Drug Abuse

What constitutes a drug of abuse?

A drug which: alters consciousness and cognitive ability of user, has long-term psychological effects upon user, is addictive

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Why do people take drugs?

Stimulation (heroin, PCP, caffeine). Relaxation (cannabis, alcohol), sexual gratification (amyl nitrate). Creativity (LSD)

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How are drugs classified?

Misuse of drugs act 1971. Based on the harm of drug to the user

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Give examples of drugs in class A

Heroin, cocaine, ecstasy, LSD, magic mushrooms. Most dangerous

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Give examples of drugs in class B

Amphetamines, codeine (painkiller), cannabis, ketamine (animal injections, dental surgery, anesthetic), mephedrone

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Give examples of drugs in class C

BDZ (CD/POM), GHB/GBL, anabolic steroids, benzylpiperazines

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What are legal drugs? (1)

Not covered by misuse of drugs act 1971. Associated with drugs taken for 100s of years

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What are legal drugs? (2)

Different from legal highs (don't resemble class A and B narcotics). Legal highs based on pre-existing class A and B drugs.

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Why does a legal drug stay legal?

Long history of use (culture). Doesn't affect performance in low doses (except alcohol). Financial revenue (taxation). Public pressure

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What is the public perception of drugs?

Alcohol is more harmful to others but legal. Heroin is less harmful to others but illegal

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What is the relationship between drug dosage and dependence?

Heroin is very lethal with high dependence. LSD is less lethal with low dependence (graph)

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How are drugs reclassified?

Heavily influenced by society and media pressure (e.g. cannabis changed from class C to class B)

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Give examples of legal drugs

Caffeine (CNS stimulant). Nicotine. Ethanol (CNS depressant, remove inhibition)

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What are the demographics of drug use? (1)

Common in older people, people might use 1-2 times a year, wide use of cannabis, less frequent use of cocaine

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What are the demographics of drug use? (2)

More common in men. Users are more likely to drink alcohol (addictive personality). Anxious people more likely to use (want to feel better).

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What is the criminality of drug abuse (possession)?

Temporary drugs - confiscated. Class C (<2 years in prison/unlimited fine, not an offence to possess them for personal use). Class B (<5 years in prison/unlimited fine). Class A (<7 years in prison/unlimited fine).

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What is the criminality of drug abuse (supply and production)?

Temporary class drugs or Class C (<14 years in prison/unlimited fine). Class B (<14 years in prison/unlimited fine). Class A (life in prison/unlimited fine)

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Give examples of drugs with psychological addiction

Ketamine (short-acting, tolerance can develop). Cannabis (tolerance for heavy users, often replaced with another addiction)

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What is the general mechanism for pharmacological addiction (1)

Mesolimbic and mesocortical tracts (reward pathways) stimulated. Stop drugs (lose stimulation, craving). Linked with harder drugs

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What is the general mechanism for pharmacological addiction (2)

Increased NT release, decreased NT release, decreased/increased receptor expression. Increased receptor sensitivity (bigger response via secondary messenger)

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Describe the mechanism of addiction to nicotine (1)

Activation of mesolimbic pathway stimulates reward pathway, increase in DA release. Reduce sensitivity of NAChR

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Describe the mechanism of addiction to nicotine (2)

Brain increases production of NAChR to compensate. Increase reward pathway sensitivity. Lasts for several months (craving)

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Describe the mechanism of addiction to nicotine (3)

Need to wait for brain to break down NAChR to normal receptor level (reason why people have difficulty giving up smoking)

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State features of ethanol addiction

Linked to effects on mesolimbic system. Withdrawal effects: shaking, irritability, poor judgment. Cortical syndrome: alcoholic brain damage, people lose time. Support (AA)

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State features of heroin addiction

Highly addictive (high potency, rapid hit, short half-life). Chemical: increased production of morphine 6-glucuronide (used to determine long-term users)

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Describe the pharmacological addiction to amphetamines (1)

Potentiates CNS biogenic amine stimulation by blocking biogenic amine reuptake and metabolism. Receptor down regulation, reduction in biogenic amine synthesis

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Describe the pharmacological addiction to amphetamines (2)

Erodes pharmacological effect (tolerance, addiction). Usually taken with other drugs (ethanol, heroin)

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What are the neurochemical changes at cellular level for withdrawal? (1)

Increased expression of receptors. Increased sensitivity of receptors. Decreased synthesis of endogenous neurotransmitters

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What are the neurochemical changes at cellular level for withdrawal? (2)

When removing drug, need to wait for body chemistry to return back to normal – gene expression, protein breakdown (10 half-lives, drug with half-life of 10 hours x 10 = 100 hours)

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What are the withdrawal methods?

