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The Endocannabinoid System and Harm Reduc on with Cannabis

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The Endocannabinoid System and Harm Reduc on with Cannabis The Endocannabinoid System and Harm Reduc6on with Cannabis Gregory Gerdeman, PhD Mary Lynn Mathre, RN, MSN, CARN Cannabis is real medicine • Cannabis is safe medicine • Studying cannabis led to discovery of the Ethan Russo, MD ENDOCANNABINOID SYSTEM (ECS) • Cannabinoid receptors (acvated by THC) • Endogenous THC-like cannabinoid signaling molecules (endocannabinoids) • Endocannabinoid metabolic enzymes • ECS is a “master regulator” of human physiology Effects of cannabis in the brain are undeniably the root of human aOracGon and aversion – both – to this plant that has been culvated and ulized as medicine for longer than any historical record. A Gmeline of major discoveries in the research of cannabis and the cannabinoids 1964 – Gaoni and Mechoulam isolate Δ9-THC from hashish 1980’s – “Tetrad” test of cannabinoid effects is developed, and used to test syntheGc analogs. 1988 – CB1 cannabinoid receptor is idenGfied. 1992 – Anandamide is discovered as first endocannabinoid The focus of cannabis research in the 2nd half of the 20th century was not so even-handed. • How does marijuana make someone… • Stoned Led to … The • Lazy endocannabinoid • Addicted (including to other drugs) system • Violent!!! • Mentally impaired for life… brain damage model (THC as neurotoxin) • Insane (paranoid schizophrenia) Mainstream scienGfic concepGons of the endocannabinoid system are now well beyond the exclusive domain of drug abuse research … Endocannabinoid signaling as a synapGc circuit breaker in neurological disease István Katona & Tamás F Freund Nature Medicine, Sept 2008, pp923 - 930 Endocannabinoids as guardians of the nervous system Physical trauma or seizure acvity rapidly and significantly elevates endocannabinoids in the brain. Administering endocannabinoids to animals: • aOenuates many kinds of chemically or electrically induced seizure acGvity • reduces the extent and severity of brain injury following experimentally inflicted head wounds • reduces the severity of inflammaon that naturally follows brain injury, and which has enormous clinical consequence for recovery What about drug abuse and addicon? Prevailing NIDA-funded paradigm is exclusively one of risk, abuse and addicGon. Yet, clinical use of cannabis to successfully treat drug abuse has a long history that includes esteemed doctors. Results of preclinical animal research in the modern NIDA era are also uerly inconsistent with labeling cannabis simpliscally as a “dangerous and addicGve drug” and having “no accepted medical use.” 1988 – 1990 A cannabinoid receptor in the brain! Uptake of [18F]MK-9470 in human brain Prominence in reward centers and circuits relevant to addicon Burns H. D. et.al. PNAS 2007;104:9800-05 Herkenham, M. et.al. PNAS 1990; 87: 1932-36 Neurocircuitry of addicon It’s all much more complicated than dopamine Principal neurotransmiers: Glutamate – excitatory (+) GABA – inhibitory (-) Dopamine – can enhance or decrease excitability Dopamine is much more than a “pleasure signal” Research into dopamine as a trigger to reward and addic4on has helped drive neuroscience outside the addic4on paradigm. • Ac4on selec4on • Mo4vated behavior • Motor programs / sensorimotor integra4on • Implicit memory (procedural, non-declarave) Koob, G. and Volkow, N. (2010) AND Neuropsychopharm Reviews 35: 217-238 • Addic4on as a pathology of habit forma4on Neurocircuitry of addicon It’s all much more complicated than dopamine Principal neurotransmiers: Glutamate – excitatory (+) GABA – inhibitory (-) Dopamine – acetylcholine – pepGdes Endocannabinoids regulate ALL of the above As dopamine drug-abuse model expanded foundaGonal understanding of how the brain works, research into cannabis as a drug of abuse is leading to similar revoluons in understanding nervous system funcGon, and homeostac wellbeing. Major findings • Endocannabinoids and retrograde synap4c signaling • ECS mi4gates neuroinflammaon Koob, G. and Volkow, N. (2010) Neuropsychopharm Reviews 35: 217-238 • THC is anomalous as a drug of abuse Retrograde synapGc signaling by endocannabinoids eCB signaling provides negaGve feedback to excitatory synapses. Glutamate (+) Neuron 1 -blocks excitotoxicity and seizures -regulates informaon processing -mechanisms of learning & memory - including the circuitry of pleasure/ eCBs reward and decision-making Neuron 2 eCB signaling also acts to DISINHIBIT certain neurons by tuning down inhibitory synapses -regulates informaon processing - mechanisms of learning & memory - filtering and gain at synapses Gerdeman & Schechter (2010) in The Pot Book Excitotoxicity An EXCITATORY synapse is formed when an axon terminal EXCITES its target cell to elicit a response. Presynapc axon release site An excitatory glutamatergic