The Nuero-Science
& Toxicology
of Marijuana

Louisiana Association of Drug Court Professionals

Lafayette, Louisiana

June 26, 2015

Judge Mary A. Celeste (Ret.)

 The following presentation may not be copied

in whole or in part without the written permission of the author

© Celeste

Overview

Legal History of MJ

Neuro-Science THC/Cannabis

Science/Medical Marijuana

THC Toxicology

Role of the Toxicologist

Early History

Early MJ History

3000 B.C. Siberia burial grounds

3000 B.C. Chinese as Medicine

Regulations and restrictions on the sale as a drug began as early as 1619

U.S. Washington Hemp in Mt Vernon.

1910-20 USA
Marijuana as a Poison

1910 there was a wave of legislation aimed to strengthen requirements for sale

Legislation restricted all narcotics, including cannabis, as poisons, limit their sale to pharmacies, and required doctor's prescriptions.

Under poison laws definitions had to labeled as poison

Outright prohibitions began in the 1920s

1930-40’S


1950s-1970 USA

Boggs Act 1952

Narcotics Control Act1956.

Act made a first-time possession offense a minimum of two to ten years with a fine up to $20,000.

1969 Leary v. U.S. decision the U.S. Supreme Court held the Marijuana Tax Act to be unconstitutional, since it violated the 5th Amendment privilege against self-incrimination.


1950s-1970 USA

In response, Congress passed the Control Substances Actas Title II of the Comprehensive Drug Abuse Prevention and Control Act of 1970, which repealed the Marijuana Tax Act

Cannabis became a Schedule I Control Substance with the creation of the Control Substances Act. 1970 along with heroine and LSD

On December 1, 1975, the Supreme Court ruled that it was "not cruel or unusual for Ohio to sentence someone to 20 years for having or selling cannabis

Control Substances Act

A controlled (scheduled) drug is one whose use and distribution is tightly controlled because of its abuse potential or risk.

Five categories for drugs Schedule I is reserved for what the DEA considers to be the "most dangerous" drugs without currently accepted medical value.

Control Substances I-V

Schedule I — drugs with a high abuse risk. These drugs have NO safe, accepted medical use in the United States. Some examples are heroin, marijuana, LSD, PCP, and crack cocaine.

Schedule II — drugs with a high abuse risk, but also have safe and accepted medical uses in the United States. These drugs can cause severe psychological or physical dependence. Schedule II drugs include certain narcotic, stimulant, and depressant drugs. Some examples are morphine, cocaine, oxycodone (Percodan®), methylphenidate (Ritalin®), and dextroamphetamine (Dexedrine®).

Schedule III, IV, or V — drugs with an abuse risk less than Schedule II. These drugs also have safe and accepted medical uses in the United States. Schedule III, IV, or V drugs include those containing smaller amounts of certain narcotic and non-narcotic drugs, anti-anxiety drugs, tranquilizers, sedatives, stimulants, and non-narcotic analgesics. Some examples are acetaminophen with codeine (Tylenol® No.3), paregoric, diazepam (Valium®), alprazolam (Xanax®), propoxyphene (Darvon®), and pentazocine (Talwin®).

2015 Schweder Challenges Schedule I Classification

Defense attorneys argued it's impossible to say marijuana has no accepted medical value, and that the federal classification of the plant is unconstitutional for several reasons:

23 states have legalized marijuana for medical purposes;

A growing body of research exists highlighting marijuana's medical promise;

Federal view of marijuana is evolving,

Judge Upholds Federal Government's Classification That Marijuana Is 'Dangerous'

United States v. Bryan R. Schweder, et al., judge in California on Wednesday denied a motion from a group of nine defendants charged with growing marijuana who were contending the federal government's classification marijuana of as one of the "most dangerous" substances is unconstitutional.

June 2, 2015 Eastern District California Court Denies Motion to Reconsider in Schweder Marijuana Case

Marijuana History 1990-2005

1996 California is the first State to decriminalize medical marijuana

2005 U.S. Supreme Court rules in U.S. v. Oakland Cannabis Buyers’ Cooperative and Gonzales v. Raichthat the federal government has a right to regulate and criminalize cannabis, even for medical purposes

Congressional MJ Bills
Carers Act

March 2015 Carers Act (The Compassionate Access, Research Expansion and Respect States) first-ever bill in the U.S. Senate to legalize MMJ.

Bipartisan group of senators reclassify MJ as a Schedule II controlled substance.

