Otrimed Research is conducting the following Trial for Cannabis Use Disorder:
To evaluate tapering/titration of nabilone in combination with gabapentin (PP-01) for the mitigation of withdrawal symptoms, utilizing the Cannabis Withdrawal Core Symptoms Score (CWCSS), to measure cannabis withdrawal symptoms in participants with moderate to severe cannabis use disorder (CUD) seeking to discontinue cannabis.
1. Generally healthy individuals between the ages of 18 and 55, inclusive
2. Meets DSM-5 diagnostic criteria for current moderate to severe CUD as confirmed by a licensed physician or psychologist or addiction medicine specialist (see Section 20.7)
3. Body Mass Index (BMI) within 18.0 to 38.0 kg/m2, inclusive
4. A female study participant must meet one of the following criteria:
● If of childbearing potential – agrees to use one of the accepted contraceptive regimens from Screening to the first administration of the study medication, during the study, and for at least 30 days after the last dose of the study medication.
● An acceptable method of contraception includes one of the following:
● Abstinence from heterosexual intercourse
● Hormonal contraceptives (birth control pills, injectable/implant/insertable hormonal birth control products, transdermal patch)
● Intrauterine device (with or without hormones)
● OR agrees to use a double barrier method (e.g., condom and spermicide) during the study and for at least 30 days after the last dose of the study medication
● If the female is of non-childbearing potential – should be surgically sterile (i.e., has undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation) or is postmenopausal (at least 1 year without menses) as confirmed by follicle-stimulating hormone (FSH) levels of ≥ 40 mIU/mL
5. A male study participant who is fertile and engages in sexual activity must agree to use a double barrier method (e.g., condom and spermicide) and agree to not donate sperm during the study and for at least 90 days after the last dose of the study medication
6. Seeking to minimize withdrawal symptoms related to cannabis discontinuation in participants seeking to discontinue cannabis
7. Have experienced at least three withdrawal symptoms as defined by DSM-5 Cannabis Withdrawal Syndrome diagnostic criteria or two withdrawal symptoms as defined by DSM-5 and have experienced cravings when previously trying to discontinue or reduce the use of cannabis.
8. Meet Criterion C on the DSM-5 Cannabis Withdrawal Scale.
9. Participants should be self-reported heavy cannabis users:
a. Report at least 6 days per week of cannabis use for at least 1 year and use of cannabis multiple times per day
b. Report using at least 1.5 grams or greater each day of dry leaf flower or the equivalent of cannabis
10. Have a urine drug screen positive for THC/THC metabolites at Screening and Randomization
11. Capable of giving informed consent and complying with study procedures
12. Ability to take study drug capsules and agree to daily monitoring of capsule intake
13. Have regular access to the internet and access to video/virtual capabilities for telemedicine visits by any means
14. Not be heavy users of alcohol and be able to abstain from alcohol during the study period
15. Stated willingness to comply with all study procedures including twice weekly visits, daily evening video calls, restrictions, and availability for the duration of the study
1. Lifetime history of DSM-5 diagnosis of schizophrenia or schizoaffective disorder, or Bipolar 1 within the previous 2 years
2. Current DSM-5 criteria for a psychiatric disorder that in the Investigator's judgment is unstable, would be disrupted by the study medication, or is likely to require new pharmacotherapy or psychotherapy during the study period. Individuals who are currently stable on psychotropic medication for at least 3 months may be included at the discretion of the Investigator’s judgment.
3. Participants who meet DSM-5 criteria for any substance use disorder other than cannabis, nicotine, or caffeine use disorders
4. Participants using cannabis for a medical condition requiring use such as epilepsy
5. Unstable medical conditions, such as acquired immunodeficiency syndrome (AIDS), cancer, uncontrolled hypertension, insulin-treated diabetes or uncontrolled Type 2 diabetes, pulmonary hypertension, or heart disease
6. Positive test results for human immunodeficiency virus (HIV)-1/HIV-2 Antibodies (Abs), Hepatitis B surface Antigen (HBsAg), or Hepatitis C Antibody (HCVAb) and evidence of a chronic active infection
7. Currently legally mandated to participate in a substance use disorder treatment program
8. Current or recent history of significant violent or suicidal behavior, the risk for suicide or homicide
9. Currently meets the diagnosis of the eating disorder.
Marijuana is the most used federally illegal drug in the US; 48.2 million people, or about 18% OF Americans, used it at least once n 2019.
3 in 10 people who use marijuana have cannabis use disorder. The risk is greater in adolescent users.
Marijuana use directly affects the part of the brain responsible for memory, learning, attention, decision-making, coordination, emotion, and reaction time.
Long-term users are at increased risk of developing psychosis or schizophrenia.
