“Marijuana: How Safe is This Plant?"

Lukasz M. Konopka AM, PhD, ECNS Spectrum Center for Integrative Neuroscience, McHenry IL

June 14, 2017 Spectrumin.com

23rd Annual Summer Institute on Addictions

No commercial interests are represented in this presentation!!!

The Brain is Important!

An adult-brain weighs 1.7 kg in a 70 kg person. 20% of cardiac output goes to the brain.

The brain’s primary fuels are glucose and oxygen. The adult brain contains 100 billion neurons.

Brain development continues through the age of 30. Brain plasticity implies a significant capacity for learning.

Not all learning is advantageous (abuse, substance dependence, etc.). Gender differences exist in the human brain.

0- 8 weeks - “a critical period of development”

At nine months the brain is 25% of the adult size

250,000 neurons are added per minute. After birth - 700 new connection are added per second. At 24 months, the brain weighs 80% of the adult brain.

The Brain Learns: Plasticity • All behaviors are seen and interpreted by the naïve brain. New born children

will recognize their mother’s voice immediately after birth. Infants recognize faces at two months.

• Modeling through observation is important. Routine and repetition are very important to a young child. They facilitate learning and help the brain select and understand priorities. Children will have memories of events as early as the age of two.

• We are products of our genes and our environments (micro-macro). • Plasticity is a process of learning and growth. In adolescent brains,

external stressors are powerful than in the adult brain. • The process of learning based on plasticity influences who we

become as individuals; we carry within us schemas of our own experience, as well as the experience of past generations.

• What do we learn and how do we become functioning adults?

• Adolescents are more likely to: • act on impulse • act selfishly • misread or misinterpret facial expressions, prosody, and social situations • get into predicaments and accidents • engage in conflicts • seek out dangerous or risky behaviors: drugs, sex, illegal activities

• Adolescents are less likely to: • pause, i.e., think before they act • experience empathy for self and others • consider the consequences of their actions • change behaviors by learning from experiences with dangerous or inappropriate behaviors

• 2015 by the American Academy of Child and Adolescent Psychiatry.

We know that :

How do we learn?

Chemical communication Neurotransmitters: DA, NE, Serotonin, Glutamate, GABA…

Enriched Environments - Novelty!!! • Animals raised in toy-filled surroundings (high level of novelty) have more

neuronal branching and connections than isolated animals. • Enriched environments result in more brain neurons available for learning and

memory; result in enhanced performance.

Deprived Enriched

Journal of Cerebral Blood Flow & Metabolism 22:89–96 © 2002

Formation of Long-Term Potentiation (neuronal structural changes)

Repetition!!!

Neurons and the Brain: Hierarchical Organization

Trends Cogn Sci. 2014 Apr; 18(4): 211–217.

Positive Emotionality/Extraversion PEM/E is modulated by the function of the central dopaminergic system and is moderated by the D2 receptor gene.

High Negative Emotionality/Neuroticism (NEM/N) is modulated by the glutamatergic outputs from the right anterior cingulate cortex (rACC) and ventromedial prefrontal cortex (vmPFC) to the amygdala and insula and is moderated by the serotonin transporter (5-HTT) gene.

Constraint (CON) careful and reserved, is modulated by a circuit including the pre-Supplementary, Motor Area (preSMA) and right Inferior Frontal Gyrus (rIFG) to the striatum and the sub-thalamic nucleus (STN) and is moderated by the genes of the D4 receptor and the dopamine transporter (DAT).

Genes, brain circuitry, and personality in Substance Use Disorder (SUD)

Genetic Vulnerability

• Some individuals are genetically predisposed to stress and trauma, others to addictions, or both.

