Proof‐of‐concept trial of PP‐01 for mitigating cannabis withdrawal syndrome in participants with cannabis use disorder

Abstract

Background and Objectives

Cannabis withdrawal symptoms can be severe and protracted, significantly impeding the ability to abstain from cannabis use, resulting in failed quit attempts and relapse. This clinical trial evaluated safety and efficacy of PP‐01, a novel dual‑mechanism of action, investigational agent, for mitigating cannabis withdrawal symptoms in patients with cannabis use disorder (CUD).

Methods

This Phase 1b/2a randomized, double‐blind, placebo‐controlled, crossover, 5‐night, inpatient study evaluated efficacy and safety of PP‐01 (nabilone and gabapentin) in 14 adults with moderate to severe CUD. Participants with daily/near daily use of ≥1 gram/day of cannabis and a history of cannabis withdrawal were randomized to PP‐01 or placebo. Severity and bothersomeness of withdrawal symptoms were evaluated by patient daily diary. Mixed model repeated measures analysis of variance was used to compare mean differences between PP‐01 and placebo.

Results

PP‐01 significantly reduced severity (p = .0222) and bothersomeness (p = .0063) of cannabis withdrawal symptoms within 10 and 4 h post‐first dose of PP‐01, respectively. Sleep quality and cannabis cravings significantly improved following first dose through discharge. Objective withdrawal measures also statistically significantly improved. PP‐01 was well tolerated; adverse events (AEs) were mild in severity with no serious AEs.

Discussion and Conclusions

Investigational PP‐01 mitigated cannabis withdrawal symptoms in participants with moderate to severe CUD, was safe and well‐tolerated in this proof‐of‐concept study.

Scientific Significance

PP‐01 is intended as a potential treatment for cannabis withdrawal syndrome (CWS)/CUD, a serious and unmet need for which there is no Food and Drug Administration (FDA)‐approved medication.

INTRODUCTION

In 2024, approximately 64 million people in the United States used cannabis, with nearly 21 million estimated to have cannabis use disorder (CUD). ¹ Daily/near daily use of cannabis now exceeds that of alcohol. ² An expanding medical literature reports multiple serious health and societal problems associated with cannabis use and cannabis withdrawal. These include addiction, psychosis, ³ schizophrenia, ⁴ suicide, ⁵ , ⁶ cardiovascular ⁷ , ⁸ and pulmonary disorders, ⁹ cannabis hyperemesis syndrome (CHS), ¹⁰ , ¹¹ and violence, ¹² among others. Increased potency of cannabis and frequency of cannabis use, as well as ease of access and acceptability, are contributing to a considerable increase in CUD, emergency department visits, ¹³ and health‐related consequences attributable to cannabis. Cannabis withdrawal, a Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM‐5) criterion of CUD, first reported in 1999 by Haney and colleagues, ¹⁴ , ¹⁵ affects a majority of individuals who regularly use cannabis, ¹⁶ and can be severe and protracted, posing a major barrier to recovery. Despite extensive research, no agents are FDA approved to treat CUD or cannabis withdrawal syndrome (CWS), ¹⁷ an underappreciated, significant, and escalating problem in need of treatment.

The effects of delta‐9 tetrahydrocannabinol (THC), the primary psychoactive component in cannabis, are mediated by the cannabinoid type 1 (CB1) receptor, the most abundant G‐protein‐coupled receptor in the central nervous system. With chronic use, these receptors become desensitized and down‐regulated, ¹⁸ along with other downstream cellular and synaptic neuroadaptations in the mesolimbic reward pathway. ¹⁹ Discontinuation or even reduction in use frequently leads to CWS, now among the most commonly occurring DSM‐5 criteria of CUD, contributing to the continuation of cannabis use. ²⁰ It is estimated that the majority of subjects with CUD who attempt to discontinue cannabis will experience withdrawal. ²¹ A meta‐analysis reported that 54% of outpatient and 87% of inpatient participants seeking treatment for CUD experienced CWS. ¹⁶ Symptom onset can occur within 24–48 h ²² and given the relatively short central nervous system effects of most inhaled cannabis products, we are finding that some heavy users are in a near constant state of withdrawal that requires them to use cannabis every few hours to keep withdrawal symptoms in abeyance.