•Cannabis use, abuse, and withdrawal: Cannabinergic mechanisms, clinical, and preclinical findings. Kesner A, and Lovinger D. Review Article. Journal of Neurochemistry2021;157:1674-1696•Different Effects of Cannabis Abuse on Adolescent and Adult Brain. Dhein, Stefan. Review article. Pharmacology 2020; 105:609-617.•Cdc.gov/marijuana/data-statistics.htm
Cannabis use disorder or cannabis-related disorder is associated with substances derived from the cannabis plant and chemically similar synthetic compounds. Cannabis is the generic term for the psychoactive substance derived from the plant including synthetic cannabinoid compounds.Synthetic oral formulation (pills/capsule) Delta-9-tetrahydrocannabinol (delta-9-THC) is available by prescription for approved medical indications such as nausea and vomiting secondary to chemotherapy or anorexia and weight loss in individuals with AIDS.
The main psychoactive substance in cannabis Sativa is delta -9-tetrahydrocannabinol (THC) which is responsible for the “high” achieved by recreational use. THC acts on CB 1 and CB2 cannabinoid receptors and is a partial agonist. The CB1 receptors are found throughout the central nervous system, and peripheral nervous system and are the primary target of THC. It is expressed predominantly in the presynaptic membrane. It affects glutamatergic and GABAergic synapses predominantly and also affects acetylcholine and NE secretion.
The activation of the CB 1 receptor by THC can diminish the production of neuronal growth factors in neurons and affect other signaling cascades involved in synapse formation. Since these factors play an important role in brain development and in the neuronal conversion process during puberty. In adolescent cannabis users, structural changes were observed with loss of gray matter in certain brain areas. Early use of THC abuse can cause neuropsychological deficits.
From 2000 6-2014 the rate of cannabis-associated ED visits increased by an average of 12.1% annually. The rate increased 17.3% from 20 16-20 17. The rate of visits increased for both males and females.
According to the National Survey on Drug Use and Health (NSDUH), the percentage of Americans aged 12 years and older who reported past-year marijuana use demonstrated a marked 70% increase between 2006 and 2019. As cannabis legalization and use have increased across the country, the perception that cannabis is dangerous or can be harmful has decreased, especially among youth.
Currently, there are no efficacious treatments for cannabis use disorder or withdrawal symptoms. Ref: •Cannabis use, abuse, and withdrawal: Cannabinergic mechanisms, clinical, and preclinical findings. Kesner A, and Lovinger D. Review Article. Journal of Neurochemistry2021;157:1674-1696•Different Effects of Cannabis Abuse on Adolescent and Adult Brain. Dhein, Stefan. Review article. Pharmacology 2020; 105:609-617.•Cdc.gov/marijuana/data-statistics.htm
DSM DIAGNOSTIC CRITERIA
Cannabis Use Disorder: Diagnostic Criteria: DSM 5 Criteria:
A. A problematic pattern of cannabis use leading to clinically significant impairment or distress, as manifested by at least 2 of the following, occurring within a 12-month period: 1. Cannabis is often taken in larger amounts or over a longer period than was intended. 2. There is a persistent desire or unsuccessful efforts to cut down or control cannabis use. 3. A great deal of time is spent in activities necessary to obtain cannabis, use cannabis, or recover from its effects. 4. Craving, or a strong desire or urge to use cannabis. 5. Recurrent cannabis resulting in a failure to fulfill major role obligations at work, school, or home. 6. Continued cannabis use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effect of cannabis. 7. Important social, occupational, or recreational activities are given up or reduced because of cannabis use 8. Recurrent cannabis use in situations in which it is physically hazardous. 9. Cannabis use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by cannabis. 10. Tolerance, as defined by either of the following:
● a. In need of markedly increased amounts of cannabis to achieve intoxication or desired effect.
● b. Markedly diminished effect with continued use of the same amount of cannabis.
11. Withdrawal, as manifested by either of the following:
● a. The characteristic withdrawal syndrome for cannabis of the criteria set for cannabis withdrawal:
A. Cessation of cannabis use that has been heavy and prolonged (i.e., usually daily, or almost daily use over a period of at least a few months).
B. Three (or more) of the following signs and symptoms developed within approximately 1 week after criterion A: 1. Irritability, anger, or aggression. 2. Nervousness or anxiety. 3. Sleep difficulty (e.g., insomnia, disturbing dreams). 4. Decreased appetite or weight loss. 5. Restlessness. 6. Depressed mood. 7. At least one of the following physical symptoms on 6 discomfort: Abdominal pain, shakiness/tremors, sweating, fever, chills, or headache.
C. The signs or symptoms in criteria B cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
D. These signs or symptoms are not attributable to another medical condition and are not better explained by another mental disorder, including intoxication or withdrawal from another substance.
The severity of Cannabis Use Disorder:
Mild: Presence of 2 – 3 SymptomsModerate: Presence of 4 – 5 SymptomsSevere: Presence of 6 or more symptoms
Cannabis Use disorder in early remission: After full criteria for cannabis use disorder were previously met, none of the criteria for cannabis use disorder have been met for at least 3 months but for less than 12 months (with the exception of the criterion A4, “craving, or a strong desire or urge to use cannabis,” may be met).
Cannabis Use Disorder in sustained remission: To her full criteria for cannabis use disorder were previously met, none of the criteria for cannabis use disorder have been met at any time during a period of 12 months or longer with the exception that criterion a for, "craving, or a strong desire or urge to use cannabis," may be present).