophic lateral sclerosis (ALS). These include analgesia, management of amyotrophic lateral sclerosis (ALS). These include analgesia, muscle relaxation, bronchodilation, saliva reduction, appetite stimulation, and muscle relaxation, bronchodilation, saliva reduction, appetite stimulation, and sleep induction. In addition, marijuana has sleep induction. In addition, marijuana has now been shown to have strong now been shown to have strong antioxidative and neuroprotective effects, which may prolong neuronal antioxidative and neuroprotective effects, which may prolong neuronal cell survivalcell survival. … [M]arijuana should be considered in the pharmacological . … [M]arijuana should be considered in the pharmacological management of ALS.” (Carter et al, 2001, management of ALS.” (Carter et al, 2001, The American Journal of Hospice The American Journal of Hospice and Palliative Careand Palliative Care))

CancerCancer Sarfaraz et al, 2008, Sarfaraz et al, 2008, Cancer ResearchCancer Research: cannabinoids show anti-: cannabinoids show anti-

cancer activity in the treatment of cancer activity in the treatment of gliomasgliomas (brain cancer), (brain cancer), prostate prostate cancercancer, , breast cancerbreast cancer, , lung cancerlung cancer, , skin cancerskin cancer, , pancreatic pancreatic cancercancer, and , and lymphomalymphoma

Guzman et al, 2006, Guzman et al, 2006, British Journal of CancerBritish Journal of Cancer: intracranial : intracranial administration of THC prolonged survival and decreased tumor cell administration of THC prolonged survival and decreased tumor cell proliferation in two of nine patients with advanced stage GBMproliferation in two of nine patients with advanced stage GBM

Ligresti et al, 2006, Ligresti et al, 2006, JPET Fast ForwardJPET Fast Forward: CBD halts the spread of : CBD halts the spread of breast cancer cells by triggering apoptosis (programmed cell death)breast cancer cells by triggering apoptosis (programmed cell death)

Allister et al., 2005, Journal of Allister et al., 2005, Journal of NeurooncologyNeurooncology: THC selectively : THC selectively targets malignant glioma cells, inducing cell death and decreasing targets malignant glioma cells, inducing cell death and decreasing their proliferation more rapidly than a synthetic agonist.their proliferation more rapidly than a synthetic agonist.

CancerCancer Massi et al., 2004, Massi et al., 2004, JPET Fast ForwardJPET Fast Forward: CBD inhibited glioma tumor growth in : CBD inhibited glioma tumor growth in

animal and human cell samples by altering blood flow (angiogenesis) animal and human cell samples by altering blood flow (angiogenesis)

Guzman et al., 2003, Guzman et al., 2003, NatureNature: cannabinoids show anti-cancer activity in the : cannabinoids show anti-cancer activity in the treatment of treatment of lung cancerlung cancer, , brain cancerbrain cancer, , thyroid cancerthyroid cancer, , lymphomalymphoma, , skin skin cancercancer, cancer of the , cancer of the uterusuterus, , breast cancerbreast cancer, and , and prostate cancerprostate cancer..

““Cannabinoids Cannabinoids inhibit tumor growthinhibit tumor growth in laboratory animals. They do so by in laboratory animals. They do so by modulating key cell-signaling pathways, modulating key cell-signaling pathways, thereby inducing direct growth thereby inducing direct growth arrest and death of tumor cellsarrest and death of tumor cells, as well as by inhibiting tumor , as well as by inhibiting tumor angiogenesis and metastasis. angiogenesis and metastasis. CCannabinoids are selective antitumor annabinoids are selective antitumor compounds, compounds, as they can kill tumor cells without affecting their non-as they can kill tumor cells without affecting their non-transformed counterpartstransformed counterparts.”.”

MRSA MRSA (Multidrug Resistant Infections)(Multidrug Resistant Infections)

Appendino et al, 2008, Appendino et al, 2008, Journal of Natural ProductsJournal of Natural Products: administration of : administration of five select cannabinoids -- THC, CBD, CBG, CBC, and CBN -- five select cannabinoids -- THC, CBD, CBG, CBC, and CBN -- reduced skin colonization by MRSA and other drug resistant bacteria.reduced skin colonization by MRSA and other drug resistant bacteria.

"Although the use of cannabinoids as systemic antibacterial "Although the use of cannabinoids as systemic antibacterial agents awaits rigorous clinical trials, … their topical application to agents awaits rigorous clinical trials, … their topical application to reduce skin colonization by MRSA seems promising. … reduce skin colonization by MRSA seems promising. … Cannabis Cannabis sativa … represents an interesting source of antibacterial sativa … represents an interesting source of antibacterial agents to address the problem of multidrug resistance in agents to address the problem of multidrug resistance in MRSA and other pathogenic bacteriaMRSA and other pathogenic bacteria.”.”