If passed, the legislation would remove any potential of federal prosecution for individuals using marijuana for medical purposes.

Would allow marijuana to be prescribed for veterans receiving care in VA facilities.

Congressional MJ Bills

May 21, 2015 Allowing VA doctors to recommend MMJ to their patients in states where MMJ is legal.

To amend the Controlled Substances Act to provide that Federal law shall not preempt State law.

To decriminalize MJ at the Federal level

To amend the Internal Revenue Code for the taxation of MJ

Nuero-Science
Marijuana/Cannabis

Cannabis

Flowering plants that include three putative varieties, sativa, indica, and ruderalis. Indigenous to Central and South Asia

Most used illicit drug in the world

Active ingredient Delta 9 THC. Resinous substance is known as Hashish.

MJ & Its Compounds
(aka molecules)

483 chemical constituents isolated and identified in cannabis to date

THC in its neutral form is the main cannabinoid responsible for the psychoactive effects caused by cannabis intake

About 85 cannabinoids. Some are psychoactive and bind to the cannabinoid receptors and some are not and do not.

 The Human Body Systems

The Endocannabinoid System

Endocannabinoids

Endocannabinoids are in every living animal on the planet above Hydra and Mollusks, with the exception of insects

Endocannabinoids are the substances our bodies naturally make to stimulate cannabinoid receptors.

What are Receptors

Receptors are binding sites for chemicals in the brain, chemicals that instruct brain cells to start, stop or otherwise regulate various brain and body functions.

The chemicals which trigger receptors are known as neurotransmitters.

In many instances, drugs mimic these natural chemicals working in the brain i.e. Opiates/Endorphins

Receptors in Brain & Body

The sensations of slight euphoria, relaxation, and amplified auditory and visual perceptions produced by marijuana are due almost entirely to its effect on the cannabinoid receptors in the brain.

Cannabinoid Receptors
in Brain & Body

Cannabinoid receptors are present throughout the body, embedded in cell membranes, and are believed to be more numerous than any other receptor system.

Brain Receptors for Cannabis

There are currently two known subtypes of cannabinoid receptors CB1andCB2

The CB1receptor is expressed mainly in thebrain (central nervous system or CNS). Also in thelungs, liver and kidneys

Brain Receptors for Cannabis

The CB2receptor is expressed mainly in theimmune system and inHMS (hematopietic) cells the blood cells that give rise to all other blood cells. They are located in the bone marrow

 CB2 receptors have been recently discovered in the central nervous system, the microglial cells and they seem to be in certain neurons as well.

However, it remains a quite controversial and debated issue.

Brain Receptors for Cannabis

Mounting evidence suggests that there are novel cannabinoid receptors that is, non-CB1and non-CB2, expressed inendothelialcells the thin layer of simplesquamous cellsthat lines the interior surface ofblood and lymphatic vessels.

Location of Cannabinoid Recepters

Two cell receptors

Corollary
Morphine drug receptors

In 1972 brain researchers from Johns Hopkins University found that the human brain's neurons had specific receptor sites for opiate drugs: opium, heroin, codeine and morphine.

The active ingredient in all these opiates - morphine - had a chemical structure similar to endorphins, a class of chemicals present in the brain .

Endorphins are feel-good chemicals naturally-manufactured in the brain when the body experiences pain or stress. They are called the natural opiates of the body.

Cannabinoid Receptors

1992 Discovered natural transmitter or “endocannabinoid” that fits those receptors: anandamide.

More recently an even more important endocannabinoid that normally activates these receptors was discovered 2AG (2 arachidonoylglycerol)

Researchers have developed compounds to both stimulate or block CB receptors to study how they function.

Anandamide

THC begins this process by binding to the CB1 receptors for anandamide.

Anandamide is involved in regulating mood, memory, appetite, pain, cognition, and emotions.

Has been found to fight against human breast cancer

Three compounds that strongly resemble anandamide were found in dark chocolate 1996

Scheme of the endocannabinoid system

How brain cells communicate

Brain cells (neurons) communicate with each other and with the rest of the body by sending chemical “messages.”

These messages help coordinate and regulate everything we feel, think, and do.

How brain cells communicate

Typically, the chemicals (called neurotransmitters) are released from a neuron (a presynaptic cell), travel across a small gap (the synapse), and then attach to specific receptors located on a nearby neuron (postsynaptic cell).

This spurs the receiving neuron into action, triggering a set of events that allows the message to be passed along.

