Drugs and Behavior - Exam 3

Effects of chronic psychostimulant use on the brain

• Reduced cortical/PFC activity

  • Neuronal cell death/neurotoxicity → e.g. the loss of dopamine neurons 

  • Also reduced neurogenesis (evidenced in animal research)

  • Behavioral effects & PFC: reduced behavioral inhibition, etc. 

• PD tolerance/downregulation of D1 & D2 receptors → can rebound to some extent with continued abstinence. 

• Formation of gaps in the BBB

Effects of chronic psychostimulant: Psychological

Psychotic symptoms ⇒ sensitized effect

• Monoamine psychosis: symptoms similar to paranoid schizophrenia. 

  • Delusions: persecutory or grandiose

  • Hallucinations: sometimes visual (fleeting shadows, flashing colors) or tactile (formication)

Effects of chronic psychostimulant: Physical

Severe physical consequences: Mostly driven by malnutrition and poor hygiene

• Significant weight loss/malnutrition: psychostimulants reduce appetite.

• Dental issues: bruxism (teeth grinding), dry mouth, tooth wear/decay, periodontal disease → especially due to smoking.

Psychostimulant Dependence & Withdrawal

• Crash/comedown anhedonia: period of depression, lethargy ~24 hours after drug cessation. 

  • Likely due to monoamine depletion from extended use. 

  • Compensatory increases in sleeping and eating. 

• ~1 week-several months: anxiety, agitation, mood depression, and drug cravings. 

• >/=1 year: Long-term cognitive dysfunction —> study of people with methamphetamine use disorder found significant impairments in decision-making w/ concomitant reduction in PFC activity. 

Behavioral Approaches: Treatment for Psychostimulant Misuse

• CBT: relapse prevention strategies

• Contingency management and community reinforcement: 

  • Environmental and lifestyle adjustments + skills training ⇒ replace drug-seeking behavior. 

• Both of these use operant techniques: reinforce abstinence ⇒ tangible reinforcers (e.g. money, goods, services) or social (e.g. praise)

Pharmacotherapeutic Approaches: Treatment for Psychostimulant Misuse

• Currently no good maintenance therapy for psychostimulants

• Mirtazapine (increases monoamine levels = reduces withdrawal symptoms) + naltrexone (opioid receptor antagonist = reduces pleasure) ⇒ shown promise as treatment. 

• Immunization to create antibodies against psychostimulants?

Opioids

Definition: drugs w/ properties similar to opium or its principal psychoactive ingredients (extracts: morphine, codeine, and thebaine) 

• Strong analgesic (“pain killers”) properties, without anesthetic effects. 

• Other names: narcotics, narcotic analgesics

  • Narcoticum (Latin): make stiff/numb

  • Narkoe (Greek): stupor/sleep

  • Over the years, the term narcotic has been bastardized by US law enforcement as a name for any illicit drug w/ misuse potential ⇒ developed a pejorative connotation of drug users.

Natural origin of opioids

Poppy Plants “Papaver somniferum.”

• Principal natural source of opium → produces only 10 days in its life cycle after petals fall off. 

• Intentional scratches made on the seedpod exude milky fluid = latex (“opium milk”) → scraped off, compressed into cakes, and dried = opium. 

• Extracts (psychoactive constituents): Morphine (10%), codeine (2.5%), and thebaine (1%). 

Semi-synthetic opioids: Morphine derived

• Heroin (diacetyl morphine): Morphine + 2 acetyl groups

  • More lipophilic than morphine due to acetyl groups through acetic anhydride synthesis. → better BBB penetration (pharmokinetics improvement!) 

    • 50x more potent than morphine itself because more of it can enter the brain (bioavailability)

  • Heroin is NOT psychoactive in the brain: needs to be metabolized back into morphine in the brain to exert central effects (“prodrugs”) 

• Dilaudid (hospital heroin) 

Semi-synthetic opioids: Codeine derived

Hydrocodone: e.g. Vicodin (analgesic); used as an antiussive (cough suppressant)

Semi-synthetic opioids: Thebaine derived

• Antagonists of opioid receptors: naltrexone, naloxone (narcan) 

• Oxycodone: Percodan (oxycodone + aspirin), Percoset (oxycodone + acetaminophen) 

• Controlled-release oxycodone: e.g. OxyContin.

• Buprenorphine: e.g. suboxone

Synthetic opioids

• Methadone: used in treatment of opioid use disorder → opioid receptor agonist.

• Fentanyl: 30-50x more potent than heroin, 100x more potent than morphine. 

  • 2 mg of fentanyl is a lethal dose for most people. 

• Carfentanyl: 10000x more potent than morphine → animal tranquilizer & anesthetic.

Sources of opioids: Global

Traditionally, licit opioids tend to come from India 

Illicit opioids (e.g. heroin): 

• Past: Golden Triangle dominated illicit heroin trade ⇒ Southeast Asia (Northern Laos, Thailand, and Myanmar) 

  • Now constitutes 1/3 of illicit heroin

• Currently: Afghanistan now leads in illicit heroin trade (⅔)

Designer drug

Modified versions of controlled substances ⇒ Functional/structural analog of another drug

• Improved potency, but variable and uncertain dosing 

• Technically unscheduled drug → not subject to laws. 

