Drug use and abuse

Pharmacokinetics
Basic understanding of drug action at a neuronal level – pharmacokinetics is a branch of
pharmacology dedicated to the determination of the fate of substances administered externally to
a living organism. The substances of interest include pharmaceutical agents, hormones, nutrients,
and toxins.

Pharmacokinetics includes the study of the mechanisms of absorption and distribution of an

administered drug, the rate at which a drug action begins and the duration of the effect, the
chemical changes of the substance in the body (e.g. by metabolic enzymes such as CYP or UGT
enzymes) and the effects and routes of excretion of the metabolites of the drug.

ADME
Pharmacokinetics is divided into several areas including the extent and rate of absorption,
distribution, metabolism and excretion. This is commonly referred to as the ADME scheme:
 Absorption - the process of a substance entering the blood circulation.
 Distribution - the dispersion or dissemination of substances throughout the fluids and tissues
of the body.
 Metabolism (or Biotransformation) - the irreversible transformation of parent compounds
into daughter metabolites.
 Excretion - the removal of the substances from the body. In rare cases, some drugs
irreversibly accumulate in body tissue.

Plasma concentration curves

Drugs injected intravenously are removed from the plasma through two primary mechanisms: (1)
Distribution to body tissues and (2) metabolism + excretion of the drugs. The resulting decrease of
the drug's plasma concentration follows a biphasic pattern.

Substances used for medical purposes

Antipsychotics
An antipsychotic (or neuroleptic) is a tranquilizing psychiatric medication primarily used to manage
psychosis (including delusions or hallucinations, as well as disordered thought), particularly in
schizophrenia and bipolar disorder, and is increasingly being used in the management of non-
psychotic disorders. A first generation of antipsychotics, known as typical antipsychotics, was
discovered in the 1950s. Most of the drugs in the second generation, known as atypical
antipsychotics, have been developed more recently, although the first atypical antipsychotic,
clozapine, was discovered in the 1950s and introduced clinically in the 1970s. Both generations of
medication tend to block receptors in the brain's dopamine pathways, but antipsychotic drugs
encompass a wide range of receptor targets.

A number of harmful and undesired (adverse) effects have been observed, including lowered life
expectancy, extrapyramidal effects on motor control – including akathisia (an inability to sit still),
trembling, and muscle weakness – weight gain, decrease in brain volume, enlarged breasts
(gynecomastia) in men and milk discharge in men and women (galactorrhea due to
hyperprolactinaemia), lowered white blood cell count (agranulocytosis), involuntary repetitive body
movements (tardive dyskinesia), diabetes, sexual dysfunction, a return of psychosis requiring
increasing the dosage due to cells producing more neurochemicals to compensate for the drugs
(tardive psychosis), and a potential for permanent chemical dependence leading to psychosis worse
than before treatment began, if the drug dosage is ever lowered or stopped (tardive dysphrenia).
Most of these side-effects disappear rapidly once the medication is discontinued or reduced, but
others, particularly tardive dyskinesia, may be irreversible.

Temporary withdrawal symptoms including insomnia, agitation, psychosis, and motor disorders may
occur during dosage reduction of antipsychotics, and can be mistaken for a return of the underlying
condition.

Medical uses
Common conditions with which antipsychotics might be used include schizophrenia, bipolar disorder
and delusional disorder. Antipsychotics might also be used to counter psychosis associated with a
wide range of other diagnoses, such as psychotic depression.

In addition, "antipsychotics" are increasingly used to treat non-psychotic disorders. For example,
they are sometimes used off-label to manage aspects of Tourette syndrome or autism spectrum
disorders. They have multiple off-label uses as an augmentation agent in "treatment-resistant"
depression or OCD.

A survey of children with pervasive developmental disorder found that 16.5% were taking an
antipsychotic drug, most commonly to alleviate mood and behavioral disturbances characterized by
irritability, aggression, and agitation. Recently, risperidone was approved by the US FDA for the
treatment of irritability in children and adolescents with autism.[17]

Due to the chronic nature of the treated disorders, antipsychotic medications, once started, are
seldom discontinued, and the aim of the treatment is often to gradually reduce dosage to a
minimum safe maintenance dose that is enough to control the symptoms. Only when the side-
effects have become too severe and/or a patient has been symptom-free for a long period of time is
discontinuation carefully attempted. Improper discontinuation or abrupt restarting of neuroleptics
have been shown to cause dysfunction in regions of the brainstem as well as dysfunction of the
autonomic nervous system.

Common antipsychotics
First generation antipsychotics
Butyrophenones
 Haloperidol (Haldol, Serenace)
 Droperidol (Droleptan, Inapsine)

Phenothiazines
 Chlorpromazine (Thorazine, Largactil)
 Fluphenazine (Prolixin) - Available in decanoate (long-acting) form
 Perphenazine (Trilafon)
 Prochlorperazine (Compazine)
 Thioridazine (Mellaril)
 Trifluoperazine (Stelazine)

Thioxanthenes
 Chlorprothixene (Cloxan, Taractan, Truxal)
 Clopenthixol (Sordinol)
 Flupenthixol (Depixol, Fluanxol)
Second generation antipsychotics
 Clozapine (Clozaril) - Requires weekly to biweekly complete blood count due to risk of
agranulocytosis.
 Olanzapine (Zyprexa) - Used to treat psychotic disorders including schizophrenia, acute
manic episodes, and maintenance of bipolar disorder
 Risperidone (Risperdal) -Divided dosing is recommended until initial titration is completed,
at which time the drug can be administered once daily. Used off-label to treat Tourette
syndrome and anxiety disorder.
 Quetiapine (Seroquel) - Used primarily to treat bipolar disorder and schizophrenia, and "off-
label" to treat chronic insomnia and restless legs syndrome; it is a powerful sedative.

Third generation antipsychotics

 Aripiprazole (Abilify) - Mechanism of action is thought to reduce susceptibility to metabolic
symptoms seen in some other atypical antipsychotics.[78] The extent to which these effects
differ from other atypical antipsychotics is debated.[79]
 Partial agonists of dopamine.

Mechanism of action
All antipsychotic drugs tend to block D2 receptors in the dopamine pathways of the brain. This means
that dopamine released in these pathways has less effect. Excess release of dopamine in the
mesolimbic pathway has been linked to psychotic experiences. It is the blockade of dopamine
receptors in this pathway that is thought to control psychotic experiences.

Typical antipsychotics are not particularly selective and also block dopamine receptors in the
mesocortical pathway, tuberoinfundibular pathway, and the nigrostriatal pathway. Blocking D2
receptors in these other pathways is thought to produce some of the unwanted side effects that the
typical antipsychotics can produce. They were commonly classified on a spectrum of low potency to
high potency, where potency referred to the ability of the drug to bind to dopamine receptors, and
not to the effectiveness of the drug. High-potency antipsychotics such as haloperidol, in general,
have doses of a few milligrams and cause less sleepiness and calming effects than low-potency
antipsychotics such as chlorpromazine and thioridazine, which have dosages of several hundred
milligrams. The latter have a greater degree of anticholinergic and antihistaminergic activity, which
can counteract dopamine-related side effects.

Antidepressants
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major
depression and dysthymia and anxiety disorders such as social anxiety disorder. Drugs including the
monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants
(TeCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake
inhibitors (SNRIs) are most commonly associated with the term.