Catechol Methyl Transferase (COMT)

MET/MET VAL/VAL

Working memory and perseverative errors: frontal DA-amphetamine decreases errors in

COMT-VAL-VAL

PNAS May 13, 2003 vol. 100 no. 10

Cannabis use in patients who experienced maltreatment and genetic vulnerability COMT-VAL-VAL 525 individuals from the first tier and 393 individuals from the second tier using

Community Assessment of Psychiatric Experience (CAPE) scale

Replicated data

Caspi et al. Biol Psychiatry. 2005.

Short vs. Long Allele for 5HT Transporter

(Canli & Lesch 2007) Chemical communication

Patients with 5HTT-S/S are more vulnerable to stress

Caspi A et. al. 2003. Influence of Life Stress on Depression: Moderation in the 5-HTT Gene. Science 301: 386-389.

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Functional Neuroimaging Modalities • Quantitative electroencephalography (qEEG) and low resolution brain electromagnetic tomography

(LORETA) • Evoked Potentials (EP) with integrated continuous

performance task (IVA)

• Positron Emission Tomography (PET)

• Single Photon Computed Tomography (SPECT)

How can we study the brain ?

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Structure and Function • Magnetic Resonance Imaging (MRI) (gold standard)

• Positron Emission Tomography (PET)

• Single Photon Computed Tomography (SPECT)

Positron Emission Tomography (PET) PET is a functional imaging tool used to indirectly visualize neuronal activity or map specific receptor proteins. A large number of studies were published using this methodology.

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A patient with a frontal lobe injury and significant psychiatric history The brain injury was undetected for many years Data from MRI, SPECT, and LORETA converge

Converging Data

Young people are not adults!

• The brain does not finish maturing until the late 20s or early 30s.

• The process of maturation involves integration: connecting the emotional brain with the cognitive/logical brain.

• Most behavioral problems are due to altered communication between the emotional and logical brain systems (bottom, top, right and left).

Adolescent behaviors…WHY?

• Adolescent actions are guided more by the emotional and reactive amygdala and less by the thoughtful, logical frontal cortex. Evolutionarily, this is attributed to natural separation, and taking risks to find a life of their own.

• Exposure to drugs and alcohol during the teen years can change or delay these developments.

• Teens who start drinking by the age of 13 have a 43% greater chance of becoming alcoholics.

• Those who start drinking at 21 have a 10% chance.

Substance use

• Young people explore life, and today this involves explorind drugs.

• The primary driving forces are: Changes in brain function and structure during adolescence (hormones), social pressures and norms (media), peer pressure, and parental attitudes.

Theoretical Framework: Substance abuse is a variant of normal (socially acceptable) behavior (alcohol, nicotine, marijuana). Individuals who become addicted follow a classical conditioning paradigm that powerfully stimulates the brain’s reward circuitry, i.e., primarily Dopamine. Reward systems adapt to the unusually powerful stimulating effects of drugs and demands maintenance of this level of stimulation (craving). The brain’s adaptation to a drug’s stimulating effects are reflected in alterating the brain’s circuitry (may be permanent) resulting in drug dependent behaviors. Thus, the drug experience is permanently tattooed into the user’s brain.

Reward Circuitry

Anatomy of Craving -1 Emotions

• Functional imaging studies using cue-exposure paradigms in nicotine, alcohol and cocaine dependence have reported increased emotional processes in:

• ventral prefrontal • insular • amygdala • striatal • thalamus • (Addiction biology Volume 15, Issue 4 October 2010 )

Anatomy of Craving-2: Cognition

• Attentional and cognitive control circuitry was implicated in neuroimaging cue reactivity

• Increased dorsolateral prefrontal, anterior cingulate cortex, parietal

• (Addiction biology Volume 15, Issue 4 October 2010 )

Marijuana

2700 B.C.: The legendary Chinese emperor, Shennong, discovered the healing properties of marijuana.

1500 B.C.: Medical papyri from Egypt mention marijuana as a cure for eye difficulties and inflammation.

600 B.C.: Bhang, a drink of cannabis and milk, is used widely as an anesthetic in India.

A.D. 1925: The League of Nations treaty limits cannabis use to medical or scientific purposes. Aspirin is discovered, from willow bark used by Native Americans, and other newly developed drugs begin to replace cannabis as treatments for pain.