Key features of CWS as codified in the DSM‐5 may include irritability, anger, aggression, anxiety, depression, sleep disturbances, decreased appetite, restlessness, and abdominal pain, among other physical symptoms. Additionally, psychosis, ²² CHS, ²³ suicide, ⁵ and violence ¹² are increasingly being directly attributed to cannabis withdrawal. ²² , ²³ These symptoms can be severe and serious, can interfere with day‐to‐day functioning, and are associated with life‐threatening health issues. Without an FDA‐approved medication to treat CUD or CWS, a large unmet, public health need exists.

PP‐01 is an experimental agent, utilizing the combination of a CB1 receptor partial agonist (nabilone) and a GABAergic agent (gabapentin). Previous studies of nabilone monotherapy failed to ameliorate symptoms at lower doses. ²⁴ In a separate laboratory study, higher doses of nabilone (4 mg bid or 8 mg/day) demonstrated attenuation of some, but not all withdrawal symptoms, and were reported to be more likely to produce lowered blood pressure or dizziness, exceeding the criteria for capsule administration. ²⁵ Gabapentin monotherapy has been evaluated for cannabis dependence in two randomized trials. A first proof‐of‐concept study demonstrated an initial benefit in reducing cannabis withdrawal symptoms, ²⁶ and a larger follow‐up study (NCT00974376) that was completed in 2016 had a large dropout rate with no differences in urine drug screens. ²⁷ Full results from the second study have not been published. The combination PP‐01 product will be administered in a unique reverse taper and titration schema. Since the downregulated CB1 receptor during cannabis use takes up to 30 days to recover, ¹⁸ the dual mechanism of action of PP‐01 is hypothesized to permit upregulation of CB1 receptors while reducing symptoms related to the reward pathway dysregulation that occurs during cannabis use or CWS. ¹⁹ Reported here are the results of a Phase 1b/2a, randomized, double‐blind, placebo‐controlled, crossover, proof‐of‐concept trial that evaluated PP‑01 intended as a once daily oral medication to mitigate cannabis withdrawal symptoms in research participants with CUD.

METHODS

Study design

This prospective, randomized, double‐blind, placebo‐controlled, two‐period, parallel‐group, single‐center, crossover, Phase 1b/2a study evaluated the pharmacokinetics, efficacy, and safety of PP‐01 in adults currently using cannabis who had moderate to severe CUD. The protocol was approved by an Institutional Review Board (Midlands Independent Review Board, Overland Park, KS), and the study was conducted in accordance with the Declaration of Helsinki, and the International Conference on Harmonization harmonized tripartite guideline regarding Good Clinical Practice.

Eligible non‐treatment‐seeking participants were randomized to receive PP‑01 (6 mg of nabilone in combination with 600 mg of gabapentin) or placebo, in a 1:1 ratio. Participants were told that they did not need to alter their patterns of cannabis use until randomization, but needed to be abstinent during the inpatient phases.

The crossover design included two identical study periods separated by a 14‐day washout. Each period consisted of a 5‐night inpatient stay on Day 0 (check‐in) to Day 5 (discharge). Participants were monitored for contraband prior to in‐patient admission to ensure that no cannabis/cannabidiol or other prohibited product was used during the inpatient treatment periods. Following discharge from the inpatient unit on Day 5, participants were evaluated as outpatients (Day 8) to assess safety and their cannabis use. Participants were discharged from the study on Day 8 of the second period. Participants received oral doses of PP‐01 or placebo in the morning, approximately 2 h prior to a standardized breakfast on Days 1 through 4, for a total of 4 doses per period. If participants received PP‐01 in Period 1, they received placebo in Period 2; conversely, those who received placebo in Period 1 received PP‐01 in Period 2.

Participants

Eligible participants were generally healthy volunteers aged 18–55 years (any race/ethnicity and a body mass index of 18.0 to 36.0 kg/m²) who met DSM‐5 criteria for moderate to severe CUD ¹⁷ and used ≥1 gram of dry leaf cannabis or equivalent (all formulations/potencies were permitted) for ≥6 days per week for ≥6 months. Participants also had to have experienced cannabis withdrawal symptoms when previously attempting to quit, be willing to discontinue cannabis for the inpatient periods, resume their usual cannabis use if they so desired during the 14‐day washout, and have a urine drug screen positive for THC and negative for all other illicit substances at screening and at admission of each inpatient period. All eligible volunteers provided written informed consent before participating in the study.