Most typical antidepressants have a delayed onset of action (2–6 weeks) and are usually
administered for anywhere from months to years. Despite the name, antidepressants are often used
to treat other conditions, such as anxiety disorders, obsessive compulsive disorder, eating disorders,
chronic pain, and some hormone-mediated disorders such as dysmenorrhea. Alone or together with
anticonvulsants (e.g., carbamazepine or valproate), these medications can be used to treat
attention-deficit hyperactivity disorder (ADHD) and substance abuse by addressing underlying
depression. Also, antidepressants have been used sometimes to treat snoring and migraines.

Types
Selective serotonin reuptake inhibitors
The Selective serotonin reuptake inhibitors (SSRIs) are the class of antidepressants commonly used as
the first line treatment for depression because they have a favorable side-effect profile and low
toxicity. Depression can be treated by increasing the amount of available serotonin, a chemical used
in the brain to transmit signals between neurons. SSRIs are said to work by preventing the reuptake
of serotonin (also known as 5-hydroxytryptamine, or 5-HT) by the presynaptic neuron, thus
maintaining higher levels of 5-HT in the synapse. This class of drugs includes:
 Citalopram (Celexa, Cipramil)
 Escitalopram (Lexapro, Cipralex, Seroplex, Lexamil)
 Fluoxetine (Prozac, Sarafem, Symbyax)
 Paroxetine (Paxil, Aropax)
 Sertraline (Zoloft)

These antidepressants typically have fewer adverse effects than the tricyclics or the MAOIs, although
such effects as drowsiness, dry mouth, nervousness, anxiety, insomnia, decreased appetite, long-
term weight gain and decreased ability to function sexually may occur. Some side-effects may
decrease as a person adjusts to the drug, but other side-effects may be persistent.

Serotonin-norepinephrine reuptake inhibitors

Serotonin-norepinephrine reuptake inhibitors (SNRIs) are a newer form of antidepressant that work
on both norepinephrine and 5-HT. They typically have similar side-effects to the SSRIs, though there
may be a withdrawal syndrome on discontinuation that may necessitate dosage tapering. These
include:
 Duloxetine (Cymbalta)
 Venlafaxine (Effexor)

Changing the balance of serotonin and norepinephrine would help the brain cells send and receive
messages; therefore boosting the mood. That also is the main reason why these types of
medications are called dual re-uptake inhibitors.

There are some general side effects with the use of SNRIs which includes:
 Nausea
 Dry Mouth
 Dizziness
 Insomnia (numbness)
 Sleepiness
 Constipation
 Increased Blood Pressure
 Excessive Sweating
 Tremor
 Headache
 Agitation
 Muscle Weakness
Norepinephrine (noradrenaline) reuptake inhibitors
Norepinephrine (noradrenaline) reuptake inhibitors (NRIs) act via norepinephrine (also known as
noradrenaline). NRIs are thought to have a positive effect on the concentration and motivation in
particular. These include:
 Atomoxetine (Strattera)
 Mazindol (Mazanor, Sanorex)

Norepinephrine-dopamine reuptake inhibitors

Norepinephrine-dopamine reuptake inhibitors inhibit the neuronal reuptake of dopamine and
norepinephrine (noradrenaline).[17] These include:
 Bupropion (Wellbutrin, Zyban)

Selective serotonin reuptake enhancers

 Tianeptine (Stablon, Coaxil, Tatinol)

Norepinephrine-dopamine disinhibitors
Norepinephrine-dopamine disinhibitors (NDDIs) act by antagonizing the serotonin 5-HT2C receptor,
which normally acts to inhibit norepinephrine and dopamine release, thereby promoting outflow of
these neurotransmitters.
 Agomelatine (Valdoxan, Melitor, Thymanax)

Tricyclic antidepressants
Tricyclics block the reuptake of certain neurotransmitters such as norepinephrine (noradrenaline)
and serotonin. They are used less commonly now due to the development of more selective and
safer drugs.

Side-effects include increased heart rate, drowsiness, dry mouth, constipation, urinary retention,
blurred vision, dizziness, confusion, and sexual dysfunction. However, tricyclic antidepressants are
still used because of their effectiveness, especially in severe cases of major depression. As well,
people who cannot tolerate the side-effects of SSRIs, in particular agitation, may do better on
tricyclics. The tricyclics include:
Tertiary amine tricyclic antidepressants:
 Clomipramine (Anafranil)
 Doxepin (Adapin, Sinequan)
 Imipramine (Tofranil)
Secondary amine tricyclic antidepressants
 Desipramine (Norpramin)
 Nortriptyline (Pamelor, Aventyl, Noritren)

Monoamine oxidase inhibitor

Irreversible monoamine oxidase inhibitors (MAOIs) may be used if other antidepressant medications
are ineffective. MAOIs work by blocking the enzyme monoamine oxidase, which breaks down the
neurotransmitters dopamine, serotonin, and norepinephrine (noradrenaline). MAOIs can be as
effective as tricyclic antidepressants, although they are generally used less frequently because they
have a higher incidence of dangerous side-effects and interactions. A new generation of MAOIs has
been introduced; moclobemide (Manerix), known as a reversible inhibitor of monoamine oxidase A
(RIMA), which is as effective as SSRIs and tricyclic antidepressants, in depressive disorders, [19] acts in
a more short-lived and selective manner and does not require a special diet. The MAOI group of
medicines include:
 Isocarboxazid (Marplan)
 Moclobemide (Aurorix, Manerix)
 Phenelzine (Nardil)
 Selegiline (Eldepryl, Emsam)

Anxiolytics
An anxiolytic (also antipanic or antianxiety agent) is a drug used for the treatment of anxiety and its
related psychological and physical symptoms. Anxiolytics have been shown to be useful in the
treatment of anxiety disorders.

Beta-receptor blockers such as propranolol and oxprenolol, although not anxiolytics, can be used to
combat the somatic symptoms of anxiety. Anxiolytics are also known as minor tranquilizers.

Types of anxiolytics/anti-anxiety drugs
Benzodiazepines
Benzodiazepines are prescribed for short-term relief of severe and disabling anxiety.
Benzodiazepines may also be indicated to cover the latent periods associated with the medications
prescribed to treat an underlying anxiety disorder. They are used to treat a wide variety of
conditions and symptoms and are usually a first choice when short-term CNS sedation is needed.
Longer-term uses include treatment for severe anxiety. There is a risk of a benzodiazepine
withdrawal and rebound syndrome after continuous usage for longer than two weeks, and tolerance
and dependence may occur if patients stay under this treatment for longer. There is also the added
problem of the accumulation of drug metabolites and adverse effects.[4] Benzodiazepines include:
 Alprazolam (Xanax)
 Chlordiazepoxide (Librium)
 Clonazepam (Klonopin, Rivotril)
 Diazepam (Valium)
 Etizolam (Etilaam)
 Lorazepam (Ativan)
 Oxazepam (Serax)

SSRIs
Selective serotonin reuptake inhibitors or serotonin-specific reuptake inhibitor[6] (SSRIs) are a class
of compounds typically used as antidepressants in the treatment of depression, anxiety disorders,
and some personality disorders. SSRIs are primarily classified as antidepressants and typically higher
dosages are required to be effective against anxiety disorders than to be effective against depression
but nevertheless most SSRIs have anxiolytic properties, but are anxiogenic when first initiating
treatment, and in some individuals continue to be anxiety-provoking. For this reason, a low dose of a
benzodiazepine is often used for several weeks when initiating SSRI/SNRI therapy in order to
counteract the initial anxiety caused by the drugs until the therapeutic delay of the SSRI/SNRI is
finished and the drug becomes effective. Older tricyclic antidepressants (TCAs) are very anxiolytic as
well, however, side effects are greater. Examples include: imipramine, doxepin, amitriptyline, and
the unrelated trazodone. Mono-amine oxidase inhibitors (MAOIs) are very effective for anxiety, but
due to drug dangers, are rarely prescribed. Examples include: Nardil and Parnate.