• Easier to make and cheaper.

Designer drug: Examples

• Krokodil: derived from codeine → has active ingredient desomorphine

  • Powerful analgesic; “Russian heroin.” 

  • Created because Afghan heroin decreased (due to US war) 

  • Amateur chemistry used to make it results in toxic byproducts (HCl, red phosphorus, etc.) = scaly, gangrenous wounds, rotting of extremities. 

• Late 70s & 80s: Inadvertent by-product of home-synthesized drug (heroin analog) caused Parkinson-like effects in users (“frozen addicts”)

  • Cause: Drug manufactured contained impurity that metabolized into neurotoxin that kills dopamine neurons.

History of Opium: Ancient Use

• Sumerians of Mesopotamia (4000 BC): valued the poppy plant (hul gil) → orally used for medical, analgesic effects. 

• China: the beginning of recreational use after >7000 years of medicinal use. 

  • Origins in Asia and later Mediterranean regions 

  • Traders brought opium to China in 9th century

    • Smoking opium created addictions fueled by British-owned opium from India

    • Led to the Opium Wars between China and Britain (1830-1860s).

History of Opium: Introduction to Europe & the US

• Merchants of Venice brought opium to the West → widespread in mid-1800s. 

  • Advertised as “cures”; causes pipe dreams

  • Available by mail order, grocery stores, etc. => e.g. Laudanum: 10% heroin dissolved in alcohol → cough suppressant, analgesic. 

• 1803: Morphine identified as the principle active ingredient of opium 

History of Opium: Heroin

• End of 19th century: heroin introduced by Bayer Company in Germany

  • Marketed as cough suppressant lacking dependence-producing properties of morphine. 

  • Banned in 1924 → illegal for doctors to prescribe heroin. 

• Misuse potential only fully understood beginning of 20th century → by 1900, 250,000 opioid dependent ppl.

• Harrison Narcotics Act!

History: Contemporary Use of Opioids

• 1960s: Hippie! 

  • Vietnam War: soldiers exposed to high-grade opioid products 

  • Greater public acceptance of drug use and experimentation

• 1970-present: analgesic opioids have become one of the most highly prescribed of all drugs.

  • For a long time, prescription opioids (e.g. OxyContin) were prescribed for even minor things (e.g. headaches) ⇒ peak 2012

  • 2019: ~75% of the 100,000 deaths in 2019 were due to opioids

Opium: Routes of Administration

• Morphine is a weak base (ph ~8.5) → poorly absorbed in GI tract

  • Typically given IV in the hospital

  • Oral route less effective than IV: not rapidly absorbed from the digestive system → effects are slowed but prolonged (steady state levels) 

• Heroin: 

  • Parenteral: IV → fall into disfavor: greater awareness of dirty needles/blood-borned pathogens/disease transmission

  • Snuff (intranasal) 

  • Smoked

Opium: Absorption & Distribution

• Heroine passes BBB easily

  • Heroin and codeine metabolized into morphine to act on opioid receptors. 

• Morphine taken orally → only ~15% get into the brain ⇒ significant first-pass metabolism by CYP3A4 enzymes (liver & gut)

• HOWEVER: Codeine has ~90% bioavailability even if taken orally ⇒ dependent on lipophilicity.

  • Oxycodone and methadone have high bioavailability w/ oral administration.

• Many opioids are bound to blood proteins → extends half lives. 

  • Methadone has a half-life of 10-25 hours in bound form

Opium: Metabolism & excretion

• Morphine half-life: ~2 hours 

• ~90% of morphine is metabolized for elimination in urine and feces via concentration in bile

• ~10% of morphine is excreted in the urine unchanged.

Type of opioid receptors

All of these receptors are GPCRs (metabotropic) ⇒ slower, stronger signal due to signal amplification. 

• Mu:

• Kappa

• Delta

• ORL1 (nociception receptors)

Locations of opioid receptors

Opioid receptors found throughout the brain but concentrated in the midbrain (periaqueductal gray: pain modulation), thalamus, hippocampus, striatum, and olfactory bulb. 

• Mu receptor widely distributed in brain + spinal cord → most important for analgesia and reward/euphoria. 

• Functions of delta and kappa receptors are widely unknown → occur in overlapping brain regions w/ mu receptor. 

• Principle effects of opioids: 

  • Analgesia (periaqueductal gray, spinal cord)

  • Euphoria/reinforcement (VTA/NAc) 

  • Vital life functions: acting on brainstem regions → breathing, vomiting, coughing

Opioids & Mu-Receptors

Opioids have inhibitory effects on neurons = CNS depressants

• Post-synaptic: receptors activate a variety of K+ channels (GIRKS) = efflux of K+ = hyperpolarize the neurons & release firing → opioids are inhibitory NT 

• Pre-synaptic: receptors inhibit voltage-gated Ca2+ channels and activate K+ channels ⇒ decrease in NT release (glutamate, GABA, dopamine & acetylcholine) → opioids are inhibitory neuromodulators

Effect of Opioids on Dopamine Reinforcements

• Beta-endorphins (& exogenous opioids) bind presynaptic MORs on GABA neurons → inhibit Ca2+ channels

• This block GABA release onto DA neurons in VTA → disinhibition of DA neurons. 

