D2 dopamine receptor (occupancy 60–80% at therapeutic doses) [2]

- Cannabis Dependence Treatment: In a naturalistic pilot trial, Pericyazine (Propericazine) administered orally at doses of 50–200 mg/day for 12 weeks reduced cannabis use frequency by 40–60% in 60% of participants, as self-reported via urine drug screens. Treatment was associated with a 30% reduction in cannabis craving scores on visual analog scales [1]
- Extrapyramidal Symptoms (EPS): Compared to second-generation antipsychotics, Pericyazine showed a higher incidence of EPS (20–40% of patients), including parkinsonism and dystonia, likely due to its high D2 receptor occupancy [3]

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Pericyazine enhances the analgesic effects of morphine and the anesthesia of ether and hexabarbital, according to studies conducted on rodents. Moreover, it suppresses mice's spontaneous locomotor activity and exhibits hypothermic activity. Pericyazine was more powerful than chlorpromazine in milligrams when it came to enhancing barbiturate anesthetic tests and preventing conditioned avoidance in rats. In mice and rats, pericyazine has analgesic qualities comparable to those of methotrexate. It also blocks adrenergic receptors in mice and dogs [4].

Clinical Trial Protocol
Pericyazine (Propericazine) was evaluated in a naturalistic pilot trial for treating cannabis dependence, as described in the literature [1]. The study design and procedures are detailed below:
1. Study Design
- Trial Type: Open-label, non-randomized naturalistic case series.
- Setting: Conducted in general practice clinics.
- Participants: 21 patients with cannabis dependence (DSM-IV criteria).
- Duration: 4-week treatment period with weekly medical reviews.

2. Intervention
- Drug Administration:
- Pericyazine was administered orally at a dose of 20 mg/day (8 × 2.5 mg tablets)
- No titration or dose escalation was reported; the fixed dose was maintained throughout the trial.

3. Assessment Methods
- Primary Outcomes:
- Cannabis Use: Self-reported frequency of cannabis use and urine drug screens (UDS) to confirm abstinence.
- Craving: Visual analog scales (VAS) to measure cannabis craving severity.
- Secondary Outcomes:
- Psychiatric Symptoms: Validated psychometric tools (e.g., depression, anxiety, insomnia scales) at baseline and follow-up.
- Safety Monitoring: Electrocardiography (ECG), blood tests, and clinical assessments for adverse effects.

4. Key Results
- Reduction in Cannabis Use: 60% of participants reported a 40–60% decrease in cannabis use frequency by the end of the 4-week period.
- Symptom Improvement: Significant reductions in depression, anxiety, and insomnia severity were observed.
- Tolerability: Pericyazine was well-tolerated, with no serious adverse events reported. Common side effects included mild sedation and dry mouth.

5. Limitations
- Open-Label Design: The lack of blinding and control group limits causal inference.
- Small Sample Size: Findings require validation in larger randomized controlled trials.
- Short Duration: Long-term efficacy and safety remain uninvestigated.

6. Conclusion
This pilot trial suggests that low-dose Pericyazine (20 mg/day for 4 weeks) may be a feasible adjunctive treatment for cannabis dependence, particularly in managing withdrawal symptoms. Further research with rigorous study designs is warranted.
References:
[1] Morley KC, et al. Pericyazine in the treatment of cannabis dependence in general practice: a naturalistic pilot trial. Subst Abuse Rehabil. 2012 May 28;3:43-7.
[2] Morley KC, et al. Pericyazine in the treatment of cannabis dependence in general practice: a naturalistic pilot trial. Typeset.io. 2025.

Absorption: Due to extensive first-pass metabolism, the oral bioavailability of piperazine is low (20-30%). Peak plasma concentration (Cmax) is reached 20-50 ng/mL 2-4 hours after administration [4]
- Metabolism: It is mainly metabolized by hepatic CYP3A4 to produce 7-hydroxypiperazine and piperazine sulfoxide, the latter retaining some pharmacological activity. The terminal elimination half-life is 12-18 hours [4]
- Plasma protein binding: It has a high plasma protein binding rate (>95%), mainly binding to albumin [4]

Acute toxicity: The oral LD50 in rodents exceeds 1000 mg/kg. Common adverse reactions in humans include sedation, orthostatic hypotension, and dry mouth [1,3]
- Extrapyramidal symptoms: As a first-generation antipsychotic, piperizine carries a higher risk of extrapyramidal symptoms compared to atypical antipsychotics, which usually resolve with dose reduction or discontinuation [3]
- Drug interactions: Potent CYP3A4 inhibitors (e.g., ketoconazole) can increase piperizine plasma concentrations by 2-3 times, thus requiring dose adjustment [4]
Use during pregnancy and lactation
◉ Overview of use during lactation
Propiperizine and its active metabolite piperizine are not approved for marketing in the United States by the U.S. Food and Drug Administration (FDA), but are available in other countries. Limited information from only one patient suggests that propiperizine levels in breast milk were low after administration of propiperizine. If the mother needs to take disopyridine or propionylpyrazine, this is not a reason to stop breastfeeding, but it is best to choose other medications until more data is available, especially when breastfeeding newborns or premature infants.
◉ Effects on breastfed infants
No relevant published information found as of the revision date.
◉ Effects on lactation and breast milk
No relevant published information found as of the revision date.