Barbiturates
Barbiturates exert an anxiolytic effect linked to the sedation they cause. The risk of abuse and
addiction is high. Many experts consider these drugs obsolete for treating anxiety but valuable for
the short-term treatment of severe insomnia, though only after benzodiazepines or non-
benzodiazepines have failed. They are rarely prescribed anymore.

Mood stabilisers
A mood stabilizer is a psychiatric medication used to treat mood disorders characterized by intense
and sustained mood shifts, typically bipolar disorder. Used to treat bipolar disorder,[1] mood
stabilizers suppress swings between mania and depression. Mood-stabilizing drugs are also used in
borderline personality disorder[2] and Schizoaffective disorder.

Anticonvulsants
Many agents described as "mood stabilizers" are also categorized as anticonvulsants. The term
"anticonvulsant mood stabilizers" is sometimes used to describe these as a class.[3] Although this
group is also defined by effect rather than mechanism, there is at least a preliminary understanding
of the mechanism of most of the anticonvulsants used in the treatment of mood disorders.
 Valproic acid (Depakene), divalproex sodium (Depakote), and sodium valproate (Depacon,
Epilim)
 Lamotrigine (Lamictal) – Particularly effective for bipolar depression.
 Carbamazepine (Tegretol)
 Oxcarbazepine (Trileptal) - effective in about one-half of patients with bipolar disorder and
be well tolerated.
 Riluzole -Riluzole is a potential candidate for bipolar disorder therapy.
 Gabapentin (Neurontin) is not FDA approved as a treatment for bipolar disorder.
 Topiramate (Topamax) is not FDA approved for bipolar disorder, either; and a 2006
Cochrane review concluded that there is insufficient evidence on which to base any
recommendations regarding the use of topiramate in any phase of bipolar illness.

Other
 Lithium – Lithium is the "classic" mood stabilizer, the first to be approved by the US FDA, and
still popular in treatment. Signs and symptoms of toxicity include nausea, vomiting, diarrhea,
and ataxia.[9] The less common side-effects of using lithium are blurred vision, slight tremble
in the hands, and a feeling of being mildly ill. In general, these side-effects occur in the first
few weeks after commencing lithium treatment. These symptoms can often be improved by
lowering the dose.[10]
 Some atypical antipsychotics (risperidone, olanzapine, quetiapine, paliperidone, and
ziprasidone) also have mood stabilizing effects[11] and are thus commonly prescribed even
when psychotic symptoms are absent.[11]

Sometimes mood stabilizers are used in combination, such as lithium with one of the
anticonvulsants.

Narcotics
The term narcotic originally referred medically to any psychoactive compound with any sleep-
inducing properties. It has since become associated with opioids, commonly morphine and heroin
and their derivatives, such as hydrocodone. The term is, today, imprecisely defined and typically has
negative connotations.
Statutory classification of a drug as a narcotic often increases the penalties for violation of drug
control statutes. For example, although federal law classifies both cocaine and amphetamines as
"Schedule II" drugs, the penalty for possession of cocaine is greater than the penalty for possession
of amphetamines because cocaine, unlike amphetamines, is classified as a narcotic.

Non-narcotic
Analgesics: Drugs that relieve pain. There are two main types: non-narcotic analgesics for mild pain,
and narcotic analgesics for severe pain.

Cognitive enhancers
Nootropics also referred to as smart drugs, memory enhancers, neuro-enhancers, cognitive
enhancers, and intelligence enhancers, are drugs, supplements, nutraceuticals, and functional foods
that improve mental functions such as cognition, memory, intelligence, motivation, attention, and
concentration.

Nootropics are thought to work by altering the availability of the brain's supply of neurochemicals
(neurotransmitters, enzymes, and hormones), by improving the brain's oxygen supply, or by
stimulating nerve growth. However the efficacy of nootropic substances, in most cases, has not been
conclusively determined. This is complicated by the difficulty of defining and quantifying cognition
and intelligence.

Nootropics vs. cognitive enhancers

Cognitive enhancers are drugs, supplements, nutraceuticals, and functional foods that enhance
concentration and memory. Nootropics are cognitive enhancers that are neuroprotective or
extremely nontoxic. Nootropics are by definition cognitive enhancers, but a cognitive enhancer is not
necessarily a nootropic.

Recreational drugs
Many recreational substances that are currently illegal or heavily controlled have effects on the
brain or long-term functions that are typically considered secondary to their effects on perception.
This list includes substances that are illegal, or not completely illegal, but are not controlled or
exempt under a Drug schedule.
 Amphetamine-type stimulants are described above
 Tobacco – Contains nicotine, and harman & norharman which are MAOIs. Smokers have
been shown to have 30% lower MAO-A activity and 40% less MAO-B activity than non-
smokers. A meta-analysis of 41 double-blind, placebo-controlled studies concluded that
nicotine or smoking had significant positive effects on fine motor, alerting attention-accuracy
and response time (RT), orienting attention-RT, short-term episodic memory-accuracy, and
working memory-RT.

Stimulants
Stimulants are often seen as smart drugs, but may be more accurately termed productivity
enhancers. Some stimulants can enhance cognition and memory in some people, but cause
psychosis in others. They generally have a very substantial side-effect profile and are not considered
classical "nootropic" drugs. These typically improve concentration and a few areas of cognitive
performance, but only while the drug is still in the blood. Some scientists recommend widespread
use of stimulants such as methylphenidate and amphetamines by the general population to increase
brain power.
 Amphetamines
  Adrenergics
 Cholinergics
 Eugeroics ("Wakefulness Enhancers")—unproven primary mechanisms but proven efficacy
 Xanthines—reduces fatigue perception
o Caffeine

Dopaminergics
Dopaminergics are substances that affect the neurotransmitter dopamine or the components of the
nervous system that use dopamine. Attributable effects of dopamine are enhancement of attention,
alertness, and antioxidant activity. Dopamine is the primary activity of stimulants like
methylphenidate (Ritalin) or amphetamine. Dopaminergic nootropics include dopamine synthesis
precursors, dopamine reuptake inhibitors, monoamine oxidase inhibitors, and other compounds:
 Metabolic precursors—raise levels
o L-Phenylalanine—purported cognitive improvement
o L-Tyrosine (or N-Acetyl-L-Tyrosine, more bioavailable form)—purported cognitive
improvement
o L-DOPA (L-3,4-dihydroxyphenylalanine)—precursor to catecholamines (dopamine);
neurotoxic effects documented
 Reuptake inhibitors—stabilize/improve levels
o Amineptine—mild stimulant
o Methylphenidate—stimulant approved for ADHD; strong DAT inhibition
o Bupropion—atypical antidepressant; moderate DAT inhibition
 MAO-B inhibitors—prevent breakdown
o Selegiline—Mild stimulant; irreversible
o Rasagiline—Mild stimulant; irreversible
 Dopamine agonists
o Ropinirole—agonist at D2, D3, and D4 receptors
o Pramipexole—agonist at D2, D3 and D4 receptors

Concentration and memory enhancement

The nootropics in this section are purported or shown to enhance concentration or the recollection
and formation of memories.