Cold turkey. NRT. Alcohol withdrawal treated with BDZ, AA, use of antabuse (increases sensitivity to ethanol, aversion therapy). Methadone programmes (half-life of 24h)

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What are the adverse effects of antabuse?

Sweating, anxiety, insomnia, cold sweats, severe aches, nausea, vomiting, watery eyes, involuntary muscle spasms.

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What are the issues with methadone?

CYP3A4 variation (rapid metabolizers need a double dose). Inhibitors of CYP3A4 (antifungals, cimetidine, grapefruit juice), inducers (phenytoin, rifampicin).

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Describe the basis of drug testing protocols for ethanol

Roadside breath test – conversion of ethanol to acetic acid at anode and reduction of oxygen at cathode, produces a current which is detected
Legal limit is 35 micrograms per 100 mL breath. Blood test (100 mg per 100 mL blood)

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Outline cannabis metabolism

Smoke drug – one metabolite formed, 9-carboxymetabolite (regulate dose)
Eat drug – another metabolite formed, 11-hydroxymetabolite, more potent, enters brain rapidly, longer duration (can’t regulate dose)

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What are the pharmacokinetics of cannabis? (1)

Half-life of 20 h in blood, cleared via urine. Lipophilicity – in adipose tissues, clearance reduced, 1/3 dose still present after a week, chronic use – urine detection for up to 2 months

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What are the pharmacokinetics of cannabis? (2)

S/E – BP drops rapidly, go pale, pass out, vomit (treatment – sugar water)

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Describe the basis of cannabis detection

Enzyme-linked immunoassay of 9-carboxymetabolite (urine), >100 ng/mL indicates recent use within 7 days. GC-MS used as a confirmatory assay – detect production in liver (denial of use by subject)

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Describe features of heroin metabolism

Lipophilic, 2 acetyl groups, rapid absorption, hCE1 remove acetyl groups, more potent, morphine, readily crosses BBB
Presence of metabolite (hCE1 removing acetyl groups) – shows relapse

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What are gateway drugs?

Drugs that lead to the use of harder drugs (softer drugs - cannabis)

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How do gateway drugs lead to the use of harder drugs?

Hit is not hard enough. Need to get bigger and longer hits (e.g. alcohol). People taking softer drugs are more likely to be exposed to harder drugs.

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State features of narcotic toxicity

All narcotics are toxic. Some have little reported toxicity – cannabis, ketamine. CNS-related toxicity due to site of action. Most treatment is symptomatic. Treatments usually for chronic overdose (e.g. naloxone for opioid overdose)

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Describe features of cannabis toxicity

No cannabis-related deaths recorded. LD50 oral (730-1270 mg/kg). LD50 inhaled (42 mg/kg). Toxicity effect is asphyxiation. Lack of brain toxicity. Teratogenic. Psychiatric issues

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Describe features of alcohol toxicity

LD50 (494.2 g for 70 kg human). Ingested doses can be high (1 standard unit = 10 mL alcohol, 7.9 g). Easy to overdose

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How do you calculate the estimated blood alcohol concentration (EBAC)?

Widmark formula. EBAC = 0.9672 x SD / BW x Wt - Mr x Dp. SD (number of standard drinks). BW (body water constant, 0.68 males, 0.55 females). Wt (body weight in kg). Mr (metabolism constant, 0.015 males, 0.017 females). Dp (drinking period, hours).

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What are the symptoms of low doses of alcohol?

1g/L BAC = 0.1%. Nausea, vomiting, intoxication

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What are the symptoms of high doses of alcohol?

3 g/L = 0.3%. Stupor, loss of consciousness and bladder control, perturbed heart rhythm, possibility of death.

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State the stages of alcoholic liver disease

Healthy liver -> Alcoholic hepatitis (inflammation) -> hepatic steatosis (fat deposition) -> hepatic fibrosis -> hepatic cirrhosis

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Outline the pathogenesis of alcoholic liver disease

Chronic ethanol intake. Acetylhydrate leads to NADH production (lipogenesis, FA oxidation, fatty liver), oxidative stress (hepatocyte injury), lipid fibrosis (collagen synthesis, hepatic stellate cell activation, endotoxins in liver, damage)

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Describe features of ketamine toxicity

Low doses associated with psychoactive properties. Medium-high doses associated with slurred speech, immobilization, amnesia. Long-term damage to the prefrontal cortex (depression, loss of memory/cognitive function) and bladder toxicity (removal of bladde

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Describe features of MDMA toxicity (1)

Neurotoxicity for chronic users. Degeneration of serotonergic neurones. Release of reactive oxygen species in serotonergic neurones. Formation of catechol metabolites.