Elsohly et al., 2008, Elsohly et al., 2008, PhytochemistryPhytochemistry: non-cannabinoid constituents : non-cannabinoid constituents (e.g., flavonoids) in marijuana possess anti-bacterial properties (e.g., flavonoids) in marijuana possess anti-bacterial properties against malaria, methicillim-resistant Staphyloccus aureus (aka against malaria, methicillim-resistant Staphyloccus aureus (aka MRSA), and other potentially drug-resistant pathogens.MRSA), and other potentially drug-resistant pathogens.

Neurotoxicity and NeurotraumaNeurotoxicity and Neurotrauma CBD and THC are neuroprotective antioxidentsCBD and THC are neuroprotective antioxidents

Hamelink et al., 2005, Hamelink et al., 2005, JPET Fast ForwardJPET Fast Forward: CBD is significantly more neuroprotective : CBD is significantly more neuroprotective against ethanol-induced brain injury (alcohol poisoning) than standard treatment therapies.against ethanol-induced brain injury (alcohol poisoning) than standard treatment therapies.

Mishima et al, 2005, Mishima et al, 2005, StrokeStroke: CBD prevented brain injury caused by ischemia (a reduction of : CBD prevented brain injury caused by ischemia (a reduction of blood flow to the brain that causes cell death) blood flow to the brain that causes cell death)

Knoller et al., 2002, Knoller et al., 2002, Critical Care MedicineCritical Care Medicine: HU-211 relieved intracranial pressure (TBI) and : HU-211 relieved intracranial pressure (TBI) and trended toward better neurological outcomes in 67 TBI patientstrended toward better neurological outcomes in 67 TBI patients

Hampson et al., 1998, Hampson et al., 1998, Proceedings of the National Academy of SciencesProceedings of the National Academy of Sciences: THC and CBD : THC and CBD were more protective against glutamate neurotoxicity and oxidative brain damage than were more protective against glutamate neurotoxicity and oxidative brain damage than standard treatment therapiesstandard treatment therapies

US Patent #6630507 -- Cannabinoids as antioxidants and neuroprotectantsUS Patent #6630507 -- Cannabinoids as antioxidants and neuroprotectants US Patent issued: October 7, 2003US Patent issued: October 7, 2003

Grantee: Grantee: The United States of AmericaThe United States of America as represented by the Department of Health as represented by the Department of Health and Human Servicesand Human Services

What does this patent mean? Were cannabinoids to become a federally recognized What does this patent mean? Were cannabinoids to become a federally recognized medicine, medicine, no private or public company could market them for these medical no private or public company could market them for these medical purposespurposes..

Routes of Cannabis AdministrationRoutes of Cannabis Administration

Smoking (joints, pipes, water-pipes)Smoking (joints, pipes, water-pipes) Fast acting, easy titrationFast acting, easy titration

Oral ingestionOral ingestion Delayed onset, longer-lasting, more difficult to titrate, greater psychoactivityDelayed onset, longer-lasting, more difficult to titrate, greater psychoactivity

Transdermal deliveryTransdermal delivery Poor permeation, delayed onset, high concentrations requiredPoor permeation, delayed onset, high concentrations required Potential use as a topical anti-bacterial agent or localized analgesicPotential use as a topical anti-bacterial agent or localized analgesic

VaporizationVaporization Fast acting, easy titrationFast acting, easy titration

Vaporization of marijuana does not result in exposure to combustion gases and Vaporization of marijuana does not result in exposure to combustion gases and [was] preferred by most subjects compared to marijuana cigarettes. … [was] preferred by most subjects compared to marijuana cigarettes. … [It] is an [It] is an effective and apparently safe vehicle for THC deliveryeffective and apparently safe vehicle for THC delivery, and warrants further , and warrants further investigation in clinical trials of cannabis for medical purposes.” (Abrams et al., investigation in clinical trials of cannabis for medical purposes.” (Abrams et al., 2007, 2007, Clinical Pharmacology & TherapeuticsClinical Pharmacology & Therapeutics))

When Is Medical Cannabis Not When Is Medical Cannabis Not Recommended?Recommended?