Cholinergics
Cholinergics are substances that affect the neurotransmitter acetylcholine or the components of the
nervous system that use acetylcholine. Acetylcholine is a facilitator of memory formation. Increasing
the availability of this neurotransmitter in the brain may improve these functions. Cholinergic
nootropics include acetylcholine precursors and cofactors, and acetylcholinesterase inhibitors.

GABA blockers
The GABAA α5 receptor site has recently displayed memory improvements when inverse agonized.

Glutamate activators
The AMPA transmitter and the AMPA receptors are currently being researched, and there are signs
that significant memory improvement and possible alertness enhancement may occur when
agonized. The drug class for AMPA system modulation is called Ampakines. Although there are many
Ampakines currently in-research, those mentioned here are significantly notable, and/or show
reasonable signs of coming to market.
Serotonergics
Serotonergic nootropics include serotonin precursors and cofactors, and serotonin reuptake
inhibitors.

Substances used for non-medical reasons

Stimulants
Amphetamines
Amphetamine (USAN, abbreviated from alpha-methylphenethylamine) or amfetamine (INN) is a
psychostimulant drug of the phenethylamine class that produces increased wakefulness and focus in
association with decreased fatigue and appetite.

Brand names of medications that contain, or metabolize into, amphetamine include Adderall,
Dexedrine, Dextrostat, Desoxyn, Didrex, ProCentra, and Vyvanse, as well as Benzedrine in the past.
The drug is also used recreationally and as a performance enhancer. Recreational users of
amphetamine have coined numerous street names for amphetamine, such as "speed".

Physical effects
Physical effects of amphetamine can include hyperactivity, dilated pupils, vasoconstriction, blood
shot eyes, flushing, restlessness, dry mouth, bruxism, headache, tachycardia, bradycardia,
tachypnea, hypertension, hypotension, fever, diaphoresis, diarrhea, constipation, blurred vision,
aphasia, dizziness, twitching, insomnia, numbness, palpitations, arrhythmias, tremors, dry and/or
itchy skin, acne, pallor, convulsions, and with chronic and/or high doses, seizure, stroke, coma, heart
attack and death can occur.

Psychological effects
Psychological effects can include euphoria, anxiety, increased libido, alertness, concentration,
energy, self-esteem, self-confidence, sociability, irritability, aggression, psychosomatic disorders,
psychomotor agitation, grandiosity, repetitive and obsessive behaviors, paranoia, and with chronic
and/or high doses, amphetamine psychosis can occur.

Withdrawal effects
Withdrawal symptoms of amphetamine consist primarily of mental fatigue, mental depression and
increased appetite. Symptoms may last for days with occasional use and weeks or months with
chronic use, with severity dependent on the length of time and the amount of amphetamine used.
Withdrawal symptoms may also include anxiety, agitation, excessive sleep, vivid or lucid dreams,
deep REM sleep and suicidal ideation.

Dependence and addiction

Tolerance is developed rapidly in amphetamine abuse; therefore, periods of extended use require
increasing amounts of the drug in order to achieve the same effect.
Overdose
An amphetamine overdose is rarely fatal but can lead to a number of different symptoms, including
psychosis, chest pain, and hypertension.

Mechanism of action
Primary sites of action
Amphetamine exerts its behavioural effects by modulating several key neurotransmitters in the
brain, including dopamine, serotonin, and norepinephrine. However, the activity of amphetamine
throughout the brain appears to be specific;[21] certain receptors that respond to amphetamine in
some regions of the brain tend not to do so in other regions. For instance, dopamine D2 receptors in
the hippocampus, a region of the brain associated with forming new memories, appear to be
unaffected by the presence of amphetamine.[21]

Dopamine is a chemical messenger heavily active in the mesolimbic and mesocortical reward
pathways. The anatomical components of these pathways — including the striatum, the nucleus
accumbens, and the ventral striatum — have been found to be primary sites of amphetamine action.

Endogenous amphetamines
Amphetamine has been found to have several endogenous analogues; that is, molecules of a similar
structure found naturally in the brain.[26] l-Phenylalanine and β-Phenethylamine are two examples,
which are formed in the peripheral nervous system as well as in the brain itself. These molecules are
thought to modulate levels of excitement and alertness, among other related affective states.

Serotonin
The interaction between amphetamine and serotonin is apparent only in particular regions of the
brain, such as the mesocorticolimbic projection. Recent studies additionally postulate that
amphetamine may indirectly alter the behavior of glutamatergic pathways extending from the
ventral tegmental area to the prefrontal cortex.[39] Glutamatergic pathways are strongly correlated
with increased excitability at the level of the synapse. Increased extracellular concentrations of
serotonin may thus modulate the excitatory activity of glutamatergic neurons.[39]

The proposed ability of amphetamine to increase excitability of glutamatergic pathways may be of

significance when considering serotonin-mediated addiction.[39] An additional behavioral
consequence may be the stereotyped locomotor stimulation that occurs in response to
amphetamine exposure.[28]

Cocaine
Cocaine (benzoylmethylecgonine) (INN) is a crystalline tropane alkaloid that is obtained from the
leaves of the coca plant.[5]

It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic.
Specifically, it is a serotonin–norepinephrine–dopamine reuptake inhibitor (also known as a triple
reuptake inhibitor (TRI)). It is addictive because of the way it affects the mesolimbic reward pathway.
[6]


Medical effects
Cocaine is a powerful nervous system stimulant.[8] Its effects can last from 15–30 minutes to an hour,
depending on the route of administration.[9]

Cocaine increases alertness, feelings of well-being and euphoria, energy and motor activity, feelings
of competence and sexuality. Anxiety, paranoia and restlessness are also frequent. With excessive
dosage, tremors, convulsions and increased body temperature are observed. [8]
Occasional cocaine use does not typically lead to severe or even minor physical or social problems. [10]
[11]

Addiction
Cocaine dependence (or addiction) is psychological dependency on the regular use of cocaine.
Cocaine dependency may result in physiological damage, lethargy, psychosis, depression, akathisia,
and fatal overdose.

Forms of cocaine
Salts
Cocaine is a weakly alkaline compound (an "alkaloid"), and can therefore combine with acidic
compounds to form various salts.

Basic
As the name implies, “freebase” is the base form of cocaine, as opposed to the salt form. It is
practically insoluble in water whereas hydrochloride salt is water soluble.

Smoking freebase cocaine has the additional effect of releasing methylecgonidine into the user's
system due to the pyrolysis of the substance (a side effect which insufflating or injecting powder
cocaine does not create). Some research suggests that smoking freebase cocaine can be even more
cardiotoxic than other routes of administration[37] because of methylecgonidine's effects on lung
tissue[38] and liver tissue.[39]

Crack cocaine
Crack is a lower purity form of free-base cocaine that is usually produced by neutralization of
cocaine hydrochloride with a solution of baking soda (sodium bicarbonate, NaHCO3) and water

The "freebase" and "crack" forms of cocaine are usually administered by vaporization of the
powdered substance into smoke, which is then inhaled.[40]

Coca leaf infusions

Coca herbal infusion (also referred to as Coca tea) is used in coca-leaf producing countries much as
any herbal medicinal infusion would elsewhere in the world. The effects of drinking coca tea are a
mild stimulation and mood lift. It does not produce any significant numbing of the mouth nor does it
give a rush like snorting cocaine.

