Treatment Strategies in CHS (HALO)

Prospective Evaluation of Symptoms and Open Label Haloperidol in Cannabinoid Hyperemesis Syndrome (HALO)

Background:

In the gastrointestinal (GI) system, the most well-described manifestation of prolonged cannabis use is cannabinoid hyperemesis syndrome (CHS). CHS is characterized by severe cyclic nausea and vomiting and associated with abdominal pain.Currently, the generally accepted management for CHS is complete cannabis abstinence as traditional anti-emetics appear to be minimally effective. Preliminary reports from emergency departments suggest that intravenous haloperidol, a typical anti- psychotic, provides effective symptomatic relief in CHS.

Objective:

1. To learn more about how cannabis use relates to the management of CHS.
2. To learn if haloperidol is effective in treating the symptoms of CHS.

Eligibility:

Alberta residents with ongoing cannabis use, who have completed the baseline study, are ≥ 18 years and ≤ 65 years, and have gastrointestinal symptomology as measured by GCSI > 2 or PAGI-SYM > 2 (upper or lower abdominal pain subscale).

Design:

Participants will answer a series of questionnaires online. Study specific questions relating to symptoms, cannabis use, and anxiety and depression will be administered. Confirmation of cannabis cessation will be assessed with urine creatinine and cannabis metabolite measures. Salivary cortisol will be used to asses the stress response.

Study Overview

• Status: Completed
• Conditions: Cannabis Hyperemesis Syndrome
• Intervention / Treatment: Drug: Haloperidol

Detailed Description

In the gastrointestinal (GI) system, the most well-described manifestation of prolonged cannabis use is cannabinoid hyperemesis syndrome (CHS). CHS is characterized by severe cyclic nausea and vomiting and associated with abdominal pain.The pathophysiology of CHS is poorly understood but may involve alterations gut motility and/or activation of the hypothalamic-pituitary-adrenal (HPA) axis.

Our endogenous endocannabinoid system contains the cannabinoid receptor type I (CB1) and type II (CB2), and their ligands, anandamide (AEA) and 2-arachidonylglycerol (2-AG). CB1 receptors are widely distributed throughout the central and peripheral nervous system, including the myenteric plexus of the GI tract. In humans, oral Δ9-THC (an active cannabis compound) reduces gastric emptying and patients with slow transit constipation have increased expression of endogenous endocannabinoids and higher CB1 receptor expression. In CHS, chronic cannabis use may cause significant activation of peripheral, gut-located CB1.

The hypothalamic-pituitary- adrenal (HPA) axis, the main neuroendocrine system activated in response to stressful stimuli may also be involved in CHS. Activation of centrally located CB1 receptors by 2-AG plays a crucial role in down-regulating the HPA axis in recovery from stress. Reduction in 2-AG activity within the hypothalamus by stress, leads to reduced hypothalamic CB1 receptor activation; this reduced CB1 activation is also observed in prolonged cannabis use.

Currently, the generally accepted management for CHS is complete cannabis abstinence as traditional anti-emetics appear to be minimally effective.Preliminary reports from emergency departments suggest that intravenous haloperidol, a typical anti- psychotic, provides effective symptomatic relief and has become a first-line agent for acute CHS.

Outcome measures:

The primary endpoints will look at the correlation between quantitative weekly cannabis use and gastrointestinal symptoms at week 8 and the mean change of the GI symptoms from week 8 to week 12 during.

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N1
      • University Of Calgary

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Completed Baseline study prior to enrollment
2. Age ≥ 18 years and ≤ 65 years
3. Gastrointestinal symptomology as measured by GCSI > 2 or PAGI-SYM > 2 (upper or lower abdominal pain subscale)
4. Ongoing cannabis use (> 1g/wk)
5. Resident of Alberta with valid Alberta Health Care number

Exclusion Criteria:

1. Pregnancy and/or breastfeeding
2. Corrected QT interval measured on ECG > 450 ms for males or >470 ms for females
3. History of seizure, venous thromboembolism (VTE), psychosis, Parkinson's disease or spastic disorder
4. Concurrent diagnosis of or suspected gastroparesis or functional dyspepsia
5. Diabetes with neuropathy.
6. Any gastrointestinal, neurological, or other illness felt by the investigators to be potentially involved in symptom generation or pose a safety risk to inclusion in this study.
7. Previous gastric or intestinal surgery which may lead to symptoms
8. Use of concomitant medications which cannot be stopped for the 4-week haloperidol phase of the study: including narcotics, antihistamines such as diphenhydramine (Benadryl) or dimenhydrinate (Gravol), dopamine antagonists (domperidone, metoclopramide, risperidone, clozapine, quetiapine), macrolide antibiotics, prokinetics (prucalopride), tricyclic antidepressants (TCA) at doses >50 mg, barbiturates, 5HT3 antagonists (ondansetron).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HALO	Drug: Haloperidol; haloperidol intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation between quantitative weekly cannabis use and GI symptoms at week 8	GI symptoms will be measured PAGI-SYM, a 20-item Likert-type measure with six sub classes. Cannabis use will be measured by the cannabis consumption inventory (DFAQ-CU).The participants will fill out the questionnaires every 2 weeks.	1st 8 weeks of the 12 week study for outcome 1
Mean change in GI symptoms from week 8 to week 12	GI symptoms will be measured PAGI-SYM, a 20-item Likert-type measure with six sub classes. The participants will fill out the questionnaire every 2 weeks.	final 4 weeks of the 12 week study for outcome 2

Collaborators and Investigators

• Sponsor: University of Calgary
• Collaborators: Canadian Institutes of Health Research (CIHR)

Study record dates

Study Major Dates

• Study Start (Actual): October 13, 2020
• Primary Completion (Actual): June 1, 2021
• Study Completion (Actual): June 1, 2022

Study Registration Dates

• First Submitted: November 20, 2019
• First Submitted That Met QC Criteria: November 21, 2019
• First Posted (Actual): November 25, 2019

Study Record Updates

• Last Update Posted (Actual): August 10, 2022
• Last Update Submitted That Met QC Criteria: August 9, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease; Signs and Symptoms, Digestive; Pregnancy Complications; Morning Sickness; Vomiting; Syndrome; Hyperemesis Gravidarum; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Dopamine Agents; Dopamine Antagonists; Anti-Dyskinesia Agents; Haloperidol; Haloperidol decanoate
• Other Study ID Numbers: REB19-1197

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No