Potential Pharmacotherapies for Cannabis Use Disorder

Alcohol Medical Scholars Program

Leslie H. Lundahl, Ph.D.

Department of Psychiatry & Behavioral Neurosciences, Wayne State University School of Medicine

I. Introduction- rationale for pharmacotherapy

            A. Cannabis use disorders (CUDs) are common (Slide 2)                

                      1. ~ 22 mil Americans used marijuana in past month 1

                      2. ~ 13% of marijuana users meet DSM-5 criteria for Cannabis Use Disorder (CUD)1

                      3. ~305,000 individuals sought CUD Rx in 2012 (24% of all drug abuse admissions)2

                      4. Changing legal landscape = ↑ use and need for Rx

            B. Cannabis use is not without risk (Slide 3)

                      1. Physical problems (e.g., respiratory)

                      2. Mental health challenges (e.g., mood)

                      3. Cognitive impairment

                      4. Cannabis Use Disorder (defined below)

            C. Rx is challenging (Slide 4)

                      1. Few empirically supported Rxs; moderate efficacy3                  

                      2. ~ 50% achieve abstinence 4,5

          3. High relapse rates (~70%) 5,6

                      4. No FDA-approved medications for CUDs

            D.  This lecture will review: (Slide 5)

                       1. Consequences of cannabis use

                       2. How cannabis works

                       3. Potential medications for CUD Rx

II. Consequences of CB Use – CB use is not benign (Slide 6)

A.    Impaired driving (Slide 7)

   1. ↓ peripheral vision

   2. ↓ motor coordination = ↑ reaction time, ↓ judgment of time and distance

   3. Most frequently reported illicit drug in accidents and fatalities7

   4.  Acute THC → 2x risk of accident8

   5. Acute THC → 3-7x risk of being responsible for motor-vehicle accident9

             B. Amotivational syndrome10 – personality and attitude changes (Slide 8)

                       1.  Lethargy, mental slowing

                       2.  ↓ planning ability

                       3.  ↓ judgment, concentration and memory

                       4. Apathy, ↓ pursuit of age-appropriate goals (e.g., graduating high school or college, job)

             C. Impaired cognition (thinking)11 – even after period of abstinence (Slide 9)

                       1. ↓ Learning – organization and integration of complex information

                       2. ↓ Attention, concentration

                       3. ↓ Abstract reasoning and decision-making

                       4. ↓ Memory

              D. Physical health (Slide 10)

                       1. Respiratory

                                a. ↓ function12

                                b. ↑ bronchitis and infections (pneumonia)13

                       2. Stroke and temporary blood restriction in brain (transient ischemic attacks)14

              E.  Mental health – Precipitate or exacerbate certain mental health problems (Slide 11)

                       1. Anxiety 15, 16

                            a. Acute THC effects ↓ anxiety

                            b. Long-term THC use ↑ anxiety

                       2. Depression17

                            a. Depression associated with ↑ THC use

                            b. Correlational, likely not causative, BUT early onset marijuana use may ↑ depression later

                       3. Psychosis18

                            a. CB exacerbates symptoms of schizophrenia, possibly through ↑ DA release14

                            a. May precipitate schizophrenia in vulnerable; i.e. family history

                            b. Unlikely that THC causes schizophrenia (which would not otherwise have occurred)

               F. 9% of those who try marijuana will develop a Substance Use Disorder (SUD)19 (defined below)

                        1. DSM-520 definition (Slides 12-13)

                             a. At least 2 problems within same 12 months

                                        1. Tolerance (e.g., needing to use ↑ to get same effect)

                                        2. Withdrawal syndrome (i.e., not feeling well) after cessation (defined below)

                                        3. Using CB ↑ or for longer than intended

                                        4. Unsuccessful efforts to ↓ or stop

                                        5. Spending a large amount of time using CB

                                        6. Using CB → giving up important activities (e.g., family dinners )

                                        7. Continued CB use despite physical/psychological problems

                                        8. Craving (i.e., strong desire/urge) for CB

                                        9. Using CB → failure to fulfill life obligations (e.g., missing work)

                                       10. Using CB in hazardous situations (e.g., while driving)

                                       11. Continued CB use despite social/interpersonal problems

               G. Withdrawal syndrome21 when suddenly stop chronic use (Slide 14)

                       1. Symptoms must cause distress or impairment

                       2. Must include 3+ of the following

                                  a. Irritability, anger, aggression

                                  b. Anxiety, nervousness

                                  c. Sleep difficulty (insomnia, disturbing dreams)

