Abstract
Suicide is a devastating complication of psychiatric disorders characterized by despair,
hopelessness, and overwhelming mental distress or pain. Non-suicidal self-injury (NSSI),
suicide ideation (SI) and suicide attempts (SA) all fall under the umbrella of suicide
behaviour (SB). Several biopsychological theories describe SB as an attempt to relieve
mental pain. They comment on the role of tolerance-habituation to the rewarding effects
of SB-induced emotional regulation, as well as increasing physical or somatic pain
tolerance, both of which contribute to the escalating patterns of repetitive SB. The
endocannabinoid system (ECS) is involved in a wide range of homeostatic and neuromodulatory
functions including appetite/feeding, sleep, motor control, pain perception, cognition,
mood/affect, and reward processing. The downregulation of endocannabinoid signalling
has major implications for affective disorders, pain disorders, and substance use
disorders. SB can be seen as a manifestation of these disorders and has also been
linked to ECS dysfunction. Drawing from both animal and human studies, we aim to understand
repetitive SB as an endocannabinoid-mediated pain and reward disorder. We hypothesize
that mental distress triggers the first incidence of NSSI or SB, from which patients
derive stress-induced endocannabinoid-mediated analgesia. As patients become increasingly
tolerant to this mechanism of analgesia, SB escalates to override increasing mental
distress. This hypothesis calls for more research on endocannabinoid-based therapies
to prevent the progression from NSSI or SI to fatal SA.
Keywords
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References
Suicide in Canada: Key Statistics (infographic) – Canada.ca n.d. https://www.canada.ca/en/public-health/services/publications/healthy-living/suicide-canada-key-statistics-infographic.html (accessed December 29, 2021).
- Correlates of suicide attempts among self-injurers: A meta-analysis.Clin Psychol Rev. 2014; 34: 282-297
- A theory of suicide addiction.Sex Health Compulsivity. 1998; 5: 311-324
- Mental pain: a multidimensional operationalization and definition.Suicide Life Threat Behav. 2003; 33: 219-230
- Why people die by suicide.Harvard University Press, Cambridge, Massachusetts2007: 1-288
- Mental pain: a multidimensional operationalization and definition.Suicide & Life Threatening Behav. 2011; 33: 219-230
Marsicano G, Kuner R. Anatomical distribution of receptors, ligands and enzymes in the brain and in the spinal cord: Circuitries and neurochemistry. Cannabinoids and the Brain 2008;9780387743493:161–201.
- Meta-analysis of cannabinoid ligand binding affinity and receptor distribution: interspecies differences.Br J Pharmacol. 2007; 152: 583-593
- Endocannabinoid signaling and synaptic function.Neuron. 2012; 76: 70-81
- Cannabinoids and cannabinoid receptors: the story so far.iScience. 2020; 23: 101301
- Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides.Nature. 1996; 384: 83-87
- cDNA cloning, tissue distribution, and identification of the catalytic triad of monoglyceride lipase. Evolutionary relationship to esterases, lysophospholipases, and haloperoxidases.J Biol Chem. 1997; 272: 27218-27223
- Systematic review of systematic reviews for medical cannabinoids: pain, nausea and vomiting, spasticity, and harms.Can Fam Physican. 2018; 64: 78-94
Mücke M, Phillips T, Radbruch L, Petzke F, Hauser W. Cannabis-based medicines for chronic neuropathic pain in adults. Cochrane Database Syst Rev 2018;7(3):CD0121782.