Mechanism of Action
Cocaine binds directly to the DAT1 transporter, inhibiting reuptake with more efficacy than
amphetamines which phosphorylate it causing internalization; instead primarily releasing DAT
(which cocaine does not do) and only inhibiting its reuptake as a secondary, and much more minor,
mode of action than cocaine and in another manner: from the opposite conformation/orientation to
DAT.
Caffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found
in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural
pesticide that paralyzes and kills certain insects feeding on the plants.

In humans, caffeine acts as a central nervous system stimulant, temporarily warding off drowsiness
and restoring alertness. It is the world's most widely consumed psychoactive drug, but, unlike many
other psychoactive substances, it is both legal and unregulated in nearly all parts of the world.

Caffeine is toxic at sufficiently high doses, but ordinary consumption poses few known health risks,
even when carried on for years — there may be a modest protective effect against some diseases,
including certain types of cancer.

Stimulant effects
Caffeine is a central nervous system and metabolic stimulant,[7] and is used both recreationally and
medically to reduce physical fatigue and to restore alertness when drowsiness occurs. It produces
increased wakefulness, faster and clearer flow of thought, increased focus, and better general body
coordination.[8] The amount of caffeine needed to produce effects varies from person to person,
depending on body size and degree of tolerance. Effects begin less than an hour after consumption,
and a moderate dose usually wears off in about five hours.[8]

Physical effects
Consumption of large amounts of caffeine — usually more than 250 mg per day — can lead to a
condition known as caffeinism. Caffeinism usually combines caffeine dependency with a wide range
of unpleasant physical and mental conditions including nervousness, irritability, restlessness,
insomnia, headaches, and heart palpitations after caffeine use.[16]

Psychological
Four caffeine-induced disorders are recognized by the American Psychiatric Association (APA)
including: caffeine intoxication, caffeine-induced sleep disorder, caffeine-induced anxiety disorder
and caffeine-related disorder not otherwise specified (NOS).[39] In moderate doses it may reduce
symptoms of depression and lower suicide risk.[40] High doses may trigger anxiety and rarely mania
and psychosis. As of 2010 the effect of caffeine on people with ADHD is not known.[40] The DSM-IV
defines caffeine-induced sleep disorder, as an individual who regularly ingests high doses of caffeine
sufficient to induce a significant disturbance in his or her sleep, sufficiently severe to warrant clinical
attention.[39]

Caffeine can have both positive and negative effects on anxiety disorders depending on the dose. At
high doses, typically greater than 300 mg, it can both cause and worsen anxiety.[41] At low doses it
may have little effect or may reduce symptoms of anxiety. Caffeine withdrawal, on the other hand,
can cause an increase in anxiety level.[40] In moderate doses caffeine typically does not affect learning
or memory.[42] It does however improve cognitive function in people who are fatigued, due to its
effect on alertness.

Caffeine intoxication
Caffeine overdose can result in a state of central nervous system over-stimulation called caffeine
intoxication (DSM-IV 305.90),[39] or colloquially the "caffeine jitters". The symptoms of caffeine
intoxication are comparable to the symptoms of overdoses of other stimulants: they may include
restlessness, fidgeting, anxiety, excitement, insomnia, flushing of the face, increased urination,
gastrointestinal disturbance, muscle twitching, a rambling flow of thought and speech, irritability,
irregular or rapid heartbeat, and psychomotor agitation.[46] In cases of much larger overdoses, mania,
depression, lapses in judgment, disorientation, disinhibition, delusions, hallucinations, or psychosis
may occur, and rhabdomyolysis (breakdown of skeletal muscle tissue) can be provoked.[47][48]

Extreme overdose can result in death.[49][50] Treatment of severe caffeine intoxication is generally
supportive, providing treatment of the immediate symptoms, but if the patient has very high serum
levels of caffeine then peritoneal dialysis, hemodialysis, or hemofiltration may be required.[46]

Addiction, tolerance and withdrawal

With repetitive use, physical dependence or addiction are likely to occur. Also, the stimulatory
effects of caffeine are substantially reduced over time, a phenomenon known as a tolerance.
Withdrawal symptoms—including headache, irritability, inability to concentrate, drowsiness,
insomnia, and pain in the stomach, upper body, and joints—may appear within 12 to 24 hours after
discontinuation of caffeine intake, peak at roughly 48 hours, and usually last from 2 to 9 days. [53]

Mechanism of action
Caffeine antagonizes the adenosine receptors nonselectively, along with the adenosine receptor
A2a. The adenosine receptor A2a suppresses neurotransmitters such as glutamate, epinephrine,
norepinephrine, dopamine, acetylcholine, and to a lesser extent, serotonin. Consumption of caffeine
can increase these neurotransmitters. There has also been conclusive evidence that caffeine inhibits
acetylcholinesterase, an enzyme that breaks down acetylcholine.

Nicotine
Nicotine is an alkaloid found in the nightshade family of plants (Solanaceae); biosynthesis takes
place in the roots and accumulation occurs in the leaves. It functions as an antiherbivore chemical;
therefore, nicotine was widely used as an insecticide in the past[3][4][5] and nicotine analogs such as
imidacloprid are currently widely used.

In low concentrations (an average cigarette yields about 1 mg of absorbed nicotine), the substance
acts as a stimulant in mammals, while high concentrations (30–60 mg[6]) can be fatal.[7] This stimulant
effect is the main factor responsible for the dependence-forming properties of tobacco smoking.

Pharmacokinetics
As nicotine enters the body, it is distributed quickly through the bloodstream and crosses the blood–
brain barrier reaching the brain within 10–20 seconds after inhalation.[18] The elimination half-life of
nicotine in the body is around two hours.[19]

Psychoactive effects
Nicotine's mood-altering effects are different by report: in particular it is both a stimulant and a
relaxant.[40] First causing a release of glucose from the liver and epinephrine (adrenaline) from the
adrenal medulla, it causes stimulation. Users report feelings of relaxation, sharpness, calmness, and
alertness.[41] Like any stimulant, it may very rarely cause the often catastrophically uncomfortable
neuropsychiatric effect of akathisia. By reducing the appetite and raising the metabolism, some
smokers may lose weight as a consequence.[42][43]

When a cigarette is smoked, nicotine-rich blood passes from the lungs to the brain within seven
seconds and immediately stimulates the release of many chemical messengers including
acetylcholine, norepinephrine, epinephrine, vasopressin, arginine, dopamine, autocrine agents, and
beta-endorphin.[44] This release of neurotransmitters and hormones is responsible for most of
nicotine's effects. Nicotine appears to enhance concentration[45] and memory due to the increase of
acetylcholine. It also appears to enhance alertness due to the increases of acetylcholine and
norepinephrine. Arousal is increased by the increase of norepinephrine. Pain is reduced by the
increases of acetylcholine and beta-endorphin. Anxiety is reduced by the increase of beta-
endorphin. Nicotine also extends the duration of positive effects of dopamine[46] and increases
sensitivity in brain reward systems.[47] Most cigarettes (in the smoke inhaled) contain 1 to 3
milligrams of nicotine.[48]

Dependence and withdrawal

Modern research shows that nicotine acts on the brain to produce a number of effects. Specifically,
research examining its addictive nature has been found to show that nicotine activates the
mesolimbic pathway ("reward system") – the circuitry within the brain that regulates feelings of
pleasure and euphoria.[53]

As dopamine regulates the sensitivity of nicotinic acetylcholine receptors decreases. To compensate

for this compensatory mechanism, the brain in turn upregulates the number of receptors,
convoluting its regulatory effects with compensatory mechanisms meant to counteract other
compensatory mechanisms. An example is the increase in norepinephrine, one of the successors to
dopamine, which inhibit reuptake of the glutamate receptors,[57] in charge of memory and cognition.
The net effect is an increase in reward pathway sensitivity, the opposite of other addictive drugs
such as cocaine and heroin, which reduce reward pathway sensitivity.[47] This neuronal brain
alteration can persist for months after administration ceases.