Cell Communication

Cannabinoids Receptors
Work Differently From Other Neurotransmitters

The cannabinoid receptor is a new class of receptor is indicated primarily by the finding that its amino acid sequence differs significantly from that of any other known type of receptor

Cannabinoids Receptors
Work Differently From Other Neurotransmitters

EC system communicates its messages in a different way because it works “backward.”

When the postsynaptic neuron is activated, cannabinoids (chemical messengers of the EC system) are made “on demand” from lipid precursors (fat cells) already present in the neuron.

Then they are released from that cell and travel backward to the presynaptic neuron, where they attach to cannabinoid receptors.

Cell Communication

So why is this important?

Since cannabinoids act on presynaptic cells, they can control what happens next when these cells are activated.

In general, cannabinoids function like a “dimmer switch” for presynaptic neurons, limiting the amount of neurotransmitter (e.g., dopamine) that gets released

Cannabinoid Receptors & Dopamine

Brain microdialysis has proven that opiates, cocaine, amphetamines, nicotine and alcohol all affect dopamine production, whereas marijuana does not.

Is mj Physically Addictive ?
yes… AT A Reduced Risk

Marijuana is distinguished from most other illicit drugs by the locations of its brain-receptor sites for two predominant reasons:

The lack of receptors in the medulla significantly reduces the possibility of accidental, or even deliberate (No) death from THC,

The lack of receptors in the mesocorticolimbicpathway significantly reduces the risks of addiction and serious physical dependence

Is mj Addictive?
Yes Psychologically

Psychology Today: “Addicted to something is more than simply being physically dependent on a drug and experiencing physiological effects if the drug is stopped suddenly.”

 “Addiction” refers to behaviors that are compulsive, partially out of control or worse, and often escalating in severity and intensity”

cannabinoid Use Begets
Cannabinoid Receptors

Research has shown that small doses of cannabinoids from cannabis can signal the body to make more endocannabinoids and build more cannabinoid receptors.

This is why many first-time cannabis users don't feel an effect, but by their second or third time using the herb they have built more cannabinoid receptors and are ready to respond.

Science/Medical Marijuana


Other Molecules/Compounds In MJ
flavonoids terpenes Terpenoids

 Compounds that produce flavor and fragrance in plants

Some 20 Flavonoids

 120 Terpenes

Falvanoids

Some Flavonoids are cannabinoids

Psychoactive themselves, or are able to modulate or potentiate the affect of the psychoactive cannabinoids

Does beer have anthing
in common with MJ

Terpenoids

Terpenoids are found in many plants

 Most common Terpenoid is

Beta-myrcene found in bay leaves, hops lemongrass

Flavanoids

Types of flavonoids in the Cannabis plant

(cannflavine A, B and C,vitexin, isovitexin, apigenin, kaempferol, quercetin, luteolin and orientin).

The total content of flavonoids in the Cannabis' leaves and flowers can reach 2.5% of its dry weight

In broccoli, green tea, grapefruit, pomegranate

Other Phytocannabinoids

Plant that have been shown to interact directly with cannabinoid (CB) receptors i.e. Echinaceaspp

Plantsthat have been found to contain non-psychoactive cannabinoids i.e. echinacea purpura

Plant that have been suggested to exert cannabimimetic effects but do not interact directly with cannabinoid (CB) receptors i.e.Salvia divinorum

Plants to Medicine Quiz

MMJ & THC Derivatives

15 trials of medical cannabinoids have been conducted. Results have shown effectiveness in reducing pain from neuropathy, diabetes and fibromyalgia.

The FDA has approved two cannabinoid medications, dronabinal(marinol) and nabilone(cesamet).

Prescribed for controlling nausea and vomiting caused by chemotherapy and to treat anorexia in HIV patients.

Other cannabinoid-based medications are under FDA review for treating cancer pain and other conditions.

 MMJ & THC Derivatives

Sativex (clinical phases)

Marinol (FDA approved)

Cesamet (FDA approved)

Ebideolex/cannabidoil/CBD (orphan drug status)

Sativex

Available in the United Kingdom and Canada

Chemically pure mixture of plant-derived THC and Cannabidiol Formulated as a mouth spray

Relieves cancer-associated pain, spasticity and neuropathic pain in multiple sclerosis


The 2 Major THC cannabinoids

CBD Cannabidiol-Sativex

(anti-convulsive, anti-arthritic)

nonpsychoative

CBN Cannabinol-Mildly psychoactive, CBN is thought to act as a weak agonist of both the CB1 and CB2 receptors,

(anti-epileptic)

the Most Disregarded

Cannabic-chromene CBC –(anti-inflamatory)

the “stem cell” of cannabinoids. It is the precursor to THC, CBD, and CBC. “THCA” psychoactive

This could be a result of its interaction with anandamide which has been found to fight breast cancer

CBC inhibits the uptake of anandamide, which allows it to stay in the bloodstream longer.