Participants could not have a history or active schizophrenia or schizoaffective disorder, or any other unstable psychiatric disorder; have any substance use disorder other than cannabis, caffeine, or nicotine use; heavily use alcohol (defined as an average weekly intake of >14 drinks per week for men or >7 drinks per week for women); use cannabis for a medical condition or be legally mandated to participate in a substance use disorder treatment program; have current or recent history of significant violent or suicidal behavior, or risk for suicide or homicide; or have an unstable, serious medical condition. Female participants could not be pregnant or lactating, and if of childbearing potential, had to take an acceptable contraceptive for 30 days prior to first study dose through 30 days after last study dose; male participants had to use a double‐barrier method when sexually active.

Participants were prohibited from using antacids containing magnesium and aluminum hydroxides (during the inpatient stay); concurrent narcotics, opioids, illicit drugs, or any product intended to induce a feeling of being high; or dronabinol or Sativex concurrently or within 30 days of screening. Individuals could be taking a concurrent psychotropic medication if they were stable on it for at least 3 months and the psychotropic medication was compatible with PP‐01.

Outcome measures

The effect of PP‐01 on mitigating withdrawal symptoms was assessed on Day 1, on the mornings of Days 2 through 5, and then on Day 8, of Periods 1 and 2 using the 19‐item Cannabis Withdrawal Scale. ²⁸ Participants completed diary questions scaled from 0 (not at all) to 10 (extremely) to indicate their symptom severity (CWS1). The bothersomeness of each of the 19 symptoms (CWS2) was assessed in a separate diary indicating how bothered participants were by each symptom scaled from 0 (not bothered at all) to 4 (very severely bothered). Diaries were completed prior to dosing each day and at 4 h and 10 h post‐dose (Day 1 pre‐dose was considered Baseline) and were to indicate the severity and bothersomeness since the previous diary completion. The main efficacy outcomes were the CWS1 and CWS2 total scores for PP‑01 compared with placebo.

Prior to unblinding, the six most frequent and severe symptoms reported by participants in the CWS1 (severity) diary were identified and combined to form a 6‐item CWS Subscale. A 2‑item Cravings Domain and a 4‐item Sleep Domain obtained from the CWS1 were also analyzed. Sleep from the previous night was assessed each morning prior to administering study drug utilizing: a) the sleep domain derived from the CWS1, and b) a separate sleep questionnaire that evaluated quantity and quality of sleep from the previous night (completed each morning), both as secondary outcomes.

Participants also completed a self‐assessment of their overall impression of the severity (PGI‐S) and bothersomeness (PGI‐B) of their cannabis withdrawal symptoms on Day 0 (Baseline) and approximately 4 h after dosing on Days 2 and 4. Comparison of PP‐01 with placebo for PGI‐S and PGI‐B was a secondary endpoint. Cannabis withdrawal was objectively evaluated by comparing evening serum cortisol levels (as a physiologic marker of stress associated with withdrawal), body weight, and food intake for PP‐01 versus placebo. Blood samples to assess serum cortisol were obtained in the evenings of Days 0 (Baseline), 1, and 4.

Safety was assessed by collecting adverse events (AEs), vital signs, physical examination, 12‐lead ECGs, pulse oximetry, and concomitant medications. Chemistry and hematology laboratory measures, urinalysis, and urine for drug and alcohol screening were obtained at Screening, Baseline, and on Day 5 of both periods or Early termination.

Statistical analyses

Efficacy analyses were performed on the intent‐to‐treat population, which was all randomly assigned participants who received at least one dose of study drug. Analysis of each efficacy parameter was based on a standard mixed model repeated measures analysis of variance for this design. The efficacy parameter may also have been changed from baseline; if possible, otherwise, the efficacy parameter was the observed value at each timepoint and not the change from baseline. Baseline characteristics and safety assessments were descriptively analyzed. All statistical analysis and programming of tables and listings were conducted using SAS® Release 9.4 or higher (SAS Institute Inc.).

RESULTS

Participant disposition and baseline characteristics

Of 43 participants screened, 14 were enrolled and randomized (PP‐01, n = 7; placebo, n = 7). The completion rate of both Periods of the study was 86%, and overall daily study drug compliance was 100%. During Period 2, two participants did not receive study treatment; one in the PP‐01 arm was lost to follow‐up and one in the placebo arm was discontinued due to a positive urine drug screen for benzodiazepines.