- Psychiatric symptoms caused by cannabis constituents: a systematic review and meta-analysis.Lancet Psychiat. 2020; 7: 344-353
- Does cannabidiol protect against adverse psychological effects of THC?.Front Psychiatry. 2013; 4: 130
- Cannabidiol counteracts the psychotropic side-effects of δ-9-tetrahydrocannabinol in the ventral hippocampus through bidirectional control of ERK1-2 phosphorylation.J Neurosci. 2019; 39: 8762-8777
- Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis.Pain. 2017; 158: 2442-2451
- Antioxidative and anti-inflammatory properties of cannabidiol.Antioxidants. 2019; 9: 21
- The endocannabinoid system and rimonabant: a new drug with a novel mechanism of action involving cannabinoid CB1 receptor antagonism–or inverse agonism–as potential obesity treatment and other therapeutic use.J Clin Pharm Ther. 2007; 32: 209-231
- Depression-like phenotype following chronic CB1 receptor antagonism.Neurobiol Dis. 2010; 39: 148-155
- Differential regulation of the endocannabinoids anandamide and 2-arachidonylglycerol within the limbic forebrain by dopamine receptor activity.J Pharmacol Exp Ther. 2003; 306: 880-888
- Systemic administration of WIN 55,212–2 increases norepinephrine release in the rat frontal cortex.Brain Res. 2005; 1046: 45-54
- Inhibition of monoamine oxidase activity by cannabinoids.Naunyn Schmiedebergs Arch Pharmacol. 2010; 381: 563-572
- Ligand- and heterodimer-directed signaling of the CB(1) cannabinoid receptor.Mol Pharmacol. 2010; 77: 1-9
Urigüen L, Esteban S, Callado LF, Álvaro-Bartolomé M, Meana JJ, García-Sevilla JA. Endocannabinoid Regulation of Monoamines in Psychiatric and Neurological Disorders. 1st ed. Springer, New York, NY; 2013.
Zou S, Kumar U. Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System. Int J Mol Sci 19(3):833.
Hohmann AG, Suplita RL, Bolton NM, Neely MH, Fegley D, Mangieri R, et al. An endocannabinoid mechanism for stress-induced analgesia. Nature 2005;435:1108–1112.
- Endocannabinoid mechanisms of pain modulation.AAPS J. 2006; 8: E693-E708
- Addiction and the brain antireward system.Annu Rev Psychol. 2008; 59: 29-53
- Endocannabinoid system: role in depression, reward and pain control (Review).Mol Med Rep. 2016; 14: 2899
- Changes in ecological momentary assessment reported affect associated with episodes of nonsuicidal self-injury.Beh Ther. 2011; 42: 579-588
- The emotion regulation function of nonsuicidal self-injury: a momentary assessment study in inpatients with borderline personality disorder features.J Abnorm Psychol. 2017; 126: 89-95
- Are suicidal thoughts reinforcing? A preliminary real-time monitoring study on the potential affect regulation function of suicidal thinking.J Affect Disord. 2018; 232: 122-126
- An empirical study on the “cathartic effect” of attempted suicide.Psychiatry Res. 1985; 16: 123-130
- Increased serotonin after a suicide attempt: coincidence or catharsis?.Biol Psychiatry. 1988; 24: 725-727
- Short-term course of depression following attempted suicide: a preliminary report.Acta Psychiatr Scand. 1990; 81: 345-351
- Cathartic effect of suicide attempts not limited to depression.Crisis. 2003; 24: 73-78
- Risk repetition of suicide attempt, suicide or all deaths after an episode of attempted suicide: a register-based survival analysis.Aust N Z J Psychiatry. 2007; 41: 257-265
- Pain sensitivity and plasma beta-endorphin in adolescent non-suicidal self-injury.J Affect Disord. 2021; 278: 199-208
- The role of endogenous opioids in non-suicidal self-injurious behavior: methodological challenges.Neurosci Biobehav Rev. 2015; 48: 186-189
- Upregulation of CB1 receptors and agonist-stimulated [35S]GTPgammaS binding in the prefrontal cortex of depressed suicide victims.Mol Psychiatry. 2004; 9: 184-190
- Elevated levels of endocannabinoids and CB1 receptor-mediated G-protein signaling in the prefrontal cortex of alcoholic suicide victims.Biol Psychiatry. 2005; 57: 480-486
- Endogenous cannabinoid levels and suicidality in combat veterans.Psychiatry Res. 2020; 287: 112495
- Serum endocannabinoid levels in suicide attempters: A pilot study.Eur Neuropsychopharmacol. 2020; 40: 52-60
- Neural basis of reinforcement learning and decision making.Annu Rev Neurosci. 2012; 35: 287-308
- The reinforcing properties of repeated deliberate self-harm.Arch Suicide Res. 2010; 14: 329-341
- The concept of mental pain.Psychother Psychosom. 2013; 82: 67-73
- Mental Pain and Suicide: A Systematic Review of the Literature.Front Psychiatry. 2016; 7: 108
Ducasse D, Holden RR, Boyer L, Artéro S, Raffaella, Guillaume S, et al. Psychological Pain in Suicidality: A Meta-Analysis. JCP 2017;78:16108.