LSD
Lysergic acid diethylamide, abbreviated LSD or LSD-25, also known as lysergide and colloquially as
acid, is a semisynthetic psychedelic drug of the ergoline family, well known for its psychological
effects which can include altered thinking processes, closed and open eye visuals, synaesthesia, an
altered sense of time and spiritual experiences, as well as for its key role in 1960s counterculture. It
is used mainly as an entheogen, recreational drug, and as an agent in psychedelic therapy. LSD is
non-addictive, is not known to cause brain damage, and has extremely low toxicity relative to dose,
although in rare cases adverse psychiatric reactions such as anxiety or delusions are possible. [3]

LSD is typically delivered orally, usually on a substrate such as absorbent blotter paper, a sugar cube,
or gelatin. In its liquid form, it can also be administered by intramuscular or intravenous injection.

Physical Effects
LSD can cause pupil dilation, reduced appetite (for some, it increases), and wakefulness. The
following symptoms have been reported: numbness, weakness, nausea, hypothermia or
hyperthermia (decreased or increased body temperature), elevated blood sugar, goose bumps,
increase in heart rate, jaw clenching, perspiration, saliva production, mucus production,
sleeplessness, hyperreflexia, and tremors. Some users, including Albert Hofmann, report a strong
metallic taste for the duration of the effects.[11]

LSD is not considered addictive by the medical community.[12] Rapid tolerance build-up prevents
regular use, and there is cross-tolerance shown between LSD, mescaline[13] and psilocybin.[14] This
tolerance diminishes after a few days without use and is probably caused by downregulation of 5-
HT2A receptors in the brain[15][16]
Psychological Effects
LSD's psychological effects (colloquially called a "trip") vary greatly from person to person,
depending on factors such as previous experiences, state of mind and environment, as well as dose
strength. An LSD trip can have long-term psychoemotional effects; some users cite the LSD
experience as causing significant changes in their personality and life perspective.

Some psychological effects may include an experience of radiant colors, objects and surfaces
appearing to ripple or "breathe", colored patterns behind the closed eyelids (eidetic imagery), an
altered sense of time (time seems to be stretching, repeating itself, changing speed or stopping),
crawling geometric patterns overlaying walls and other objects, morphing objects, a sense that one's
thoughts are spiraling into themselves, loss of a sense of identity or the ego (known as "ego death"),
and other powerful psycho-physical reactions.[17] Many users experience a dissolution between
themselves and the "outside world".[18] This unitive quality may play a role in the spiritual and
religious aspects of LSD. The drug sometimes leads to disintegration or restructuring of the user's
historical personality and creates a mental state that some users report allows them to have more
choice regarding the nature of their own personality.

Sensory Effects
LSD causes an altered sensory experience of senses, emotions, memories, time, and awareness for 6
to 14 hours, depending on dosage and tolerance. Generally beginning within thirty to ninety minutes
after ingestion, the user may experience anything from subtle changes in perception to
overwhelming cognitive shifts. Changes in auditory and visual perception are typical.[18][20] Visual
effects include the illusion of movement of static surfaces ("walls breathing"), after image-like trails
of moving objects ("tracers"), the appearance of moving colored geometric patterns (especially with
closed eyes), an intensification of colors and brightness ("sparkling"), new textures on objects,
blurred vision, and shape suggestibility. Users commonly report that the inanimate world appears to
animate in an unexplainable way; for instance, objects that are static in three dimensions can seem
to be moving relative to one or more additional spatial dimensions.[21] Many of the basic visual
effects resemble the phosphenes seen after applying pressure to the eye and have also been studied
under the name "form constants". The auditory effects of LSD may include echo-like distortions of
sounds, changes in ability to discern concurrent auditory stimuli, and a general intensification of the
experience of music. Higher doses often cause intense and fundamental distortions of sensory
perception such as synaesthesia, the experience of additional spatial or temporal dimensions, and
temporary dissociation.

Potential adverse effects

There have been no documented human deaths from an LSD overdose.[47] It is physiologically well
tolerated and there is no evidence for long-lasting physiological effects on the brain or other parts of
the human organism.[48]

LSD may temporarily impair the ability to make sensible judgments and understand common
dangers, thus making the user more susceptible to accidents and personal injury. It may cause
temporary confusion, difficulty with abstract thinking, or signs of impaired memory and attention
span similar to brain damage.[49]

LSD may trigger panic attacks or feelings of extreme anxiety, colloquially referred to as a "bad trip".
No real prolonged effects have been proven, however people with such conditions as schizophrenia
and depression can worsen with LSD.[52]
There are some cases of LSD inducing a psychosis in people who appeared to be healthy before
taking LSD.[56] In most cases, the psychosis-like reaction is of short duration, but in other cases it may
be chronic. It is difficult to determine whether LSD itself induces these reactions or if it triggers latent
conditions that would have manifested themselves otherwise.

"Flashbacks" are a reported psychological phenomenon in which an individual experiences an

episode of some of LSD's subjective effects long after the drug has worn off, usually in the days after
typical doses. In some rarer cases, flashbacks have lasted longer, but are generally short-lived and
mild compared to the actual LSD "trip".

Pharmacokinetics
LSD's effects normally last from 6–12 hours depending on dosage, tolerance, body weight and age. [5]
Papac and Foltz (1990) reported that 1 µg/kg oral LSD given to a single male volunteer had an
apparent plasma half-life of 5.1 hours, with a peak plasma concentration of 5 ng/mL at 3 hours post-
dose.[2]

Ecstasy / MDMA
MDMA (3,4-methylenedioxy-N-methylamphetamine; methylenedioxymethamphetamine) is an
entactogenic drug of the phenethylamine and amphetamine classes of drugs. In popular culture,
MDMA has become widely known as "ecstasy", usually referring to its street pill form, although this
term may also include the presence of possible adulterants. The terms "molly" (allegedly derived
from "molecule") and "mandy" (a corruption of "MDMA") colloquially refer to MDMA in crystalline
and/or powder form, usually implying purity. MDMA can induce euphoria, a sense of intimacy with
others, and diminished anxiety.

Recreational use
MDMA is occasionally known for being taken in conjunction with psychedelic drugs, such as LSD or
psilocybin mushrooms, or even common drugs such as cannabis. As this practice has become more
prevalent, most of the more common combinations have been given nicknames, such as "candy
flipping", for MDMA combined with LSD, "MX Missile", for MDMA with psilocybin, or "kitty flipping"
for MDMA with ketamine.[20] The term "flipping" may come from the subjective effects of using
MDMA with a psychedelic in which the user may shift rapidly between a more lucid state and a more
psychedelic state several times during the course of their experience.

Subjective effects
In general, users report feeling effects within 45 minutes to an hour of consumption, hitting a peak
at approximately 2 1/2 to 3 hours, reaching a plateau that lasts about 2–3 hours, followed by a
comedown of a few hours. After the drug has run its course, many users report feeling fatigue;
other, more long-lasting effects such as diminished mental capacity, permanent sensitivity to light,
paranoia, and impaired cognitive ability have also been reported.