Cannabinoids & Brain cancer

Dr. Guzman Animal Studies

Rat MRIs

Brain Tumors

1/3 Tumors Shrunk

1/3 Totally Eradicated

1/3 No Results

Cannabinoids & Brain cancer

Clinical Human Trials St. James University Hospital Leeds England

Combination SativexTemozolomide

Insufficient scientific evidence at this time

Belendiuk, et al., “Narrative review of the safety and efficacy of marijuana for the treatment of commonly state-approved medical and psychiatric disorders,” Addiction Science & Clinical Practice Sample (2015)10:10

 Conflicting Science

PTSD

2014 University of Haifa Study Cannabis prevents the negative behavioral and physiological effects of a traumatic event and its reminders

2015 Addiction Science & Clinical Practice Sample 10:10 Belendiuk, et al., Insufficient scientific evidence for its use at this time

Examples of MJ Acute Affects

2015 Bipolar

2015 Psychosis

2015 Shorter Boys

2015 Shrinks & Rewires Brain

2014 Reduction in IQ under 21

MJ Toxicology

Marijuana Toxicology

Active

THC a/k/a delta-9-tetrahydrocannabinol is the main psychoactive substance found in marijuana

Metabolites

11-Hydroxy-THC is the main psychoactive metabolite of THC formed in the body after marijuana consumption

11-nor-9-Carboxy-THC is the main secondary metabolite of THC which is formed in the body after marijuana is consumed. It is NOT active.

.

Metabolization
Alcohol vs. Drugs

Alcohol is metabolized at a predictable rate.

Drugs are not eliminated from the body in a predictable way

Unlike alcohol, there is no retrograde extrapolation for drugs.

THC rapidly dissipates 1-2 hours after use/THC levels drops over 80% within first hour of smoking

THC Dissipation

Metabolization of Marijuana

Assumption that cannabinoids will remain detectable in urine for 30 days or longer following the use of marijuana.

THC is not found in its active form in urine rather as the metabolite THC-COOH…

For new or infrequent users, the window of time for detection (50ng/ml limit) is believed to last 1 to 2 days.

Metabolization of Marijuana

On the other hand, studies have shown that regular users can test positive (20 ng/ml limit) for THC metabolites for up to 46 consecutive days following marijuana usage.

In an extreme case, a heavy cannabis user of more than 10 years was able to test positive (20 ng/ml limit) for up to 67 days after last being exposed to marijuana.

drug concentration in blood Not auto impairment

With the exception of ethanol, there is so far no widely accepted correlation between the drug concentration in blood and a corresponding level of driving impairment among the scientific community.

Drug Metabolites

Positive test for drug metabolites is "solid proof of drug use within the last few days

“Cannot be used by itself to prove behavioral impairment during a focal event."

US Department of Transportation Report

Screening Presumptive
& Confirmatory Test

Forensic toxicology laboratories that routinely analyze DWI case samples for drugs utilize a two-tiered approach.

Samples screened for common drugs or classes of drugs using an antibody-based

Samples screen positive re-tested using a second, more rigorous technique, usually called confirmation.

detection
route of administration
Elimination

Detection time: The length of time that a drug or its metabolite is present in a given biological sample. This may vary depending on the dose (amount),

Route of administration (injected, inhaled etc.)

Elimination rate (how long it takes the body to get rid of the substance).

Role of the Toxicologist

To provide expert testimony, toxicologists look at the characteristic, appearance, behavior or observableeffects of the drug on the individual.

Reviews Law Enforcement/DRE Observations in Report

Role of the Toxicologist

Depending upon the evidentiary rules in your jurisdiction, a toxicologist may be necessary to testify at trial to establish

Authenticity of the toxicology report,

Chain of custody

Implication and validity of the test results.

Role of the Toxicologist
(1+1+3)

This is especially true in DUID cases, where the effects of drug or poly-drug consumption, and the meaning of drug concentrations, are not a matter of common knowledge to the layperson

Father of toxicology
Cannabis as a Poison?