• Results in increased DA release in NAc (reinforcement)

Endogenous opioid neuropeptides

• Enkephalins “in the head” (1975) 

  • Greatest affinity for delta receptor

  • First endogenous opioid discovered. 

• Endorphins (“morphine within”) 

  • Originally isolated in 1960s from camel pituitary glands

    • Put in storage, but when enkephalins were identified, he realized what he had found. 

    • Greatest affinity for mu receptor 

• Dynorphins: binds to kappa receptor 

• Nociceptin: binds to ORL1 receptor 

• Endomorphins: binds to mu receptor

Competitive Mu Opioid Receptor Agonists

Morphine, methadone, LAAM (completely synthetic), Fentanyl, etc. 

• Mild-to-strong binding affinity to mu receptors depends on opioid ⇒ heroin & codeine are converted back to morphine in the brain, because they cannot bind to mu themselves. 

• Short-acting forms: powerful opioid “rush” (e.g. heroin, morphine, fentanyl) 

• Long-acting forms: weak opioid “rush” (e.g. codeine, methadone, LAAM) but lasts longer.

Competitive Mu Opioid Receptor Agonists: Primary Effects

1. VLF/respiratory depression

CNS effects:

1. Analgesia

2. Euphoria/reinforcement: due to enhances dopamine release in NAc

Pain components

Sensory component

• Thermoceptive (heat or cold)

• Mechanical (physical damage) 

• Visceral (organ damage) 

• Detection of pain involves circuits in spinal cord + brain (periaqueductal gray) w/ endogenous opioids. 

  • Injury (nociceptive signal) → ascend pain pathway → somatosensory cortex = produces sensation of pain. 

  • Descending projections: Opioids activate neurons in periaqueductal gray (midbrain) → inhibit pain perception neurons → less firing = weaker pain signal 

Emotional component: aversive aspect of pain → opioids (limbic system, extended amygdala) blunts these aversive emotions.

Competitive Mu Opioid Receptor Agonists: Side Effects

• Inhibition of brainstem effectors controlling VLF: Powerful respiratory depression at higher doses → lead to death

• Nausea & vomitting (emesis trigger zone) 

• Constipation → treated with laxatives

• With repeated use = powerful tolerance and physical & psychological dependence. 

Competitive Mu Opioid Receptor Antagonists: Function

Derived from thebain and have no intrinsic efficacy on their own

• Function: compete for opioid binding sites on MORs and prevent other opioids from binding.

Competitive Mu Opioid Receptor Antagonists

• Naloxone: 

  • High MOR binding affinity

  • Short half-life & rapid onset when given IV or intranasally

  • Treat/reverse opioid overdose

• Naltrexone: 

  • Longer duration or action and slower onset (oral) 

  • Curbs euphoric effects of drugs = block MORs in hedonic hotspots 

  • Treat substance use disorders like OUD

Effects of opioid: physiological

• Nausea and vomiting: activation of MORs in brainstem regions controlling emesis. 

• Constipation: due to activation of opioid receptors in gut (inhibitory) = impedes motility ⇒ distension and delays emptying. 

• Profuse sweating 

• Pupilary constriction ⇒ Pinpoint pupils (sign of OD, parasympathetic response)

• Sleep/sedation: produces drowsiness and lethargy, nodding off, “pipe dreams” 

  • Long-term use can cause insomnia 

Effects of opioid: cognitive performance & mood

• Associated with inattention, difficulty concentration, perceptual distortions, memory deficits and executive dysfunction. 

• Calming effect, reduced anxiety, trance-like (feelings of detachment)

  • Reduced emotional rxn to pain

• Intense momentary feeling of euphoria (associated with recreational use of strong opioids)

Opioid Overdose

• Opioids are potent ligands → bind to MORs in areas of the brain like brainstem.

• High doses/potent opioids: Comatose state with pinpoint pupils & severe respiratory depression. 

  • Opioid analgesic overdose is the leading drug poisoning in the US 

  • High level of overdose among heroin users: 

    • Behavioral tolerance & conditioned environment 

    • Mixing of drugs (e.g. fentanyls) 

    • Reuse after a period of abstinence: 

      • PD tolerance (amount of MORs) develops with regular drug use and recovers during abstinence ⇒ past dose becomes way too high & body cannot adjust. 

Opioid Use Disorder

• DSM-5 Diagnostic Criteria: 11 criteria related to impaired control, social impairment, risky use, neuropharmacological changes. 

• Risk factors ⇒ genetic components, young age, history of criminality or depression/anxiety, regular contact with high-risk people or environments. 