                                  d. Decreased appetite or weight loss

                                  e. Restlessness

                                  f. Depressed mood

                       3. And at least 1 of the following:

                                  a. Abdominal pain

                                  b. Sweating

                                  c. Shakiness/tremors

                                  d. Fever/chills

                                  e. Headache

                       4. Time course – starts 24-72 h after cessation, peaks within 1 wk, lasts 1-2 wks

III. How cannabis works22, 23 (Slide 15)

A. Cannabinoids (CB) - ~ 400 chemicals act on CB receptors, alter neurotransmitter release in brain (Slide 16)

B. Natural CBs

    1.  Endogenous (in body) - Anandamide (“bliss”)

    2.  Exogenous - CB Sativa plant (marijuana) – > 84 cannabinoids

         a. Tetrahydrocannabinols (THC) - Mimic anandamide, causes psychoactive effects of cannabis

         b. Cannabidiol (CBD) – 40% of cannabis plant, is not psychoactive        

             C.  CB receptors – at least 2 types (Slides 17-19)

                   1. CB1 – primarily in brain and spinal cord (CNS), widespread, explains diffuse effects of THC

                        a. Mediates CB effects on memory, learning, problem solving, coordination/balance

                        b. Activated by anandamide (natural CB) and other CBs

                        c. Modulates neurotransmitters in brain and body

                   2. CB2 – immune cells outside CNS, accounts for immune function/anti-inflammatory effects

            D. Effects also determined by specific neurotransmitters modulated (Slide 20)

                       1. Dopamine (DA) - reward-motivated behavior, learning, motor control, pleasurable effects        

                               a. CBs indirectly ↑ DA release by blocking action of GABA  

                               b. ↑ in DA = euphoria, positive feelings             

                       2. GABA - inhibitory neuromodulator that “quiets” the brain

                                a.  CBs ↓ GABA release →  sensory enhancements, anxiety

                                b.  ↑ GABA → ↑ muscle relaxation, sleepiness

                       3. Glutamate – excitatory neuromodulator

                                a. CBs ↓ glutamate release → relaxation and ↓ memory

                                b. ↑ glutamate release → anxiety, insomnia and possible seizures            

IV. Potential CUD Rx Medications (Slide 21)

A.    Psychosocial Rx for CUD: Goal → Preparing for life without drugs (Slide 22)

1. Cognitive Behavioral Therapy (CBT)24

a. Basic idea: thoughts → feelings and behaviors

                                 b. Teach pts to identify & correct problematic thoughts and behaviors

c.  Explore positive & negative CB consequences

                                 d. Learn to identify craving quickly to avoid CB use

                         2.  Relapse prevention therapy (RPT)25 (Slide 23)

                                 a. Identify, avoid or cope with high-risk situations

                                 b. ↑ effective non-CB use coping skills (e.g., handling stress)

                                 c. ↑ pt’s belief that he/she can change

                                 d. Keep CB use “lapses” short; before problems ↑

            B. We need to do more (Slide 24)

                        1. Rates of “success” are modest: ~50% achieve abstinence

                        2. 70% relapse rate

                        3. Meds help with other drugs (e.g., alcohol Rx), so might help with CB

                        4. Pharmacotherapy as adjunct to behavioral Rx

                        5. Develop CUD meds based in CB effects

            C. Some definitions (Slide 25)

              1. Agonist - creates an action

                a. Drug binds to and stimulates receptors

                b. E.g., heroin, morphine, oxycodone are opioid receptor agonists; THC is CB1 agonist