The patient has a personal or family history of mental illness or schizophreniaThe patient has a personal or family history of mental illness or schizophrenia

The patient will be driving shortly after administrationThe patient will be driving shortly after administration

The patient is pregnantThe patient is pregnant

The patients is an adolescentThe patients is an adolescent

The patients suffers from lung problemsThe patients suffers from lung problems

The patient has a history of heart disease or heart attackThe patient has a history of heart disease or heart attack

The patient has high blood pressureThe patient has high blood pressure

The patient has diagnosed liver disordersThe patient has diagnosed liver disorders

BOTTOM LINE: Always consult with your physician before beginning cannabis therapy!BOTTOM LINE: Always consult with your physician before beginning cannabis therapy!

What About Marinol?What About Marinol? Single, isolated synthetic cannabinoidSingle, isolated synthetic cannabinoid

Lacks the synergistic effect of multiple cannabinoids, flavonoids, and terpinesLacks the synergistic effect of multiple cannabinoids, flavonoids, and terpines

Highly psychoactive/dysphoricHighly psychoactive/dysphoric

Difficult to titrateDifficult to titrate

Delayed onset/first pass syndromeDelayed onset/first pass syndrome

Typically more expensive than natural cannabisTypically more expensive than natural cannabis

Patients prefer natural cannabis when given the choice (Musty et al., 2001, Patients prefer natural cannabis when given the choice (Musty et al., 2001, Journal of Cannabis TherapeuticsJournal of Cannabis Therapeutics))

Marinol/dronabinol is legalMarinol/dronabinol is legal

Other Cannabis-Derived PharmaceuticalsOther Cannabis-Derived Pharmaceuticals

Cessamet/NabiloneCessamet/Nabilone

Rimonabant/AcompliaRimonabant/Acomplia

SativexSativex

““The growing interest in the underlying science has been matched The growing interest in the underlying science has been matched by a growth in the number of cannabinoid drugs in pharmaceutical by a growth in the number of cannabinoid drugs in pharmaceutical development from two in 1995 to 27 in 2004.” (NIH, 2006)development from two in 1995 to 27 in 2004.” (NIH, 2006)

More About MeMore About Me

Paul Armentano is the Deputy Director of NORML and the NORML Foundation, Paul Armentano is the Deputy Director of NORML and the NORML Foundation, where he has worked for over twelve years. Mr. Armentano is an expert in the where he has worked for over twelve years. Mr. Armentano is an expert in the field of marijuana policy, health, and pharmacology. He has served as a field of marijuana policy, health, and pharmacology. He has served as a consultant for Health Canada, The Beth Israel Deaconess Medical Center, Safety consultant for Health Canada, The Beth Israel Deaconess Medical Center, Safety First: A Reality-Based Approach to Teens and Drugs, and the Canadian Public First: A Reality-Based Approach to Teens and Drugs, and the Canadian Public Health Association, and he is a former consultant to GW Pharmaceuticals. He Health Association, and he is a former consultant to GW Pharmaceuticals. He frequently serves as a legal consultant and expert witness for the defense in frequently serves as a legal consultant and expert witness for the defense in cannabis-associated criminal cases.cannabis-associated criminal cases. Mr. Armentano is the author of over 500 Mr. Armentano is the author of over 500 published papers and magazine articles, and was a 2008 recipient of the 'Project published papers and magazine articles, and was a 2008 recipient of the 'Project Censored Real News Award for Outstanding Investigative Journalism.’ He is the Censored Real News Award for Outstanding Investigative Journalism.’ He is the co-authorco-author of the book Marijuana is Safer: So Why Are We Driving People to of the book Marijuana is Safer: So Why Are We Driving People to Drink? (2009, Chelsea Green). He is on the faculty of Oaksterdam University in Drink? (2009, Chelsea Green). He is on the faculty of Oaksterdam University in Oakland. He lives in northern California with his wife and son.Oakland. He lives in northern California with his wife and son.

Contact me at: paul@norml.org.Contact me at: paul@norml.org.

For More InformationFor More Information

Emerging Clinical Applications for Cannabis and CannabinoidsEmerging Clinical Applications for Cannabis and Cannabinoids http://www.norml.org

International Association of Cannabis as MedicineInternational Association of Cannabis as Medicine http://www.cannabis-med.org

Medical Marijuana Pro ConMedical Marijuana Pro Con http://medicalmarijuana.procon.org

ASA’s booklets on medical marijuana conditionsASA’s booklets on medical marijuana conditions http://www.safeaccessnow.org/section.php?id=135

Marijuana Medical HandbookMarijuana Medical Handbook (Gieringer et al, 2008, Quick (Gieringer et al, 2008, Quick American)American)

National Center of Biotechnology InformationNational Center of Biotechnology Information http://www.ncbi.nlm.nih.gov