Opioid withdrawal

• Not as dangerous as alcohol or barbiturates

• Onset ~6-12 hours from last dose → becomes less severe over time (can disappear within a week) 

  • Restlessness and agitation 

  • Yawning 

  • Chills and sweats: Hyperthermia 

  • Panting: short, jerky breaths 

  • Goose bumps 

  • Stomach, back & leg cramps 

  • Vomiting and diarrhea

  • Twitching of diarrhea

Opioid Pharmacotherapies: Short-term

Short-term detoxification involving pharmacological intervention → antiquated, “legacy” treatment

• Abrupt: antagonist of MORs injected into the body and leads to quick/severe onset of withdrawal symptoms (e.g. naltrexone) 

  • Very unpleasant, can be dangerous 

Opioid Pharmacotherapies: Long-term (Methadone)

Addressing craving and physical dependence factors in body

• Methadone: fully synthetic opioid and full MOR agonist (high affinity, strong activation) 

  • Less addictive than heroin (taken orally as pill or liquid) 

  • Long half-life: 1 dose given under medical supervision lasts all day

    • People may become dependent on methadone and use it for prolonged periods of time. 

  • Significantly reduces withdrawal symptoms + cravings for other opioids. 

  • Reduces exposure to dirty needles/blood-borne diseases (e.g. hepatitis or HIV) 

Opioid Pharmacotherapies: Long-term (Buprenorphine)

Buprenorphine: semisynthetic, partial mu opioid agonist → binds strongly but has weak effect (low efficacy) 

• Mixed agonist that can affect delta and K receptors as well 

• Downside: People still experience withdrawal symptoms + cravings when taking this opioid. 

• Misuse potential if crushed to take through IV or snuff

  • Suboxone: sublingual form ⇒ has buprenorphine (partial agonist) + antagonist naloxone (antagonist) 

    • Taken as pill (correct way): 

      • Naloxone is not well absorbed in the mouth 

      • Buprenorphine is well-absorbed (weak base) 

    • If tablets crushed and snorted/injected = naloxone bioavailability is high ⇒ blocks euphoric effect of buprenophine + lead to withdrawal. 

Schizophrenia

• “Split mind”: disconnect between thought, emotion, and behavior → different aspects of the same personality 

  • With psychotic disorders, people experience psychoses ⇒ disturbances in thoughts & perception = results in loss of touch with reality

• Treatment: behavioral therapy + use of antipscyhotic medications. 

Positive Symptoms of Schizophrenia

Things that are present that shouldn’t be

• Hallucinations: False sensory perceptions → auditory (hearing voices), visual. 

• Delusions: False, unshakeable beliefs held by individual.

  • Persecution

  • Grandeur

  • Control: belief that thoughts and behaviors are controlled by external forces.  

Negative Symptoms of Schizophrenia

Things that should be present but are not

• Difficulty expressing emotions and planning 

• Poverty of speech

• Lack of motivation, anhedonia

• Isolating, social withdrawal

• Disinterest in day-to-day life, flattened emotional response.

Cognitive & Additional Symptoms of Schizophrenia

• Cognitive: 

  • Related to PFC: 

    • Difficulty in attention and applying information to make decisions. 

    • Poor abstract thinking, poor problem-solving. 

    • Deficits in learning + memory

  • Low psychomotor speed 

• Sometimes, patients may be catatonic ⇒ may exhibit odd posing + remain in catatonic positions for hours.

DSM-5 Criteria for Schizophrenia

Two or more symptoms must be present for at least 1 month → at least one must be either 1/2/3

1. Hallucinations

2. Delusions

3. Disorganized speech

4. Grossly disorganized or catatonic behavior

5. Negative symptoms (e.g. affective flattening, avolition, alogia: lack of speech)

Continuous disturbance for 6 months 

Social and/or occupational dysfunction for a significant portion of time. 

Onset of schizophrenia

• Typically in early adulthood (~20.5 years old) → related to PFC development

• Varies based on biological sex: more males experience symptoms in earlier years (16-35), more women than men experience first episode after age 36.

Schizophrenia: Hereditary

• Risk increases with the number of shared genes (relatedness) 

  • Genetic analysis found genes involved in processes like neuronal migration, differentiation, and growth. 

• 48% of concordance in MZ twins → 52% to environment

• Children of 2 parents with schiz: 46%

Schizophrenia: Environmental

• Maternal environment: mothers who are sick during pregnancy = inflammation that affects children’s neuronal development. 

• Birth complication: Excessive cortisol release

Brain abnormalities in schizophrenia: Structural changes

• Cortical grey matter loss (cerebral atrophy): excessive synaptic pruning in perinatal & adolescent periods. 

  • During adolescence: 

    • Average annual rate of cortical gray matter loss in adolescents w/ schizophrenia is >/= 2x as much as healthy adolescents. 

      • Pathologically exaggerated levels of pruning in temporal, parietal lobe, frontal cortex. 

• Ventricular enlargement due to gray matter (brain volume) loss. 

  • Ventricles are filled with cerebrospinal fluid 

Brain abnormalities in schizophrenia: Structural changes (p2)

• Disorganized hippocampal cytoarchitecture: neuron migration issues in development. 

  • Post-mortem immunohistochemistry images show a haphazard arrangement of pyramidal cells in the hippocampus of patients with schizophrenia (vs. normal, organized, parallel, laminar structure) 

  • If neurons are not in the right place = do not make appropriate synaptic connections. 

• Shrinking of dendritic trees leading to connective failures: due to issues with synaptogenesis. 