                        2. Partial agonist – activates, but only partially

              a. Drug binds to receptors, with a “ceiling” effect

              b. E.g., buprenorphine is opioid partial agonist

                1’. Produces mild euphoria

                2’. Allows opioid cessation with decreased withdrawal, relative to full agonist withdrawal

                        3. Inverse agonist - opposite pharmacological effect (Slide 26)

                    a. Drug binds to receptors, not just absence of agonist effect (antagonist)

                    b. E.g., rimonabant (Accomplia) binds to receptor & reverses THC-induced ↑ in appetite

                        4. Antagonist – blocks agonist drugs from activating receptors

                    a. Binds to receptor, but no “high”

                    b. E.g. naltrexone for opioids, prevents drug from affecting brain

            D. Investigational CUD Medications (Slide 27)     

                        1.  Treatment Targets

                                 a. Overdose

                                 b. Detoxification/Withdrawal

                                 c. Rehabilitation/Relapse Prevention

            2. Overdose (Slide 28)

         a. Rx Goal:  Block effects of drug

         b. CB OD not fatal as CB receptors not densely expressed in brainstem

         c. Possible Rx: CB inverse agonist, rimonabant

                        3. Detoxification and Withdrawal (Slide 29)

                                  a.  Rx Goal: Treat acute effects of stopping drug use, ↓ w/d effects, craving

          b. (Partial) Agonist Rx – replacement (binds to receptor, “mimics” preferred drug)

                1. Pros: safer form, ↓ craving, allows focus on therapy and long-term recovery

                                        2. Cons: Develop physiological dependence/tolerance to Rx   

                         4. Agonist Detox and Withdrawal (Slide 30)

                                    a. Dronabinol (Marinol) – synthetic THC

                         1. Partial agonist of CB1 receptors; similar to using Nicotine Replacement Therapy

                         2. FDA-approved for chemo-related nausea, AIDS-wasting disease

                         3. Pros     

                                a′. ↓ anxiety, poor sleep, misery26

                         b′. ↓ craving27

                                c′. ↓irritability, loss of appetite2

                         4. Cons

                                a′. ↑ drug liking26  and did not ↓ use28

                                b′. ↓ bioavailability and slow onset of action29

                                    b. Nabilone (Cesamet) – synthetic THC (Slide 31)

                         1.  CB1 receptor agonist

                         2.  FDA approved for chemotherapy-induced nausea

                         3.  Pros

                                 a′. ↓ irritability, sleep and appetite disruption, relapse in lab29

                                 b′.  Urinary metabolites distinct from CB

                                         4.  Cons

                                                 a′. ↑ positive mood9

                                                 b′. Doesn’t help with abstinence initiation

                                         5. Clinical trial ongoing

                    c. Nabiximols (Sativex) (Slide 32)

                         1. Cannabinoid combination therapy: THC with CBD ~ 1:1 ratio

                                         2. CBD found in cannabis plant, non-psychoactive, indirect agonist/antagonist?   

                                         3. CBD might block some pleasurable effects of THC

                                         4. Oromucosal spray; in Canada/Europe used to treat MS, epilepsy, neuropathic pain

                         5. Pros

                                  a′. ↓ severity/timecourse of w/d

                                  b′. ↓ depression, irritability, craving

                                  c′. ↑ Rx retention30

                          6. Cons

                                  a′. At 1 mo 69% relapsed30

                                  b′. Diversion

                                  c′. Impaired driving

                         5. Non-agonist Detox and Withdrawal (Slide 33)

                                    a. Gabapentin (Neurontin) – restore normal GABA (inhibitory) function

                                         1. Similar to GABA, ↑ GABA biosynthesis → “brain quieting”

                         2. Anticonvulsant, used for neuropathic pain, epilepsy

                         3. Pros: ↓ w/d sx (dysphoria, sleep disturbance, craving) and use31

                         4. Cons: ↑ suicidal thoughts

                                         5. Clinical trial ongoing

                    b. Fatty acid amide hydrolase (FAAH) inhibitors (Slide 34)