Participants' mean age was 31.2 years (range 23–44); 57% were female, 71% were Black and 29% White. The mean age at first use of cannabis was approximately 14 years (range 6–22 years), and mean duration of use was approximately 17 years (range 4–31 years). Participants' self‐reported mean daily amount of cannabis prior to admission was approximately 3.5 grams. Cannabis use was not different between periods (3.35 grams in Period 1 and 3.66 grams in Period 2). All participants met study entry DSM‐5 criteria for moderate (36%) or severe (64%) CUD and reported having withdrawal symptoms when previously attempting to quit cannabis. The most frequently occurring DSM‐5 CUD criteria are shown in Table 1; besides withdrawal, which was an inclusion criterion, the most common were cravings (100%) and tolerance (93%).

Table 1.

Participant frequency of DSM‐5 criteria for cannabis use disorder.

Criteria, n (%)	All Participants (N = 14)
Characteristic withdrawal syndrome for the substance; or the substance is taken to relieve or avoid withdrawal symptoms	14 (100)
Craving, or a strong desire or urge to use cannabis	14 (100)
Need for markedly increased amounts of the substance to achieve intoxication or desired effect; or diminished effect with continued use of the same amount	13 (92.9)
Great deal of time spent obtaining, using, or recovering from the effects of cannabis	11 (78.6)
Persistent desire or unsuccessful effort to cut down or control use	9 (64.3)
The substance is taken in larger amounts or over a longer period than was intended	8 (57.1)
Continued use despite having persistent or recurrent social or interpersonal problems caused by or exacerbated by the effects of use	5 (35.7)
Giving up or reducing important social, occupational, or recreational activities because of use	4 (28.6)
Recurrent use in situations that could be physically hazardous	4 (28.6)
Recurrent use resulting in failure to fulfill major obligations at work, school, or home	3 (21.4)
Continued use despite knowledge of having a persistent or recurrent physical or psychological problem caused by or exacerbated by use	3 (21.4)

Efficacy

Statistically significant and clinically meaningful differences in CWS1 and CWS2 scores were observed, such that participants taking PP‐01 had less severe withdrawal, and were less bothered by withdrawal symptoms, than participants who took placebo. Significant benefits were observed as soon as the 10‐h, post‐dose timepoint for CWS1 (p = .0222) and the 4‐h, post‑dose (the first measured timepoint) for CWS2 (p = .0063); and these significant improvements were sustained through Day 4 (the last study‐dose day; Table 2). Participants' withdrawal symptoms were better with PP‐01 than with placebo, regardless of the period in which it was received. Mean CWS1 total score for each timepoint is shown in Figure 1a; lower scores represent less severe withdrawal symptoms. Of note, based on diaries completed prior to the first dose, withdrawal symptoms started within 24 h of discontinuing cannabis for most participants. No significant difference in symptoms was found on Day 8 between PP‐01 and placebo.

Table 2.

MMRM p values for least squares mean differences between PP‐01 and placebo in CWS1 and CWS2 total scores and CWS1 domain scores.

Timepoint	CWS1				CWS2
	Total score	6‐Item subscale	Cravings domain	Sleep domain	Total score
Day 1
4 h post‐dose	0.0642	0.0009	0.0766	–	0.0063
10 h post‐dose	0.0222	0.0001	0.0076	–	0.0015
Day 2
Pre‐dose	0.0002	0.0000	0.0058	0.0005	0.0003
4 h post‐dose	0.0000	0.0000	0.0007	–	0.0001
10 h post‐dose	0.0009	0.0000	0.0689	–	0.0001
Day 3
Pre‐dose	0.0004	0.0000	0.0149	0.0207	0.0049
4 h post‐dose	0.0011	0.0000	0.0247	–	0.0027
10 h post‐dose	0.0057	0.0000	0.0131	–	0.0037
Day 4
Pre‐dose	0.0020	0.0000	0.0247	0.0067	0.0003
4 h post‐dose	0.0026	0.0000	0.0001	–	0.0020
10 h post‐dose	0.0017	0.0000	0.0015	–	0.0069

Abbreviations: CWS1, Cannabis Withdrawal Scale 1 (severity); CWS2, Cannabis Withdrawal Scale 2 (bothersomeness); MMRM, mixed models repeated measures.

Figure 1.

Mean scores for (A) total Cannabis Withdrawal Scale for symptom severity (CWS1) and (B) CWS1 6‐item subscale, and (C) cravings and (D) sleep domains with PP‐01 versus placebo on Days 1 through 4 at predose, and at 4 h and 10 h post‐dose. Lower scores represent less severe withdrawal symptoms. *p < .05, ^† p < .01, ^‡ p < .001, ^§ p < .0001 based on analyses of the least square mean differences between PP‐01 and placebo.