- Psychological pain: a review of evidence.J Psychiatr Res. 2006; 40: 680-690
- Brain regions associated with psychological pain: implications for a neural network and its relationship to physical pain.Brain Imaging Behav. 2013; 7: 1-14
- Quality of life in chronic pain is more associated with beliefs about pain, than with pain intensity.Eur J Pain. 2005; 9: 15-24
- Differential patterns of physical symptoms and subjective processes in generalized anxiety disorder and unipolar depression.J Anxiety Disord. 2010; 24: 250-259
- A common ground for pain and depression.Nat Neurosci. 2019; 22: 1612-1614
- Comorbid chronic pain and depression: shared risk factors and differential antidepressant effectiveness.Front Psychiatry. 2021; 12
- Non-suicidal self-injurious behavior, endogenous opioids and monoamine neurotransmitters.J Affect Disord. 2010; 124: 134-140
- Endogenous opioids regulate glucocorticoid-dependent stress-coping strategies in mice.Neuroscience. 2016; 330: 121-137
- Pain threshold and pain tolerance as a predictor of deliberate self-harm among adolescents and young adults.Indian J Psychiatry. 2021; 63: 142
- What do plasma beta-endorphin levels reveal about endogenous opioid analgesic function?.Eur J Pain. 2012; 16: 370-380
- Synergistic effect of chronic pain and nonsuicidal self-harm on pain sensitivity.Eur Arch Psychiatry Clin Neurosci. 2021; 1: 1-10
- The course of post-crisis suicidal symptoms: how and for whom is suicide “cathartic”?.Suicide Life Threat Behav. 2001; 31: 144-152
- The roles of affect dysregulation and positive affect in non-suicidal self-injury.Arch Suicide R. 2012; 16: 212-225
- Addictive characteristics of the behavior of self-mutilation.J Psychosoc Nurs Ment Health Serv. 1995; 33: 36-39
- Affect regulation and addictive aspects of repetitive self-injury in hospitalized adolescents.J Am Acad Child Adolesc Psychiatry. 2002; 41: 1333-1341
- The addictive model of self-harming (non-suicidal and suicidal) behavior.Front Psychiatry. 2016; 7: 8
- The functions and addictive features of non-suicidal self-injury: a confirmatory factor analysis of the Ottawa self-injury inventory in a university sample.Psychiatry Res. 2018; 264: 316-321
- The interpersonal theory of suicide: a systematic review and meta-analysis of a decade of cross-national research.Psychol Bull. 2017; 143: 1313-1345
- Clarifying the role of pain tolerance in suicidal capability.Psychiatry Res. 2011; 189: 362-367
- Nonsuicidal self-injury and diminished pain perception: the role of emotion dysregulation.Compr Psychiatry. 2012; 53: 691-700
- Aberrant pain perception in direct and indirect non-suicidal self-injury: an empirical test of Joiner’s interpersonal theory.Compr Psychiatry. 2013; 54: 694-701
- Predicting suicide attempts by time-varying frequency of nonsuicidal self-injury among Chinese community adolescents.J Consult Clin Psychol. 2015; 83: 524-533
- The associations between non-suicidal self-injury and first onset suicidal thoughts and behaviors.J Affect Disord. 2018; 239: 171-179
- Examining the time to transition from nonsuicidal self-injury to suicide attempt.Crisis. 2021; 42: 157-161
- Further evidence of anxiety- and depression-like behavior for total genetic ablation of cannabinoid receptor type 1.Behav Brain Res. 2021; 400: 113007
- Overcoming the psychiatric side effects of the cannabinoid CB1 receptor antagonists: current approaches for therapeutics development.Curr Top Med Chem. 2019; 19: 1418-1435