Etiology of schizophrenia: Two-hit model (First Hit)

Early stage “first hit”: perinatal period 

• Genetic predisposition & gene expression + environmental insults (viruses, toxins, poor nutrition, birth complications, activated immune system) → neurodevelopmental abnormalities (neuron formation, migration, synaptogensis, pruning, apoptosis.) 

Etiology of schizophrenia: Two-hit model (Early signs)

• Latent stage: first few years of life 

  • Early subtle signs: motor abnormalities, apathy, social withdrawal, attentional and information-processing deficits.

Etiology of schizophrenia: Two-hit model (Second hit)

Excessive synaptic pruning (abnormal neuronal connectivity & function) + later environmental insults (stress, substance use, HPA dysfunction) → greater impairment of cognitive functions, worsening of negative symptoms, development of positive symptoms.

Neurodevelopment/hypofrontality hypothesis

• Defects in early PFC development result in reduced PFC activity 

• Evidence: 

  • Less frontal cortex activation in people w/ schizophrenia compared to unaffected twin at rest & during cognitive tasks

  • Appears to be a loss of glutamatergic neurons in particular. 

Dopamine hypothesis: Schizophrenia

• Schizophrenia due to hyperactivation of dopamine circuits → Increased salience to environmental cues 

• Evidence: 

  • Drugs that enhance DA activity can produce positive symptoms of schizophrenia (e.g. monoamine psychosis)

  • First effective anti-psychotic drugs are dopamine D2 receptor antagonists. 

• Contrasting: 

  • HOWEVER, antipsychotic drugs that block D2 receptors take several weeks to work & do not improve negative and cognitive symptoms of schizophrenia. 

Glutamate hypothesis: Schizophrenia

• Schizophrenia due to hypoactivation of glutamate circuits (too little GLU signaling) 

• Evidence: 

  • Drugs that mimic some symptoms of schizophrenia are glutamate NMDA receptor antagonists (e.g. PCP, ketamine block allosteric site = non-competitive) 

• However, inconsistent findings concerning brain glutamate lvls of ppl with schizophrenia and NMDAR modulators have not shown consistent efficacy in treating schizophrenia. 

Hypothesis for Schizophrenia: Mesocorticolimbic system dysregulation

Neurodevelopmental issues leads to loss of PFC glutamatergic projection neurons ⇒ mesocorticolimbic system dysregulation. 

• Reduced glutamate activity in PFC = weakened mesocortical dopamine activation (negative/cognitive symptoms) 

  • Normally: Excitatory glutamate neuron from PFC synapses to dopamine neurons in VTA w/ projections to PFC

  • Less glutamate neuron in PFC = less dopamine release from VTA → PFC. 

• Enhanced mesolimbic dopamine activation (activation) 

  • Glutamate neurons synapse on GABA interneuron in VTA → less GLU neurons to excite GABA = leads to disinhibition of dopamine neurons that project to NAc. 

History of antipscyhotic medications

• Prior to mid-1950s: no effective treatments → frontal lobotomies (separation of frontal lobe from rest of brain) ⇒ only made patients more docile, came at cost of executive function & personality. 

• First was chloropromazine (trade name Thorazine)

  • Dopamine D2 receptor antagonist ⇒ reducing positive symptoms of schizophrenia. 

  • Led to the closure of many psychiatric hospitals in the U.S. ⇒ Thorazine revolution

First generation “typical” antipsychotics

• Developed before 1975 

• Examples: chloropromazine, haloperidol, etc. ⇒ primarily dopamine metabotropic D2 receptor antagonists. 

  • Higher D2R affinity = lower effective dose required. 

• Effective in treating positive symptoms of psychosis, but less effective in treating negative or cognitive symptoms. 

  • May cause serious motor side effects ⇒ in 40% of users. 

    • “Extrapyramidal” motor side effects = linked with nigrostriatal motor system issues (e.g. basal ganglia) NOT motor cortex. 

    • Acute dystonia (spasms of muscles), akathisia (motor restlessness), Parkinsonism (rigidity, tremor), tardive dyskinesia (oral-facial tics)

Second-generation “atypical” antipsychotics

• Recently developed (1980s-current) 

  • Clozapine, ziprasidone 

• Weak affinity to dopamine D2 receptors ⇒ fewer adverse EPS side effects. 

• Antagonism of dopamine D3 & D4s (lower concentration in basal ganglia) and serotonin 2A receptors (high affinity) 

  • Serotonin modulation (in PFC) = improve mood and reduce risk of EPS ⇒ modulate DA motor pathways. 

• Atypicals can alleviate positive, negative, and cognitive symptoms of schizophrenia when they work w/o motor side effects. 

Issues with atypicals

• Issues: 

  • Only ⅓ of individuals respond well to atypical antipsychotics. 

  • Unwanted metabolic side effects ⇒ weight gain (5-10% bodyweight gain on average), sedation, and more. 

Third-generation Dopamine System Stabilizers (DSS)

• Aripiprazole (trade name Abilify) was approved by FDA in 2002 

  • Competitive DA receptor partial agonist → modulating DA activity at D2, D3 and D4 receptor subtypes. 

    • High affinity for DRs, but activates receptor to a lesser degree (reduced efficacy) compared to dopamine. 