The participants' most frequent and most severe cannabis withdrawal symptoms (identified prior to unblinding) as measured by the CWS1 6‐item subscale were statistically significantly lower in the PP‐01 versus placebo arms at 4 h post‐dose (p = .0009), and this significant effect was maintained through Day 4 (Table 2). Additionally, statistically significant reductions in the Cravings domain (starting 10 h post‐dose [p = .0076] through Day 4), and significant improvement in the Sleep domain upon awakening (starting after the first dose on the morning of Day 2 [p = .0005] and other select timepoints) were observed (Table 2). Mean CWS1 6‐Item subscale, Cravings, and Sleep domain scores for each timepoint are shown in Figure 1b–d; lower scores represent less severe withdrawal symptoms. Similar to the 19‐item scale, no significant differences were seen between PP‐01 and placebo by Day 8.

Participants taking PP‐01 described their overall impression of their withdrawal symptoms as being less severe (PGI‐S) and less bothersome (PGI‐B) compared with those taking placebo, with statistical significance observed on Day 2 (p = .0063 and p = .0172, respectively).

The sleep questionnaire revealed improved quality of sleep with statistically significant differences favoring PP‐01 following the first dose (Day 2) and continuing through Day 5 (p < .05 for all timepoints). The amount of time slept each day was greater by 30 min to 1.7 h when participants were treated with PP‐01 versus placebo. Those treated with PP‐01 also napped more time than those treated with placebo.

Mean body weights for those randomized to PP‐01 or placebo were not different at Baseline (Day 0). Starting at Day 2 and continuing through Day 5 (Day 4 was the last day of study drug administration), statistically significant differences (p < .05) in weight were observed between groups (Figure 2a). Participants receiving placebo lost approximately 2 kg between Baseline and Day 5, consistent with decreased appetite and food intake, whereas weight was maintained when taking PP‐01. Food and snack consumption was statistically significantly higher when participants received PP‐01 than when receiving Placebo (p < .05), except on Day 2 for meal consumption. Following discharge and resumption of their usual cannabis use, placebo participants' weights increased back to baseline.

Figure 2.

Mean body weight and evening cortisol levels with PP‐01 versus placebo. (A) Mean body weight (kg) with PP‐01 versus placebo from in‐patient, check‐in (Day 0) to outpatient follow‐up (Day 8). (B) Mean evening cortisol levels (mcg/dL) with PP‐01 versus placebo on Days 0, 1, and 4. *p < .05, ^† p < .01 for PP‐01 versus placebo.

At Baseline (Day 0), evening serum cortisol levels were not different between the PP‐01 and placebo groups. On the evening of Day 1, approximately 12 h after dosing, the mean cortisol level in the placebo group was numerically higher than in the PP‐01 group (8.931 vs. 6.562 μg/dL, respectively) until Day 4, when the difference became statistically significantly (10.569 vs. 6.585 μg/dL, respectively, p = .0013) with higher evening cortisol consistent with more severe withdrawal in the participants taking placebo. The difference between PP‐01 and placebo change from Baseline was also statistically significant (p = .0039) (Figure 2b).

Safety

Twelve subjects received both PP‐01 and placebo, 13 participants received PP‐01, and 13 received placebo. No deaths, severe AEs, serious AEs, or AEs leading to drug withdrawal were reported. Overall, all 14 participants experienced a treatment‐emergent AE (TEAE) during the study; 10 (77%) in the PP‐01 group and 8 (62%) in the placebo group. All TEAEs but one were assessed by the Principal Investigator as at least possibly related to study drug. All TEAEs were mild and mostly related to feeling high, relaxed, and fatigued. Two participants experienced presyncope while receiving placebo, thought to be related to withdrawal symptoms; standing heart rate was statistically significantly higher in the placebo vs. PP‐01 group by Day 3. There were no ongoing AEs at the end of the study.

DISCUSSION

Cannabis utilization, CUD, and CWS are all escalating at an alarming rate in the United States and globally. Cannabis withdrawal symptoms can be severe and protracted, significantly impeding an individual's ability to abstain from cannabis use. This can result in failed quit attempts and relapse, perpetuating a chronic cycle of dependence and exposing users to a multitude of potential morbidities. Currently, no product is FDA‐approved to assist patients with CUD who wish to or who must discontinue cannabis use (e.g., due to psychosis, CHS, other health consequences, peri‐operatively, legal issues, employment issues, pregnancy).