A.D. 1930: Harry J. Anslinger is appointed commissioner of the Federal Bureau of Narcotics. He considers marijuana a corrupting influence and helps to turn public opinion against the drug.

Neurotransmitter involved in drug using behavior Independent of the type of substance used: nicotine, alcohol, cocaine, opiates THC, etc., common final path of euphoric experience involves augmentation of the Dopamine (DA) release. The primary anatomical sites involve Nucleus Accumbens and Mesolimbic (DA) circuit. Glutamate as well as GABA may play a significant, however indirect role, in this process.

Why does marijuana alter brain function?

The two most well understood endocannabinoid molecules are called anandamide and 2‐arachidonoylglycerol (2‐AG).

endocannabinoid molecules are

Exoconnabinoid molecules are plant derived, THC, CBD, CBN

CDB

Cannabinol (CBN) is a weak in terms of psych activity found only in trace amounts. Targets CB2

Cannabidiol (CBD) Not psychoactive and. Used in Epilepsy treatment

Cannabidiol

The Effects of Marijuana Use

“Use of high-potency (skunk-like) cannabis carries the highest risk for psychotic disorders. In the present larger sample analysis, we replicated our previous report and showed that the highest probability to suffer a psychotic disorder is in those who are daily users of high potency cannabis.” Lancet Psychiatry on Feb. 18, 2015

"Exposure to cannabis during adolescence and young adulthood increases the risk of psychotic symptoms later in life. Cannabis use at baseline increased the cumulative incidence of psychotic symptoms at follow up four years later..”

British Medical Journal Dec 2004

Compelling arguments and data suggest that those with a predisposition for mental illness can exacerbate those symptoms by using cannabis.

”If someone has a genetic vulnerability or has an existing mental health issues, marijuana should be avoided." University of Washington Alcohol and Drug Abuse Institute (ADAI)

“The prevalence of depression and anxiety increased with higher extents of cannabis use, but this pattern was clearest in female participants.“ Nov. 23, 2002 - British Medical Journal

“Weekly or more frequent cannabis use in teenagers predicted an approximately twofold increase in risk for later depression and anxiety...”

"There is an increased risk of depression, suicidal thoughts and schizophrenia as a result of marijuana use, even among people with no prior history of a disorder.... Recent evidence suggests that some people's genetic make-up may predispose them to be particularly vulnerable to the effects of marijuana on mental health."

May 3, 2005 - Office of National Drug Control Policy (ONDCP)

http://headsup.scholastic.com/students/endocannabinoid

Modulation of K+ channels

THC and frontal lobe volumes - significant reduction

PNAS | November 25, 2014 | vol. 111 | no. 47 | 16913–16918

Recreational marijuana use impacts white matter integrity and subcortical (but not cortical) morphometry 466 recreational users aged 22–35 years.

NeuroImage: Clinical Volume 12, February 2016, Pages 47–56

Recreational marijuana use impacts white matter integrity and subcortical (but not cortical) morphometry 466 recreational users aged 22–35 years.

NeuroImage: Clinical Volume 12, February 2016, Pages 47–56

Recreational marijuana use impacts white matter integrity and subcortical (but not cortical) morphometry 466 recreational users aged 22–35 years.

NeuroImage: Clinical Volume 12, February 2016, Pages 47–56

L-Amygdala

R-Nucleus Accumbens

Treatment is difficult

• Adults seeking treatment for marijuana use disorders who have used marijuana nearly every day for more than 10 years and have attempted to quit more than six times.

Cognitive-behavioral therapy: A form of psychotherapy that teaches people strategies to identify and correct problematic behaviors in order to enhance self-control, stop drug use, and address a range of other problems that often co-occur with them. Contingency management: A therapeutic management approach monitors target behavior and the provision (or removal) of tangible, positive rewards when the target behavior occurs (or does not). Motivational enhancement therapy: A systematic form of intervention designed to produce rapid, internally motivated change; the therapy does not attempt to treat the person but rather mobilize his or her own internal resources for change and engagement in treatment.