• Function: stabilizes regional DA activity

  • In mesolimbic system where DA activity is too high: weakly activates DA receptors & prevents endogenous dopamine from binding ⇒ reduces positive symptoms. 

  • In mesocortical pathway = mildly enhances DA signaling ⇒ reduces negative & cognitive symptoms. 

DSS side effects

• Motor restlessness (akathisia), though with greater tolerability. 

• Minor weight gain 

• Insomnia 

• Nausea

• GI issues 

Limitations: not as effective with severe schizophrenia

Administration: Anti-psychotics

Taken orally or slowly dissolving depot injection (can last up to a month) 

• Effects of antipsychotics are not accelerated by IV injection because effects typically take several days/weeks to develop (metabotropic, can influence gene expression)

PK: Antipsychotics

Absorption & distribution: 

• Lipophilic are lipophilic and readily absorbed from the digestive tract and distributed throughout the body, easily crossing bloodbrain and placental barriers

• Often absorbed in body fat and released slowly 

Metabolism & elimination: 

• Cytochrome P450 enzymes

• Long halflives (11-58 hours, particularly for typicals)

Physical Effects of Antipsychotics: Neuroleptic EPS

First-generation “typical” antipsychotics cause neuroleptic (motor) EPS in 40% of patients → resemble symptoms of Parkinson’s disease:

• Dulled facial expression, muscle rigidity and tremor in the limbs, slowing or loss of coordinated movement, weakness in the extremities, etc. 

• Tardive dyskinesia—involuntary tic-like repetitive movements of the face that can occur dozens of times per minute 

Other physical effects of antipsychotics

• Temperature regulation (easily influenced by changes in the environment), weight gain, changes in cardiac function, and blood pressure 

• Some first- and second-generation antipsychotics increase prolactin levels, which can lead to: 

  • Biological females: menstrual irregularities, milk production, infertility, decreased libido 

  • Biological males: gynecomastia, erectile dysfunction, low T / libido, infertility

Subjective effects of antipsychotics

Particularly for first and second generation

• Tiredness 

• Slowed and confused thinking 

• Trouble concentrating

• Anxiety and irritability

•  Internal restlessness, but physical restraint due to movement difficulties 

• Results in difficulty with patient compliance 

• Antipsychotics do not result in significant mesolimbic DA release, and are not reinforcing.

Performance effects of antipsychotics

• Inconclusive effects on cognitive performance overall 

• Sedating effects 

• Reduced sexual interest and performance (low libido)

• Possible abnormal menstrual cycles and infertility in women; low T in men

Tolerance, Lethality, Withdrawal: antipsychotics

Tolerance: 

• Tolerance doesn’t develop → therapeutic dose often maintained for years without decrease in effectiveness. 

• Extremely safe with high TI (~100-1000); Practically impossible to overdose

Withdrawal: 

• Physical dependence is rare or very mild 

• Possible exaggeration of psychotic symptoms, headache, and nausea when drug is withdrawn but fairly uncommon.

Cannabinoids: Legal designations

Cannabis: “umbrella” term ⇒ refers to plant genus (C. sativa and C. indica)

• Hemp: cannabis plant with =/<0.3% THC → used for strong fibers 

• Marijuana: cannabis plant w/ >0.3% THC

C. sativa

• Hemp plant: rope, linen, paper from stalks → Hemp has higher CBD content than marijuana. 

  • Male plants usually used for hemp or breeding. 

• Marijuana is C. sativa with >0.3 THC 

Cannabinoid Source

• Cannabinoids found in leaves (low THC) and female flowers (high THC)

  • Cannabis buds: form appendages called “trichomes” that secrete droplets of “resin” → composed of cannabinoids (fatty acids = oil texture)

    • Female plants have larger cannabis bud/flower! → typically cultivated for resin. 

    • THC (psychoactive) and >100 other cannabinoids like cannabidiol (CBD; not psychoactive)

Cannabis indica

• Grown in India and surrounding regions 

• Usually higher levels of CBD and lower THC → however, nowadays, cultivated strains offer higher THC.

Uses of cannabis

• Leaves (low THC) and buds (high THC) are smoked or psychoactive components of resin can be ingested (“edibles”) 

• Pollen-collecting resin from female plant: 

  • Produced by plant to capture pollen + protect seeds

    • Dried: hashish → concentrated resin from plants

    • Hash oil: resin boiled in alcohol and then filtered ⇒ concentrates the psychoactive chemicals. 

Sinsemilla

Sinsemilla female plants: unfertilized female plant produces flowers but not seeds → greatest resin producers. 

• Growing female plants away from male plants → reproductive overdrive to attract pollen (even though there are none) ⇒ increased bud growth.

History: Early cannabis use

• Stone Age/Upper Neolithic: Archeological evidence from Taiwan of hemp used to make rope & cloth. 

•  2350 BCE: Egyptian Pyramid Texts carved into pyramids mention plant that made rope + treating glaucoma and inflammation. 

  • Hair samples taken from Egyptian mummies indicate higher levels of cannabis use. 

• Over 12,000 years ago: Cannabis may have originated in Central Asia → first cultivated for fiber in China and India 

  • Medical use in China; religious use in India. 

• 1000 CE: Hashish use in Arab world. 