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Describe features of MDMA toxicity (2)

Formation of catechol leads to formation of redox-cycling quinones (glutathione conjugated and transported across brain to form ROS). Thought to cause PD (doperminergic neurone damage)

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Describe features of heroin toxicity (1)

LD50 (75-600 mg). Variation in purity, toxicity of cutting agents. Co-administered (CYP3A4 inhibitor) drugs e.g. cocaine. Constipation is the most common S/E. Nausea/vomiting can cause death via aspirin of vomit. Respiratory depression (fatal)

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Describe features of heroin toxicity (2)

Regular users get location tolerance. Injection into different area causes sudden increase in dose and toxicity. Toxic leukoencephalopathy (in small % of users)

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Describe features of heroin overdose treatment

Naloxone. IV 2 mins or IM 5 mins. Half-life of 80 mins (might require repeated doses). Dose administer and patient monitored for 2-3 mins. If no effect, repeat exposure every 2 mins until 10 mg has been delivered. If no response, alternative treatments mu

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What are the symptoms of methadone toxicity?

Pinpoint pupils, hypoventilation, drowsiness, coma, rapid onset (co-administration with CYP3A4 inhibitors). Effects can be reversible (except coma)

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Describe features of legal high toxicity

Little safety data. May contain impurities (enantiomers arising during synthesis, other cutting agents). Little safety data on impurities. Legal highs - as dangerous as ecstasy and amphetamines

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Describe features of methedrone toxicity

Very little data No EC50 or LD50. Effects - teeth grinding, dilated pupils, poor concentration and memory, hallucinations, erratic behaviour, increased HR, increased sweating, discolouration of extremities (methaemoglobinaemia)

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What is polynarcotic ingestion?

Long-term users regularly combine drugs to enhance the hit. Due to reduction in the hit achieved with drug alone (e.g. heroin)

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Describe features of benzodiazepines

Taken with alcohol/opiates to increase hit (overdose/toxicity). Metabolized via CYP3A4 and glucuronidation. Inhibitors (antidepressants, antifungals). Inducers (rifampicin, phenytoin, carbamazepine). Substrates of glucuronidation have little effect (loraz

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Describe features of methadone

CYP3A4 rapid metabolizers need to take twice the standard dose. Inhibitors of CYP3A4 (increase methadone concentration) - cimetidine, fluconazole, ketoconazole, flucoxamine, grapefruit juice. Inducers - phenytoin, rifampicin

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Describe features of MDMA

Metabolites of MDMA are suicide inhibitors of CYP2D6. Turns all users into poor metabolizer phenotype. 2D6 is non-inducible, need to wait for synthesis of new 2D6 (can take up to 10 days)

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What is the effect of MDMA on prescribed drugs?

Metabolism of drugs reduced (TCAs). Increased concentration of drug (half-life). Increased toxicity. Removal of drug will reverse symptoms. Prodrugs lose their efficacy. Effects are commensurate with proportion of drug metabolised by 2D6

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Describe features of morphine (clinically used drug of abuse) (1)

Act on mu-opioid receptors. Most effective analgesics. Induce euphoric effects (basis of addiction)

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Describe features of morphine (clinically used drug of abuse) (2)

Structure-activity – 2 OH groups, polar, tertiary amine (analgesic activity), loss/increase of activity depends on substitution of OH

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What are the medical uses of morphine? (1)

Analgesia for acute and chronic pain (severe trauma, MI, end-stage cancer). Relief of coughing & anti-diarrhoeal). ROA (SC, IM, IM, intrathecal, rectal). Less potent than heroin (diacetyl groups of morphine make entry into brain more rapidly)

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What are the medical uses of morphine? (2)

Oral route has lower bioavailability than IV. Extensive metabolism within GIT by CYP2D6. Injection is the preferred ROA. Kaolin/morphine (discontinuted) used to treat diarrhoea, for 12+ years, morphine 0.0092%

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Outline the metabolism of morphine

Via UGT2B7 (inactive), via UGT2B7 (active metabolite, cross BBB – marker for morphine addict (levels higher in chronic addicts)

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State features of morphine addiction

One of the most highly addictive drugs due to high potency, rapid hit, short half-life. Chemical (increased production of morphine 6-glucuronide). Similar effects to heroin

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Describe features of codeine

Prodrug converted to morphine in liver (glucuronidation). Used for short-term treat acute moderate pain (toothache, period pain, headache, neuralgia, rheumatic pain, if not relieved by aspirin ibuprofen and paracetamol alone). POM in pure form. Used in OT

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Describe features of OTC codeine

In combination with paracetamol, ibuprofen, aspirin. 8 mg. Used for 3 days (due to addiction). Not suitable for children under 12 years (severe respiratory distress).