- Involvement of CB1 cannabinoid receptors in emotional behaviour.Psychopharmacology. 2002; 159: 379-387
- Reduced sensitivity to reward in CB1 knockout mice.Psychopharmacology. 2004; 176: 223-232
- The effects of genetic and pharmacological blockade of the CB1 cannabinoid receptor on anxiety.Eur J Neurosci. 2002; 16: 1395-1398
- Early age-related cognitive impairment in mice lacking cannabinoid CB1 receptors.PNAS. 2005; 102: 15670-15675
- Endocannabinoid system and drug addiction: new insights from mutant mice approaches.Curr Opin Neurobiol. 2013; 23: 480-486
- Effect of delta-9-tetrahydrocannabinol on behavioral despair and on pre- and postsynaptic serotonergic transmission.Prog Neuropsychopharmacol Biol Psychiatry. 2012; 38: 88-96
- Antidepressant-like effects of Δ9-tetrahydrocannabinol and rimonabant in the olfactory bulbectomised rat model of depression.Pharmacol Biochem Behav. 2012; 102: 357-365
- Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission: role of 5-HT1A receptors.Neuropharmacology. 2016; 103: 16-26
- Cannabidiol induces rapid and sustained antidepressant-like effects through increased BDNF signaling and synaptogenesis in the prefrontal cortex.Mol Neurobiol. 2019; 56: 1070-1081
- Cannabinoids for the treatment of mental disorders and symptoms of mental disorders: a systematic review and meta-analysis.Lancet Psychiat. 2019; 6: 995-1010
- Animal models to improve our understanding and treatment of suicidal behavior.Transl Psychiatry. 2017; 7: e1092-e
- Selective alterations of the CB1 receptors and the fatty acid amide hydrolase in the ventral striatum of alcoholics and suicides.J Psychiatr Res. 2010; 44: 591-597
- Regional distribution and effects of postmortal delay on endocannabinoid content of the human brain.Neuroscience. 2008; 152: 1032-1039
- Influence of dorsolateral prefrontal cortex and ventral striatum on risk avoidance in addiction: A mediation analysis.Drug Alcohol Depend. 2015; 149: 10-17
- Dorsolateral prefrontal cortex drives mesolimbic dopaminergic regions to initiate motivated behavior.J Neurosci. 2011; 31: 10340-10346
- Neurobiological interactions between stress and the endocannabinoid system.Neuropsychopharmacology. 2016; 41: 80-102
- Effects of acute and repeated restraint stress on endocannabinoid content in the amygdala, ventral striatum, and medial prefrontal cortex in mice.Neuropharmacology. 2008; 54: 108-116
- Acute restraint stress enhances hippocampal endocannabinoid function via glucocorticoid receptor activation.J Psychopharmacol. 2012; 26: 56-70
- Changes in spinal and supraspinal endocannabinoid levels in neuropathic rats.Neuropharmacology. 2007; 52: 415-422
- The Role of the Cannabinoid System in Pain Control: Basic and Clinical Implications.Curr Pain Headache Rep. 2020; 24
- Role of the Cannabinoid System in Pain Control and Therapeutic Implications for the Management of Acute and Chronic Pain Episodes.Curr Neuropharmacol. 2006; 4: 239
- Amygdala activity contributes to the dissociative effect of cannabis on pain perception.Pain. 2013; 154: 124-134
Information for Health Care Professionals: Cannabis (marihuana, marijuana) and the cannabinoids (report) - Canada.ca n.d. https://www.canada.ca/content/dam/hc-sc/documents/services/drugs-medication/cannabis/information-medical-practitioners/information-health-care-professionals-cannabis-cannabinoids-eng.pdf (accessed December 29, 2021).