The most common effects reported by users include:[22]

 A general and subjective alteration in consciousness
 A strong sense of inner peace and self-acceptance
 Diminished aggression, hostility, and jealousy
 Diminished fear, anxiety, and insecurity
 Extreme mood lift with accompanying euphoria
 Feelings of empathy, compassion, and forgiveness toward others
  Feelings of intimacy and even love for others
 Improved self-confidence
 The ability to discuss normally anxiety-provoking topics with marked ease
 An intensification of all of the bodily senses (hearing, touch, smell, vision, taste)
 Substantial enhancement of the appreciation of music quality
 Mild psychedelia, consisting of mental imagery and auditory and visual distortions
 Stimulation, arousal, and hyperactivity (e.g., many users get an "uncontrollable urge to
dance" while under the influence)
 Increased energy and endurance
 Increased alertness, awareness, and wakefulness
 Increased desire, drive, and motivation
 Analgesia or decreased pain sensitivity

Adverse effects
The top side-effects were difficulty concentrating, jaw clenching, grinding of the teeth during sleep,
lack of appetite, and dry mouth/thirst (all occurring in more than 50% of the 74 volunteers).

After-effects
Effects reported by some users once the acute effects of MDMA have worn off include:
 Psychological
o Anxiety and paranoia[27]
o Depression
o Irritability[30]
o Fatigue[31][32]
o Impaired attention, focus, and concentration,[29] as well as drive and motivation (due
to depleted serotonin levels)[28]
o Residual feelings of empathy, emotional sensitivity, and a sense of closeness to
others (afterglow)
 Physiological
o Dizziness, lightheadedness, or vertigo[32]
o Loss of appetite[28][29]
o Gastrointestinal disturbances, such as diarrhea or constipation[27]
o Insomnia[27][28][29]
o Aches and pains, usually from excessive physical activity (e.g., dancing)[28][29][31]
o Exhaustion[30][32]
o Jaw soreness, from bruxism[32][33][34]

Overdose
Upon overdose, the potentially serious serotonin syndrome, stimulant psychosis, and/or
hypertensive crisis, among other dangerous adverse reactions, may come to prominence, the
symptoms of which can include the following:

 Psychological
o Disorientation and/or confusion
o Anxiety, paranoia, and/or panic attacks
o Hypervigilance or increased sensitivity to perceptual stimuli, accompanied by
significantly increased threat detection
o Hypomania or full-blown mania
o Derealization and/or depersonalization
o Hallucinations and/or delusions[36]
 o Thought disorder or disorganized thinking
o Cognitive and memory impairment potentially to the point of retrograde or
anterograde amnesia[37]
o Acute delirium
 Physiological
o Myoclonus or involuntary and intense muscle twitching
o Nystagmus or involuntary eye movements
o Hyperreflexia or overresponsive or overreactive reflexes[38]
o Tachypnoea or rapid breathing and/or dyspnea or shortness of breath
o Palpitations or abnormal awareness of the beating of the heart
o Angina pectoris or severe chest pain, as well as pulmonary hypertension (PH)[39]
o Cardiac arrhythmia or abnormal electrical activity of the heart
o Circulatory shock or cardiogenic shock
o Vasculitis or destruction of blood vessels[40]
o Cardiotoxicity or damage to the heart[41]
o Cardiac dysfunction, arrest, myocardial infarction, and/or heart failure[42][43][44]
o Hemorrhage and/or stroke[45][46]
o Severe hyperthermia, potentially resulting in organ failure[47][48]
o Syncope or fainting or loss of consciousness
o Organ failure (as mentioned above)
o Possible brain damage
o Coma or death

Long-term effects on serotonin and dopamine

MDMA causes a reduction in the concentration of serotonin transporters (SERTs) in the brain. The
rate at which the brain recovers from serotonergic changes is unclear. One study demonstrated
lasting serotonergic changes in some animals exposed to MDMA.[62] Other studies have suggested
that the brain may recover from serotonergic damage.[63][64]

Cannabis
Cannabis is a genus of flowering plants that includes three putative varieties, Cannabis sativa,[1]
Cannabis indica,[1] and Cannabis ruderalis. Cannabis has long been used for fibre (hemp), for seed
and seed oils, for medicinal purposes, and as a recreational drug. The psychoactive product consists
of dried flowers of plants selectively bred to produce high levels of THC and other psychoactive
chemicals. Various extracts including hashish and hash oil are also produced from the plant.[3]

Cannabis plants produce a unique family of terpeno-phenolic compounds called cannabinoids, which
produce the "high" one experiences from smoking marijuana. The two cannabinoids usually
produced in greatest abundance are cannabidiol (CBD) and/or Δ9-tetrahydrocannabinol (THC), but
only THC is psychoactive. Although overall cannabinoid production is influenced by environmental
factors, the THC/CBD ratio is genetically determined and remains fixed throughout the life of a plant.
[26]
Non-drug plants produce relatively low levels of THC and high levels of CBD, while drug plants
produce high levels of THC and low levels of CBD.

Recreational use
The psychoactive effects of Cannabis are known to have a biphasic nature. Primary psychoactive
effects include a state of relaxation, and to a lesser degree, euphoria from its main psychoactive
compound, tetrahydrocannabinol. Secondary psychoactive effects, such as a facility for philosophical
thinking, introspection and metacognition have been reported amongst cases of anxiety and
paranoia.[90] Finally, the tertiary psychoactive effects of the drug cannabis, can include an increase in
heart rate and hunger, believed to be caused by 11-Hydroxy-THC, a psychoactive metabolite of THC
produced in the liver.

Normal cognition is restored after approximately three hours for larger doses via a smoking pipe,
bong or vaporizer.[90] However, if a large amount is taken orally the effects may last much longer.
After 24 hours to a few days, minuscule psychoactive effects may be felt, depending on dosage,
frequency and tolerance to the drug.

Various forms of the drug cannabis exist, including extracts such as hashish and hash oil[3] which,
because of appearance, are more susceptible to adulterants when left unregulated.
The plant Cannabis sativa is known to cause more of a "high" by stimulating hunger and by
producing a rather more comedic, or energetic feeling. Conversely, the Cannabis indica plant is
known to cause more of a "stoned" or meditative feeling, possibly because of a higher CBD to THC
ratio.[91]

Heroin
Heroin (diacetylmorphine or morphine diacetate (INN)), also known as diamorphine (BAN), is an
opiate analgesic synthesized by C.R Alder Wright in 1874 by adding two acetyl groups to the
molecule morphine, a derivative of the opium poppy. When used in medicine it is typically used to
treat severe pain, such as that resulting from a heart attack. It is the 3,6-diacetyl ester of morphine,
and functions as a morphine prodrug (meaning that it is metabolically converted to morphine inside
the body in order for it to work).[4]

The white crystalline form considered "pure heroin" is usually the hydrochloride salt,
diacetylmorphine hydrochloride. When heroin is supplied illegally, though, it is often adulterated to
a freebase form, dulling the sheen and consistency to a matte-white powder.[5]

As with other opioids, diacetylmorphine is used as both an analgesic and a recreational drug.
Frequent and regular administration is associated with tolerance and physical dependence, which
may develop into addiction.