synapse Postsynapc target dendrite (or cell body) Animaon from: Katona, I and Freund, T (2008) Nature Medicine 14: 923-930 hap://www.nature.com/nm/journal/v14/n9/extref/nm.f.1869-S1.swf MulGple cannabinoid pathways to brain resilience and repair Excitotoxicity (cell damage due to excessive excitaon and calcium signaling) ReacGve oxygen species (ROS) and nitrosylaon - cannabinoids as anoxidants Microglial acGvaGon Innate Immune Response Pro-inflammatory cytokines Neuroinflammaon Vasodilaon and cerebral perfusion Neurogenesis – growth of new neurons from neuronal stem cells Synapc modulaon by endocannabinoids Intrinsic defense against excitotoxicity A mechanism intrinsic to numerous circuit-level processes of learning & memory Encoding of explicit, declarave memory. • Episodic memory, spaal orientaon • involving hippocampus Consolidaon and exncon of behavioral habits, procedural memory • sGmulus-response behavior in rodent models • automac rouGnes, resistant to devaluaon. • These kinds of S-R habits are facilitated by amphetamines • Impaired by blocking CB1 cannabinoid receptors, BUT • NOT facilitated by exogenous cannabinoids and … • Ex@ncon or unlearning of S-R habits is also hampered by blocking CB1 receptors. • Involving OFC, striatum and mesolimbic dopamine systems (basal ganglia) Neurobiological axis of stress • Fear percepGon and its translaon into acute HPA stress responses • Terminang the HPA stress response (long loop corGsol feedback) • ExGnguishing fearful/traumac memories • Involving PFC, amygdala, hypothalamus So, is cannabis an addicve drug … how does ECS fit the drug abuse paradigm? Condioned Place Preference (CPP) THC and synthec cannabinoids are found to be anomalous Drug-paired compared to typical drugs of context abuse. Many studies fail to find place preference or instead find place aversion to CBs. Posive CPP results, when found, are narrowly dose dependent. (Panagis, et al., 2007) Parker et al. (2004) : CPP to smulants reversed by THC or CBD or rimonabant! eCBs are important for the neural encoding and/or recall of behavioral context! Drug abuse paradigms… how does ECS fit? Self-administraon Cue! Drug of interest (i.e., THC or synthec CB1 agonist) Again, CB agonists are highly atypical… most methods requiring drasc restraint (esp. in mice), food or water deprivaon, prior cocaine self-admin, or a combinaon of these. (Panagis, et al., 2007) But see studies by S. Goldberg, Z. Jusnova and colleagues. But, why? Cannabis is oen a rewarding experience in humans! Studying the ECS in detail is revealing: • insight into how cannabis is rewarding (how it’s different from the dopamine model) • neurobiology of why dependence/addicGon CAN occur • how frequent is a “cannabis dependence disorder” (DSM V) • Genec variaon in ECS genes ( FAAH, CNR1) may contribute suscepbility to addicGon •and anxiety •and depression (drug-resistant) By far the most compelling theme that has emerged from cannabis addicGon research – and most consistent across groups – is the evidence that endocannabinoid signaling modulates cue-induced relapse to the seeking of OTHER drugs. Reinstatement of drug seeking Protocol: Subjects learn to self-administer drug whenever a CUE indicates drug availability. Cue! Drugs!!! Reinstatement of drug seeking Protocol: Subjects learn to self-administer drug whenever a CUE indicates drug availability. Followed by… Prolonged absnence No cue. Lever pressing yields no drug. Drug seeking behavior is ex4nguished. Reinstatement of drug seeking Protocol: Subjects learn to self-administer drug whenever a CUE indicates drug availability. Cue! To seek or not Prolonged absnence to seek? No cue. Lever pressing yields no drug. Drug seeking behavior is ex4nguished. Followed by… Reinstatement Pretreang animals with CB1-acng compounds BLOCK reinstatement of drug seeking in many studies. Drug abuse paradigms Reinstatement of drug self-administraon CB1 receptors are found to be necessary for condioned (cue- directed) reinstatement of drug seeking behaviors. • A model of relapse in drug addicts Consistent for numerous psychosmulant drugs of abuse: • Cocaine (De Vries, Nat Med, 2001) • Nicone (Cohen, Neuropsychopharm, 2005;) • Sucrose and nicone (De Vries, Behav Brain Res, 2005) • Methamphetamine (Anggadiredja, Neuropsychopharm, 2004) * also blocked relapse with THC* CBD found to block heroin reinstatement (Ren, J. Neurosci. 2009) CB1 blockade also reduced breakpoint for cocaine self-admin (Soria, Neuropsychopharm, 2005; Orio et al. J Neurosci, 2009) Take home: In translaGng to clinical reality, do not oversimplify... The human reward circuitry is not a simple on/off switch, even in the addicted brain. Nonetheless the circuits of stress, reward, habit learning and relapse to compulsive drug seeking are finely modulated by eCB signaling... targeGng this system makes at least as much sense as other pharmacotherapeucs
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