- Effect of cannabis use in people with chronic non-cancer pain prescribed opioids: findings from a 4-year prospective cohort study.Lancet Public Health. 2018; 3: e341-e350
- Cannabinoid use and self-injurious behaviours: a systematic review and meta-analysis.J Affect Disord. 2021; 278: 85-98
- Endocannabinoid signalling in reward and addiction.Nat Rev Neurosci. 2015; 16: 579-594
- Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors augments cAMP accumulation in striatal neurons: evidence for a Gs linkage to the CB1 receptor.J Neurosci. 1997; 17: 5327-5333
- Preferential limbic expression of the cannabinoid receptor mRNA in the human fetal brain.Neuroscience. 2003; 118: 681-694
- Attenuation of cue-induced heroin-seeking behavior by cannabinoid CB1 antagonist infusions into the nucleus accumbens core and prefrontal cortex, but not basolateral amygdala.Neuropsychopharmacology. 2008; 33: 2483-2493
Desfossés J, Stip E, Ait LB, Lipp O, Jean-Pierre Chiasson, Furtos A, et al. Plasma endocannabinoid alterations in individuals with substance use disorder are dependent on the “mirror effect” of schizophrenia. Front Psychiatry 2012;3:85.
- Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers.Mol Psychiatry. 2012; 17: 642-649
- Decreased cannabinoid CB1 receptors in male tobacco smokers examined with positron emission tomography.Biol Psychiatry. 2018; 84: 715-721
- Reduced cannabinoid CB1 receptor binding in alcohol dependence measured with positron emission tomography.Mol Psychiatry. 2013; 18: 916-921
- Chronic exposure to morphine, cocaine or ethanol in rats produced different effects in brain cannabinoid CB1 receptor binding and mRNA levels.Drug Alcohol Depend. 2002; 66: 77-84
- Cannabinoid mechanism in reinstatement of heroin-seeking after a long period of abstinence in rats.Eur J Neurosci. 2003; 17: 1723-1726
- Role of receptor internalization in the agonist-induced desensitization of cannabinoid type 1 receptors.J Neurochem. 2008; 104: 1132-1143
- Cross-sensitization and cross-tolerance between exogenous cannabinoid antinociception and endocannabinoid-mediated stress-induced analgesia.Neuropharmacology. 2008; 54: 161-171
- The bivalent rewarding and aversive properties of Δ 9-tetrahydrocannabinol are mediated through dissociable opioid receptor substrates and neuronal modulation mechanisms in distinct striatal sub-regions.Sci Rep. 2019; 9: 9760
- Nonacute effects of cannabis use on motivation and reward sensitivity in humans: a systematic review.Psychol Addict Behav. 2018; 32: 497-507
- Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor.Br J Pharmacol. 2015; 172: 4790-4805
- Early phase in the development of cannabidiol as a treatment for addiction: opioid relapse takes initial center stage.Neurotherapeutics. 2015; 12: 807-815
- Role of cannabidiol in the therapeutic intervention for substance use disorders.Front Pharmacol. 2021; 12626010
- A phase I, randomized, double-blind, placebo-controlled, single ascending dose, multiple dose, and food effect trial of the safety, tolerability and pharmacokinetics of highly purified cannabidiol in healthy subjects.CNS Drugs. 2018; 32: 1053-1067
- A placebo-controlled investigation of the analgesic effects, abuse liability, safety and tolerability of a range of oral cannabidiol doses in healthy humans.Br J Clin Pharmacol. 2021; 88: 347-355
- Altered pain perception in self-injurious behavior and the association of psychological elements with pain perception measures: a systematic review.Psychiatria Danubina. 2015; 27: 346-354
- Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects.Br J Pharmacol. 2011; 163: 1344
- The effects of Δ 9-tetrahydrocannabinol on the dopamine system.Nature. 2016; 539: 369-377
- Further human evidence for striatal dopamine release induced by administration of Δ9-tetrahydrocannabinol (THC): selectivity to limbic striatum.Psychopharmacology. 2015; 232: 2723
- Neuronal and molecular effects of cannabidiol on the mesolimbic dopamine system: Implications for novel schizophrenia treatments.Neurosci Biobehav Rev. 2017; 75: 157-165
- Abuse potential assessment of cannabidiol (CBD) in recreational polydrug users: a randomized, double-blind, controlled trial.Epilepsy Behav. 2018; 88: 162-171
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Published online: July 09, 2022
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