Research has shown that pregnant women who use marijuana have a 2.3 times greater risk of stillbirth.

Medical Use of Marijuana In Illinois https://www.marijuanadoctors.com/medical-marijuana/IL

• Patients in Illinois diagnosed with severe, debilitating or life-threatening medical conditions are afforded legal protection under the Illinois Medical Marijuana law, as per the Compassionate Use of Medical Cannabis Pilot Program Act

• “Adequate supply” is specifically defined as “2.5 ounces of usable cannabis during a period of 14 days, derived solely from an intrastate source”. The cultivation of cannabis by Illinois patients and caregivers, is NOT permitted.

Epilepsy Multiple animal studies have suggested that THC, one of the main psychoactive chemicals in cannabis, may inhibit the brain activity thought to cause seizures. Nevertheless, high-quality human studies are lacking and leave many open questions.

Cancer Although numerous trials have indicated that medical marijuana increases appetite and reduces chemotherapy-related nausea in the short term, it may not be as effective as other recently developed drugs. Therefore, marijuana is not considered a first-line treatment for these symptoms.

Glaucoma Several studies have found that smoking marijuana lowers pressure inside the eye, relieving glaucoma-related discomfort for about three to four hours. Yet a number of pharmaceutical drugs have been shown to be more effective and longer lasting than medical marijuana.

HIV/AIDS In one randomized controlled trial, patients given a cannabis-like compound were twice as likely to gain weight as patients given a placebo—a boon for people battling the wasting effects of this disease. The treatment's long-term effectiveness remains untested.

Multiple sclerosis (MS) A large trial published in 2012 found that a cannabis extract significantly decreased muscle stiffness and other MS symptoms. A smaller study found that smoking cannabis worked better than a placebo in reducing both spasticity and pain in treatment-resistant participants. Given the few therapies available for MS, a 2011 review concluded that medical marijuana might be a viable way to manage certain symptoms.

Pain and inflammation Studies have suggested that marijuana is only slightly better than a placebo in reducing acute inflammation, and in some patients, it may even increase the perception of pain. When taken in combination with other medications, however, various cannabis-derived drugs have been shown to be moderately effective for reducing chronic neuropathic pain.

Medical Marijuana Patient in Illinois

• Must be at least 18 years-of-age

• Must be a legal resident in the State of Illinois with proof of residency

• The qualifying patient has been diagnosed by a physician as having a debilitating medical condition and has obtained medical records showing the diagnosis of that condition.

• • Obtain written documentation from a physician licensed in the State of Illinois

stating that the patient has qualified.

• Upon receiving a recommendation from a physician, patients are required to register with the Illinois Department of Public Health, upon which he or she will receive a state-issued Medical Marijuana I.D. card.

How to get medicinal Marijuana

• The federal government classifies marijuana as a Schedule I drug. Therefore doctors are unable to prescribe marijuana to their patients

• Medical marijuana doctors in Illinois can supply patients with a medical marijuana recommendation in compliance with state law.

Marijuana will impact Neuronal Activity • 1) pain • 2) inflammation • 3) appetite • 4) seizures • 5) glaucoma

Summary • We need to provide education but move away from merely lecturing teens

about behaviors. • We need to develop programs aimed at preventing risky adolescent

behaviors, develop critical thinking skills, and involve and educate parents. • We need to develop effective programs that offer practical strategies for

making in-the-moment decisions, inhibiting impulsivity and emotionally driven behaviors.

• Practice delayed reward/gratification • Provide a opportunities to create brain links between the emotional and

rational brain that will translate into rational behaviors based on critical thinking.

• Use a person-centered approach with each patient.

THC use and…

Thank You!!!