                          1.  Inhibiting FAAH → ↑ CB levels + CB1 receptor activation32

                          2.  Pros: Not directly stimulating receptor → ↑ selective and safer effects

                          3. Cons: Not known; basic studies needed

                          4. Clinical trial ongoing

                        6. Rehabilitation/Relapse prevention (Slide 35)

                                    a. Rx Goal: Block pleasurable effects of drug

            b. Antagonist (blockade) Rx – Binds to receptor, blocks agonist from activating receptors

                                        1. E.g., Opioids - naltrexone (Revia)- opioid antagonist, ↓ pleasurable effects, craving

                                        2. Pros: No tolerance, not addictive

                            3. Cons: Does not relieve craving

                         7. Antagonist Rehabilitation (Slide 36)

                                    a. Cannabidiol (CBD) – CB antagonist

                                         1. In cannabis; 5HT receptor partial agonist; FAAH inhibitor?


                         2. Possible antidepressant, anxiolytic, anti-psychotic effects30

                         3. Preclinical studies show ↓ THC effects32

                         4. Human studies just beginning 

                         8. Antagonist Rehabilitation (Slide 37)

                                    a. Naltrexone (opioid antagonist)

                                         1. Opioid/CB receptor system interaction


                         2. In animals, ↓ THC self-administration33;  In humans, mixed results

                         3. Acute Rx → ↑ “high” and cerebrovascular effects34

                                         4. Repeated Rx → ↓ subjective effects and use35

                                         5. Pros: Repeated (chronic) dosing seems to work

                                         6. Cons: Chronic dosing → ↓ adherence

                                         7. Clinical trial needed

          c. Non-antagonist Rehabilitation (Slide 38)

                       1.  Rimonabant (Accomplia)

                                                  a.  CB1 inverse agonist, “reverses” CB1 activity (doesn’t block)

                                                  b.  Obesity Rx (Europe)

                                                  c.  Pros: ↓ rapid heart rate, ↓ “high”36,37

                                                  d. Cons: withdrawn from market (anxiety, depression, suicidal thoughts)

                                                  e. Rxs that inhibit transmission at CB1 receptors produce serious side effects

                                      2.   N-acetylcysteine (NAC) (Slide 39)

                                                  a. Amino acid derivative, OTC supplement

                                                  b. Acetaminophen OD, cystic fibrosis, Chronic Obstructive Pulmonary Disorder

                                                  c. Restores normal glutamate activity disrupted by chronic drug use

                                                  d. Pros: ↓ use in adolescents38

                                                  e. Cons: did not ↓ craving39

                                                  f. Multi-site clinical trial ongoing

V. Promising Results (Slide 40)

A.    Target: Detox (achieve initial abstinence)

1. Gabapentin (Neurontin)

2. NAC

B.     Target: Rehabilitation (↓ relapse)

            1. CB agonists (agonist replacement)

            2. Nabilone (Cesamet)

            3. Dronabinol (Marinol)

VI. Future directions for pharmacotherapy for CUD (Slide 41)

A.    Need larger, randomized clinical trials to test Rx efficacy of most promising medications

B.     Clinical safety trials - FDA approval

C.     Need to consider novel approaches

1. Develop CB1 antagonist for blockade without serious side effects (i.e., neutral antagonist)

2. Develop Rx that ↑ CB1 signaling

3. Combine two or more pharmacotherapies (similar to buprenorphine for opioids)

              D. Increase mechanistic understanding of endocannabinoid system

              E. Address comorbid SUDs as both potential and necessary Rx targets

VI. Summary (Slide 42)

         A. CUDs are common:  ~ 12% of the US population meets criteria for CUD

         B. CB use associated with adverse consequences

                     1.  Impaired driving, impaired learning/memory

                     2. ↑ risk for respiratory & cerebrovascular complications

                     3. ↑ risk for and exacerbation of depression, anxiety, and psychosis

         C. Existing Rx only moderately effective with unacceptably high relapse rates

         D. No magic bullet - efficacious Rx likely involve both behavioral and pharmacological approaches

         E. Most promising medications: Nabilone, Gabapentin, NAC, Dronabinol, or combination

         F. Awaiting results of studies on CBD, FAAH inhibitors





























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