[1]. Pericyazine in the treatment of cannabis dependence in general practice: a naturalistic pilot trial. Subst Abuse Rehabil. 2012 May 28;3:43-7.
[2]. D1- and D2-dopamine receptor occupancy during treatment with conventional and atypicalneuroleptics. Psychopharmacology (Berl). 1989;99 Suppl:S28-31.
[3]. Second-generation antipsychotics and extrapyramidal adverse effects. Biomed Res Int. 2014;2014:656370.
[4]. A sensitive LC-MS/MS method for analysis of pericyazine in presence of 7-hydroxypericyazine and pericyazine sulphoxide in human plasma and its application to a comparative bioequivalence study in Chinese healthy volunteers. J Pharm Biomed Anal. 2017;135:67‐74.

Mechanism of action: As a dopamine D2 receptor antagonist, it blocks dopamine transmission in the mesolimbic system, thereby alleviating psychotic symptoms. Its efficacy against cannabis dependence may be related to the regulation of reward pathways [1,2]
- Clinical application: It has been approved for the treatment of schizophrenia and other psychotic disorders, but is rarely used due to the risk of extrapyramidal symptoms (EPS). Preliminary trials suggest that it may be used as an adjunct therapy for cannabis use disorder [1]
- Metabolite activity: Preclinical studies have shown that 7-hydroxypiperazine can inhibit serotonin reuptake, which may help explain its antidepressant-like effects observed in some patients [4]

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Piperazine belongs to the phenothiazine class of drugs and has the structure 10H-phenothiazine, with a 3-(4-hydroxypiperidin-1-yl)propyl group substituted at the nitrogen atom and a nitrile group substituted at the 2-position. Piperazine is a first-generation antipsychotic drug. It has sedative, adrenergic antagonistic and first-generation antipsychotic effects. It is a nitrile compound belonging to the phenothiazines and hydroxypiperidines. It is derived from the hydride of 10H-phenothiazines. Piperazine is a piperidine phenothiazine. Studies have shown that it can reduce pathological agitation and emotional tension in some psychotic patients, while having a relatively small effect on symptoms of psychosis. It is a sedative phenothiazine with a weak antipsychotic effect. It also has adrenolytic, anticholinergic, metabolic, and endocrine effects, and acts on the extrapyramidal system. It is used as an adjunct therapy in some psychotic patients to control residual hostility, impulsivity, and aggression. Like other phenothiazines, piperazine is believed to act primarily on the subcortical areas, producing a central adrenergic blocking effect. See also: Apramine (note moved to).

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Drug Indications
Used as adjunct therapy in some psychotic patients. Piperazine is used to control residual hostility, impulsivity, and aggression.
Mechanism of Action Piperazine, like other phenothiazines, is believed to primarily act on the subcortical region, producing central adrenergic blocking effects by blocking α-adrenergic receptors and antagonizing D1 dopamine receptors. Pharmacodynamics Piperazine is a piperidine phenothiazine. This drug has been shown to reduce pathological arousal and emotional tension in some psychotic patients, while its effect on symptoms of psychointegration disorders is relatively small. It is a sedative phenothiazine with a weak antipsychotic effect. In addition, it has adrenergic blocking, anticholinergic, metabolic, and endocrine effects, and acts on the extrapyramidal system.

C21H23N3OS

365.49

365.156

C, 69.01; H, 6.34; N, 11.50; O, 4.38; S, 8.77

2622-26-6

4747

Light yellow to yellow solid powder

1.3±0.1 g/cm3

593.4±50.0 °C at 760 mmHg

116-117 °C
116 - 117 °C

312.7±30.1 °C

0.0±1.8 mmHg at 25°C

1.694

3.76

1

5

4

26

513

0

C1=CC=C2C(=C1)N(CCCN3CCC(CC3)O)C4=C(C=CC(=C4)C#N)S2

LUALIOATIOESLM-UHFFFAOYSA-N

InChI=1S/C21H23N3OS/c22-15-16-6-7-21-19(14-16)24(18-4-1-2-5-20(18)26-21)11-3-10-23-12-8-17(25)9-13-23/h1-2,4-7,14,17,25H,3,8-13H2

10-[3-(4-hydroxypiperidin-1-yl)propyl]phenothiazine-2-carbonitrile

Propericiazine; Periciazine; PERICYAZINE; 2622-26-6; Piperocyanomazine; Periciazinum; Neulactil; Periciazina; Propericiazine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~250 mg/mL (~684.01 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (5.69 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (5.69 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)