Usage
Long-term effects of intravenous usage, including - and indeed primarily because of - the effects of
the contaminants common in illegal heroin and contaminated needles.[11]

Medical use
Under the chemical name diamorphine, diacetylmorphine is prescribed as a strong analgesic in the
United Kingdom, where it is given via subcutaneous, intramuscular, intrathecal or intravenous route.
Its use includes treatment for acute pain, such as in severe physical trauma, myocardial infarction,
post-surgical pain, and chronic pain, including end-stage cancer and other terminal illnesses.

Recreational use
Diacetylmorphine, almost always still called by its original trade name of heroin in non-medical
settings, is used as a recreational drug for the transcendent relaxation and intense euphoria it
induces.

Tolerance quickly develops, and users need more of the drug to achieve the same effects. Its
popularity with recreational drug users, compared to morphine, reportedly stems from its perceived
different effects.[18] In particular, users report an intense rush, an acute transcendent state of
euphoria, that occurs while diacetylmorphine is being metabolized into 6-monoacetylmorphine (6-
MAM) and morphine in the brain.

Adverse effects
Like most opioids, unadulterated heroin does not cause many long-term complications other than
dependence and constipation.[36] Adulterated "street" heroin however is considered to be one of the
most harmful drugs especially if consumed intravenously.
 Intravenous use of heroin (and any other substance) with non-sterile needles and syringes or
other related equipment may lead to:
o The risk of contracting blood-borne pathogens such as HIV and hepatitis
o The risk of contracting bacterial or fungal endocarditis and possibly venous sclerosis
o Abscesses
 Poisoning from contaminants added to "cut" or dilute heroin
 Chronic constipation
 Addiction
 Tolerance
 Physical dependence can result from prolonged use of all opioids, resulting in withdrawal
symptoms on cessation of use

Withdrawal
The withdrawal syndrome from heroin (the so-called cold turkey) may begin within 6 to 24 hours of
discontinuation of the drug; however, this time frame can fluctuate with the degree of tolerance as
well as the amount of the last consumed dose. Symptoms may include: sweating, malaise, anxiety,
depression, akathisia, priapism, extra sensitivity of the genitals in females, general feeling of
heaviness, cramp-like pains in the limbs, excessive yawning or sneezing, tears, rhinorrhea, sleep
difficulties (insomnia), cold sweats, chills, severe muscle and bone aches; nausea, vomiting, diarrhea,
cramps, watery eyes[45] and fever.[46]

Recreational uses:
 Euphoria, Transcendent relaxation
Medicinal uses:
 Powerful analgesic (pain killer), Cough suppressant, Anti-diarrheal

Contraindications:
 Alcohol, Barbiturates and benzodiazepines, Stimulants, Other opioids

Central nervous system:

 Drowsiness, Disorientation, Delirium
Neurological:
 Analgesia, Tolerance, Addiction (physical dependence)
Psychological:
 Addiction (psychological dependence), Anxiolysis, Confusion, Euphoria, Somnolence
Cardiovascular & Respiratory:
 Bradycardia, Hypotension, Hypoventilation, Shallow breathing, Respiratory depression
Gastrointestinal:
 Nausea, Protracted vomiting, Constipation, Dyspepsia (heartburn)
Musculoskeletal:
 Analgesia, Ataxia, Muscle spasticity
Skin:
 Itching, Flushing/Rash
 Miscellaneous:
 Dry mouth (xerostomia), Miosis (pupil constriction), Urinary retention

Large doses of heroin can cause fatal respiratory depression, and the drug has been used for suicide
or as a murder weapon.

Opiates
In medicine, the term opiate describes any of the narcotic opioid alkaloids found as natural products
in the opium poppy plant, Papaver somniferum.[1]

Opiates are so named because they are constituents or derivatives of alkaloids found in opium,
which is processed from the latex sap of the opium poppy. The major biologically active opiates
found in opium are morphine, codeine, and thebaine. Semi-synthetic opiates such as hydrocodone,
hydromorphone, and oxymorphone are derived from these substances. Papaverine, noscapine and
approximately 24 other alkaloids are also present in opium, but have little to no effect on the human
central nervous system, and are not considered to be opiates.

Opiates belong to the large biosynthetic group of benzylisoquinoline alkaloids.

The full synthesis of opiates from naphthoquinone (Gates synthesis) or from other simple organic
starting materials is tedious and not economical. Thus, most of the opiate-type analgesics in use
today are extracted from Papaver somniferum or semi-synthesized from thebaine.[2]

In the traditional sense, opiate has referred to only the alkaloids in opium and the natural and semi-
synthetic derivatives of opium. The term is often incorrectly used to refer to all drugs with opium- or
morphine-like pharmacological action, which are more properly classified under the broader terms
opioid.

The alkaloids
Morphine
The most frequently-reported occurrences of opiate-induced pulmonary edema are among
recreational heroin users.[3][4] Although uncommon, reports of morphine-induced pulmonary edema
are not unheard of.[5] The primary difference is the more careful supervision of morphine
administration compared to the lack of supervision and medical expertise among illicit heroin users.
On the other hand, morphine may also be used in the treatment of pulmonary edema. [6][7] Despite
morphine's being the most medically-significant alkaloid, larger quantities of the milder codeine—
most of it manufactured from morphine—are consumed medically, as codeine has a greater and
more predictable oral bioavailability than morphine, making it easier to titrate one's dose.

Codeine
Esters of Morphine
Semi-natural opiates that are either morphine prodrugs or are so similar to morphine that they are
not semi-synthetic, but are more natural in nature due to the fact that they are morphine salts.

Withdrawal effects
Opiate withdrawal syndrome effects are associated with cessation of prolonged opiate usage.
In facilities the logical threat of relapse is possible when Post-acute-withdrawal syndrome is under-
emphasized to patients in transitional phases, especially with short-term suboxone, methadone or
health facilities.

Depressants
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxyl functional group (-OH) is
bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to
three other atoms.[1]

Common names
Chemical Formula IUPAC Name Common Name
Monohydric alcohols
CH3OH Methanol Wood alcohol
C2H5OH Ethanol Grain alcohol
C3H7OH Isopropyl alcohol Rubbing alcohol
C4H9OH Butyl alcohol Butanol
C5H11OH Pentanol Amyl alcohol
C16H33OH Hexadecan-1-ol Cetyl alcohol
Polyhydric alcohols
C2H4(OH)2 Ethane-1,2-diol Ethylene glycol
C3H5(OH)3 Propane-1,2,3-triol Glycerin
C4H6(OH)4 Butane-1,2,3,4-tetraol Erythritol
C5H7(OH)5 Pentane-1,2,3,4,5-pentol Xylitol
C6H8(OH)6 Hexane-1,2,3,4,5,6-hexol Mannitol, Sorbitol
C7H9(OH)7 Heptane-1,2,3,4,5,6,7-heptol Volemitol
Unsaturated aliphatic alcohols
C3H5OH Prop-2-ene-1-ol Allyl alcohol
C10H17OH 3,7-Dimethylocta-2,6-dien-1-ol Geraniol
C3H3OH Prop-2-in-1-ol Propargyl alcohol
Alicyclic alcohols
C6H6(OH)6 Cyclohexane-1,2,3,4,5,6-hexol Inositol
C10H19OH 2 - (2-propyl)-5-methyl-cyclohexane-1-ol Menthol

Physical and chemical properties

Alcohols have an odor that is often described as “biting” and as “hanging” in the nasal passages.
Ethanol has a slightly sweeter (or more fruit-like) odor than the other alcohols.

Barbiturates
See above

Benzodiazepines
See above