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Describe features of codeine addiction (1)

Effects similar to heroin (warmth, well-being, relaxation). Tolerance of drug (increased doses give the same high). Leads to loss of appetite, constipation, nausea, drowsiness. Large pharmacogenetic variation in metabolism (some patients require higher do

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Describe features of codeine addiction (2)

Lowers BP/RR (worse with alcohol/BDZ/opiates). Treated with naloxone. Toxic dose when combined with another painkiller (problematic with paracetamol). Addiction observed in newborn babies

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Which enzymes are used to metabolism codeine?

UGT2B7 and CYP2D6. 4 phenotypes, PM, IM, EM, UM (impacts on morphine concentration and response/effect)

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Describe features of pethidine (1)

Synthetic opioid (class A). Used for relief of pain in labour. Intrathecal administration. Can slow down labour. Pain of contractions designed to decrease time between contractions. Inhibiting pain reduces positive feedback mechanism

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Describe features of pethidine (2)

Pethidine is the active form. Can be metabolised to norpethidine (neurotoxic), pethidinic acid or norpethidinic acid (inactive)

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Describe features of pethidine addiction

Same effects as heroin. Heavy users appear confused and slow. Develop tolerance over time (higher doses required). Limited use in labour (but issue in USA). Overdose cannot be treated with naloxone

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Describe features of cannabis and MS (illegal therapeutic use)

MS - demyelination disease (myelin sheath is destroyed), autoimmune disease, symptoms. Cannabis seen as being effective in pain relief and treating spasticity associated with MS. But conflicting results (worsens cognition, no effect on disease progression

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Describe features of cannabis oil and childhood epilepsy

Cannabis extracts relieve seizure symptoms but associated with neurological developmental concerns

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Describe features of MDMA and PD (1)

Neurodegenerative disease characterised by the degeneration of the dopaminergic neurones of the substantia nigra. Gives rise to both motor and non-motor symptoms.

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Describe features of MDMA and PD (2)

MDMA can reduce uncontrollable arm and leg movements. Block L-DOPA induced dyskinesia (due to increased 5HT release)

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Describe features of MDMA and PD (3)

Single-dose MDMA can cause neurodegeneration. Degeneration of serotonergic neurones. Systemic administration can lead to release of ROS in serotonergic neurones due to formation of catechol metabolites

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Describe features of MDMA and PD (4)

Formation of catechols leads to the formation of redox-cycling quinones. These are glutathione conjugated and transported across the brain to form ROS. Cause PD later in life (dopaminergic damage, one day (3 tabs) sufficient to cause damage

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What are the MDMA drug interactions? (1)

MDMA binds to CYP2D6 (after 1-2 doses, turns user into poor metaboliser). Effects last for 7-10 days (need to wait for more 2D6 to be synthesised, cannot induce synthesis of 2D6. Increases half-life of POMs

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What are the MDMA drug interactions? (2)

Antipsychotics (chlorpromazine - cognitive depression, coma, respiratory arrest). Antidepressants (TCAs - imipramine - tachycardiac, hallucinations, respiratory arrest, coma, death)

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Describe features of sativex

Treatmentofpainand spasticity in MS and analgesia in patients with advanced cancer. Contains a mix of THC and CBD. First cannabis-based prescription medicine in the world. Not for pain relief

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Describe features of epidiolex

Treatment of Dravet and Lennox Gastaut syndromes (severe form of childhood epilepsy). Doesn't contain THC, only CBD.

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Describe features of nabilone

Synthetic cannabinoid similar to THC. Treatment of nausea and vomiting in patients undergoing cancer chemotherapy

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Describe features of MDMA-based therapies for PD

None developed (have not passed studies/trials). MDMA analogues still under test - UWA-101 lead compound, not psychoactive, better at improving L-DOPA effect than MDMA. Non-toxic in vitro

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Drug Abuse

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