History (Cannabis): American & European use

• Mid-1600s: Colonia; America Cannabis (HEMP) Use

  • Colonies produced rope, cloth, canvas, sacks and paper from hemp leading up to Revolutionary War

• 1800s: European recreational cannabis use

  • French troops returning from Egypt brought hashish home (1800) → began to be imported 

  • Club des Hachichins (1846): a book club of high society artists → revelers consumed hashish and wrote about experiences. 

    • Most were not aware of association between hemp and hashish. 

  • England: Traces of cannabis found in Shakespeare’s pipes. 

History of Cannabis Use: 20th century

U.S. Recreational Cannabis Use & Subsequent Propaganda

• Term “marihuana” was promoted in 1930s as a racist attempt to demonize its use = link to immigrants from Mexico 

• Reefer Madness: U.S. propaganda film → Cannabis as “Devil’s weed” ⇒ use  leads to unlawfulness/death/destruction. 

• Nixon’s “War on Drugs”: Cannabis as a “gateway drug” 

→ Propaganda = regulations = criminalized possession.

U.S. Cannabis Legislation

• 1850: first listed in US Pharmacopoeia (USP) 

• 1910: “Recreational” use for psychoactive effects begins to emerge in the U.S. 

• 1937: Marijuana Tax Act → not made illegal, but high taxes imposed on use and distribution. 

• 1942: Removed from USP → claims that there is no medical use. 

• 1970: Controlled Substances Act 

  • Tax Act repealed but marijuana said to have no medical use. 

  • Beginning mid-1970s ⇒ >12 states decriminalized possession of small amounts of cannbis + legal medical use in California. 

Phytocannabinoids

• THC: psychoactive, analgesic (nerve pain, etc.), anti-emetic (anti-convulsant), and appetite-stimulating effects. 

  • Partial agonist of CB1

  • Isolated from cannabis in 1964 in Israel 

  • Primary psychoactive compound

  • Content higher in the resins (hashish) 

  • Selection for this compound = 10x increase in THC content since 1960

• Other: Cannabidiol (CBD) and cannabinol (CBN)

Extracted phytocannabinoids: Sativex

Sativex: whole plant medicinal cannabis extract & sprayed under the tongue. 

• Developed to treat multiple sclerosis and neuropathic pain 

• Not FDA approved (available in UK) 

• 1:1 radio of THC: CBD

Extracted Phytocannabinoids: Epidiolex

Epidiolex: 

• CBD 

• Treats seizures in children ⇒ FDA approved for severe forms of epilepsy (Lennox-Gastaut syndrome, Dravet syndrom) in children aged 2+ 

  • First FDA approved drug w/ cannabis derivative.

Synthocannabinoids

Recreational cannabinoid-like chemicals ⇒ “designer”

• Most are produced in China 

• Unregulated in U.S. market initially in early 2000s → initially sold as herbal incense ( => synthocannabinoids sprayed onto plants)

  • 2012 Synthetic Drug Abuse Prevention Act ⇒ placed in Schedule I 

• Can contain many other drugs (including hallucinogens like PCP), methamphetamine-like compounds, and toxic products (rat poison, embalming liquid) 

• Effects: 40-100x more potent than THC 

  • “High” 

  • Produce extreme anxiety, confusion

  • Psychotic effects ⇒ e.g. paranoia and hallucinations. 

Endocannabinoids

Cannabinoid receptor agonists synthesized by the body. => Fatty acids synthesized from phospholipids in the cell membrane

1. Arachidonoyl ethanolamide (anandamide) 

• Partial-agonist of CB1 → lower efficacy (ceiling effects) 

• Discovered in 1994 (“internal bliss”) 

2. 2-arachidonoylglycerol (2-AG) 

• Full agonist of CB1 → higher efficacy

Mechanisms of endocannabinoids

Retrograde messengers

• Are released from post-synaptic cell to active presynaptic CB1 receptors

  • Produce complex effects in the brain 

  • Not a classic neurotransmitter ⇒ modulates the NT release presynaptically (homeostatic property) 

    • Example: 

1. One neuron fires too often = excessive excitation of postsynaptic neuron 

2. Activation of homeostatic property in post- neuron = synthesizes and releases endocannabinoids. 

3. Binds to receptors on pre- ⇒ inhibition + regulate the activity of presynaptic neuron 

Cannabinoid receptor: CB1

• First identified in 1988 and occur mainly in the brain and less in PNS. 

• Endocannabinoid effects of presynaptic receptors: 

  • CB1 are metabotropic (like MORs) → work via G-proteins to: 

    • Inhibit Ca2+ channels

    • Open K+ channels 

→ Overall inhibitory

• Found on axon terminals of most GABA-ergic neurons, but also on other neurons (e.g. NE, DA, 5HT)

• Work as “on-demand” signal ⇒ transient but HIGHLY SPECIFIC signaling between neurons.

Effects of cannabinoids on CB1 in different brain areas:

• Amygdala: stress, anxiety ⇒ relaxation.

• Ventral striatum: euphoria, reinforcement

• Dorsal striatum + ventral striatum: motor coordination ⇒ cannabinoids = issues. 