PP‐01 is an investigational, dual mechanism of action product entering Phase 3 clinical trials, that is intended to mitigate withdrawal symptoms in patients with CUD to help patients discontinue or reduce their cannabis use. PP‐01 received Fast Track Designation from the FDA, affirming an unmet need and the severity of cannabis withdrawal. This proof‐of‐concept study demonstrated that PP‐01 was safe and effective in mitigating CWS in participants with CUD. The Cannabis Withdrawal Scale questionnaire demonstrated statistically significant and clinically meaningful differences in the severity and bothersomeness of cannabis withdrawal symptoms when participants received PP‐01 compared with placebo. Additionally, no period effect was noted as PP‐01 improved participants' withdrawal symptoms versus placebo in both periods.

The benefit of PP‐01 was observed at nearly every timepoint, as early as 4 h post first dose, and was sustained through discharge on Day 5 with single‐daily dosing on Days 1 through 4. Additional analyses showed that 6 items on the CWS questionnaire were more significant for a majority of participants experiencing withdrawal, and again these items were statistically significantly reduced with PP‐01 compared with placebo. Cravings were also significantly reduced in participants treated with PP‐01. Despite morning dosing in this study (to accommodate blood samples for pharmacokinetic collection), the CWS1 sleep domain and a separate sleep questionnaire both revealed improved quality of sleep with statistically significant differences favoring PP‐01. PP‑01 is intended to be given at bedtime to help alleviate cannabis‐withdrawal‐related sleep problems and to reduce daytime fatigue related to PP‐01. Participants' self‑assessments of their withdrawal severity (PGI‐S) and bothersomeness (PGI‐B) were also significantly reduced with PP‐01 versus placebo. Study results were robust as evidenced by the consistency of effect across multiple endpoints.

Body weight, evening serum cortisol, food intake, and heart rate were measured to assess physiological consequences of withdrawal. Weight loss was significant when participants received placebo, consistent with a decrease in appetite and food intake associated with withdrawal, while weight was maintained with PP‐01 treatment. Lower evening serum cortisol levels suggest reduced stress associated with acute withdrawal when participants received PP‐01. Standing heart rate was also statistically significantly elevated when participants received placebo compared with those receiving PP‐01.

PP‐01 was well tolerated with no severe or serious AEs, or any safety signals. While dose reduction was permissible by the protocol, none were needed. Although there were more TEAEs with PP‐01 than with placebo, all were mild and mostly related to feeling high, relaxed, or fatigued. These side effects should be minimized by the intended timing of dose administration, which is to be before bedtime. Presyncope was reported in two participants while taking a placebo, and standing heart rate was increased in the placebo group, which was consistent with cannabis withdrawal.

This is a Phase 1b/2a study, and therefore limited by its design as a shorter‐duration study. Further clinical evaluation is needed to test the reverse taper/titration hypothesis of PP‐01 for efficacy and safety. Also, by design, this study had a smaller sample size that was somewhat addressed by the crossover design, but results will need to be replicated in a larger sample. Additionally, this study was conducted at one study site, therefore generalizability to a larger population is important and is in progress. Psychometric evaluation based on the 6‐item domain needs further qualitative and quantitative assessments to help establish a fit‐for‐purpose patient‐reported outcome measure for the Phase 3 program.

Conclusion

PP‐01 mitigated CWS in this Phase 1b/2a well‐controlled, double‐blind, randomized, proof‐of‐concept study in participants with moderate to severe CUD. Benefits of PP‐01 were robust, rapid, and sustained over 5 days, demonstrating a consistency of effect impacting both psychological and physical outcome measures. Rapid relief of symptoms, as observed here, is critical for patients seeking to discontinue or reduce their cannabis use. The safety and efficacy data from this proof‐of‐concept study support the ongoing development of PP‐01 for this important and escalating medical and societal problem to help make recovery possible for those seeking help with cannabis addiction.

CONFLICT OF INTEREST STATEMENT

This study was sponsored by PleoPharma, Inc. AFS is a clinical outcome assessment consultant to PleoPharma with stock/equity options. HK is a statistical consultant to PleoPharma. SG, JC, and GC are employees of PleoPharma with stock/equity options. The authors, alone, are responsible for the content and writing of this paper.

DATA AVAILABILITY STATEMENT

Research data are not shared.