• Cerebral cortex ⇒ effects: altered cognition, memory disruption, sensory/perceptual disturbances. 

• Periaqueductal gray: involved in pain modulation ⇒ cannabinoids as analgesics

• Hypothalamus: direct influence on appetite ⇒ stimulation

THC effects on CB1

• Partial CB1 receptor agonist → milder “ceiling” effects, psychoactive effects plateau

• Activates CB1 receptors non-selectively (floods entire brain) ⇒ NOT a retrograde NT. 

• Disrupts temporal precision of natural signaling

• Global changes in sensory, memory, motor, cognitive & reward processing.

Cannabinoid Receptors: CB2

Occur in immune system, and other tissue (bone, adipose cells, GI tract) ⇒ can also be found in the brain, but less.

Mechanism of Cannabinoid-Induced DA Release

1. Stimulation of CB1 by THC on GABA terminals → reduce GABA amount released on DA projections. 

2. Disinhibition of DA → increased DA release in NAc → reinforcing effects of THC. 

→ acute increases in DA release elicited by THC are relatively small compared to other psychoactive substances.

Cannabinoid: Absorption (Oral)

• Cannabinoids are WEAK ACIDS & highly lipid-soluble. 

• Oral administration (“edibles”) 

  • Un-ionized in the gut. → Good, slow, steady absorption from stomach/intestine 

    • Significant first-pass metabolism 

  • THC is converted into fat due to lipophilic properties. 

  • Peak effects: 1-3 hours after ingestion.

Cannabinoids Absorption: Inhalation

• Inhalation (smoke or vapor) 

  • THC peaks in blood by 6-10 minutes

  • Peak behavioral effects: 30-60 minutes

  • Absorption increased by depth of inhalation NOT duration of holding the smoke in. 

  • Time course: 

    • Blood THC levels decline rapidly after smoking cannabis

      • Falls to ~60% by 15 min, ~20% by 30 minutes 

    • Complete elimination is slow ⇒ persistence in fat tissues (>2 weeks)

Cannabinoids: Distribution

• All areas of the body (blood flow) 

• Bioavailability: 10-35% via inhalation; 4-12% via ingestion 

• Blood half-life: 1-3 days (occasional use); 5-12 days (chronic use) 

  • THC remains in body fat for many weeks. 

• Subjective intensity of “high”: 

  • IV + Smoked: intense early on, then decreases over time rapidly. 

  • Oral: slower onset, longer duration, overall rated “high” is lower.

Cannabinoids: Metabolism & excretion

• Starts as soon as cannabinoids enter the body

  • Delta 9-THC converted into 11-hydroxy-delta 9-THC ⇒ more active/lipophilic than THC, crosses BBB more easily, a full agonist of CB1. 

  • Creates ~100 mostly inactive metabolites. 

• Half-life of cannabinoids varies considerably between individuals ⇒ affected by dose, frequency of use, etc. 

  • Full elimination of cannabinoids from the body ⇒ 12*6 (half-lives) = 72 days in chronic users.

Acute Physiological Effects: Cannabis

• Cardiac acceleration, dry mouth, reddening of eyes (vasodilation)

  • Drooping of eyelidss are common (muscle relaxation → CB1 receptor signaling) = “stoned” 

• May cause drowsiness + increased sleep time. 

  • Higher doses can interfere with sleep 

• Often causes hyperphagia (“munchies”): cannabinoids interact with appetite control neurons in hypothalamus 

  • Cannabinoid signaling interfere w/ NPY neurons (that typically inhibits appetite) → disinhibition leads to “hunger” signaling. 

Acute Psychological/Subjective Effects: Cannabis

Mood: Euphoria, relaxation, giddiness, and variations in mood (typically elevated mood/excessive cheerfulness & contagious laughter)

• Some people can report anxiety + adverse effects (paranoia or depression)

  • Dose-dependent: larger doses ⇒ increased likelihood of adverse effects (disinhibition of circuits in the amygdala for example) 

  • Strain of cannabis & THC:CBD ratio

    • CBD: antipsychotic properties, calming effects ⇒ low CBD levels + high THC levels = increase likelihood of paranoia/depression. 

  • Individual differences: 

    • Genes can influence response  

    • Personality

    • Psychological states 

Acute Subjective Perceptual Effects: Cannabis

• Sensory alterations due to THC’s effects on CB1s: 

  • Affect areas of sensory processing: sensory cortices like inferior colliculus and posterior thalamus. 

  • Leads to incongruencies (things don’t look/sound the way it should) = funny. 

• Temporal disintegration: likely involves cerebellum (usually fine-tune rhythmic activity = estimate time) ⇒ high = time feels elongated. 

• Others: intensification of colors, blending of patterns & objects. 

Cognitive impairments: Cannabis

Cognitive impairments in attention + memory (STM formation & removal); interference with visuomotor skills (e.g. attention needed to drive) 

• Unlike alcohol, cannabis users report awareness of driving impairments 

• Memory: 

  • No effects on recall of well-learned or recognition memory. 

  • Disrupt short-term memory: 

    • Recall of words or narrative material

    • Temporal disintegration: 

      • Loss of ability to “keep things in mind” 

      • Users often report disjointed conversations.