Drug Misuse & AbuseHallucinogens

Presented by/ Gina Tag Eldin

M.Sc. Pharmaceutical chemistry, 2016.

Drug Misuse and Abuse

What is a drug?– A drug is any substance used safely to cure or prevent or diagnose

a disease. – Or Broadly defined as any chemical entity or mixture of entities

not required for the maintenance of health but that alters biological function or structure when administered.

Drug abuse Vs Drug misuse!!!

– Drug misuse: To take medicine in a way that is not intended, without following the instructions on the label, inappropriate dose of legal drug, or for a long time. e.g. Dextromethorphan (Antitussive).

– Drug abuse: Any use of drugs that causes physical, psychological, or social harm to the individual user or to others affected by the drug user’s behavior or use of illegal drugs (psychoactive) to produce pleasure and remove stress. e.g. Tobacco.

Habit Vs Dependence Vs Addiction

– Habit: A healthy continued involvement with an object or activity.

– Dependence: Physiological and psychological issues i.e. Dependence is characterized by the symptoms of tolerance and withdrawal. While it is possible to have a physical dependence without being addicted.

– Addiction: An unhealthy continued involvement with a mood-altering object or activity that creates harmful consequences. Or biological attachments to consumption of substances. Habits become addictions when a chemical dependence occur i.e marked by a change in behavior caused by the biochemical changes in the brain after continued substance abuse.

Hallucinogens

– Chemical substances that alter thoughts, mood and perception. (altered sense of reality).

– Derived from the Latin verb alucinari “ to wonder in mind or to dream.”(illusion).

– Interchangeably with the term “psychedelic” which means mind revealing.

Historically, magical mushrooms (psilocybin and psilocin), peyote button (mescaline), kykeon (barely, water, mint, ergot (LSD)), ipomea paste (teotlaqualli) from morning glory plants were used in religious ceremonies and medicines.

NH

NH

O

NH

NN O

OO

OHH

H

Ergotamine

N

NCH3

O

N

H

CH3

H3C

LSD-25

Morning glory flower kykeon

Magic Mushroom Peyote button

Ergot Rye

Religious ceremonies

History– In 1938, Albert Hofman synthesized LSD-25 (ergot

derivative), accidently ingested few micrograms (250 μg) and experienced the 1st trip.

– In 1949, Sandoz began marketing LSD-25 to psychiatrists in US in psychotherapy.

– Due to recreational use, LSD has been prohibited by 1960s.

LSD-25

STREET NAMESHALLUCINOGENIC SLANGGlossary of drug slang

Clinical Symptoms (Intoxication)– Eidetic Imagery (endless)

– Depersonalization

– Perception: visual distortions, blurred vision, perception of distance and depth

– Synesthesia

– Delusions of supernatural abilities, suicide

– Euphoria or frightening experience may occur (extreme sensation)

– Flashbacks

– Prolonged adverse reactions: psychosis, paranoid states, depression

Classes of Hallucinogens

– Classical are (similar to serotonin or LSDlike agents) that share common discriminative stimulus properties and that might act via a common mechanism of action.

– Non classical hallucinogens: these groups of agents act by different mechanisms and produce distinct effects common to members within each group.

Classes (chemically)

– Indolealkylamines (Tryptamines)– Phenylethylamines (similar to nor-ep)– Anticholinergics (Deliriants)– Miscellaneous category

N

N CH3H3C

OH

N

N HH

HO

N

NCH3

O

N

H

N

N CH3H3C

H

CH3

H3C

H H

Serotonin (5-HT) Psilocin

LSD-25DMT

5-hydroxytryptamine

N,N-dimethyltryptamine

Serotonergic Hallucinogens

(similar to 5-HT)

5-HT is associated with Mood, Sleep, Appetite,

Clinical Psychosis & Hallucinogens!!

α

N

NH2

H

5-OMe MeT5-methoxymethyltryptamine

O

Neuropharmacology

Serotonin is generally an inhibitory neurotransmitter that regulates sleep, pain sensation, appetite, mood, sensory perception; it often plays a role in helping us feel relaxed.

LSD or LSD likes act like an antagonist or partial agonist at 5-HT2 and 5-HT1c receptors, agonist at multiple 5-HT1receptors; it inhibits or blocks the release of serotonin at the receptor.

This slowdown in serotonin activity causes hyperactivity in the regions of the brain which regulate our visual and emotional responses.

LSD Psilocybin/ Psilocin

DMT

Dose 70-140 g Perceptual and psychic

effects

4-10 mg 15-60 mg

Metabolism Liver, no active metabolites (6 metabolites).

Liver activation to psilocin by alkaline phosphatase

Deamination by MAOto indole acetic acid (IAA)

Administration Orally (tablets microdots or stamp)

Orally in form of mushroom or as white

powder

Inhalation or by smoking, injected (less common)

Successive breath

Toxicity LD 50 = 14 mg 17gm, 1 gm respectively not estimated

Potency 100 to 200 times than psilocin

1% as potent as LSD Difficult, due to different route of administration

Onset of action 30-40 min 30-40 min 5 min

Duration 8-12 hr 2-6 hr 15 -30 min"businessman's trip"

N

NCH3

O

N

H

CH3

H3C

LSD-25

N

NH

O

N

H

CH3

H3C

Nor-LSD

N

NCH3

O

N

H

CH3

LAE

H

N

NCH3

O

N

H

CH3

H3C

2-Oxo-LSD

O

N

NCH3

O

N

H

CH3

H3C

OOH

2-oxo-3-hydroxy-LSD

N

NCH3

O

N

H

H3C

LEO

HO

N

NCH3

O

N

H

CH3

H3C

13 or 14-Hydroxy-LSD-glucuronide

O-glucoronoid

The Metabolites of LSD In active

N

N CH3H3C

OH

HPsilocin

N

N CH3H2C

O

HPsilocybin

Alkaline Phosphatase

H

PO

OOH

Physiological Conditions

Psilcybe mushrooms(“Magic” mushrooms)

Prodrug Active

N

N CH3H3C

H

DMT

N

COOH

H

MAO-A

IAA

X

Iproniazide

LSD Psilocybin/ Psilocin

DMT

Dose 70-140 g Perceptual and psychic

effects

4-10 mg 15-60 mg

Metabolism Liver, no active metabolites (6 metabolites).

Liver activation to psilocin by alkaline phosphatase

Oxidation by MAOto indole acetic acid (IAA)

Administration Orally (tablets microdots or stamp)

Orally in form of mushroom or as white

powder

Inhalation or by smoking, injected (less common)

Successive breath

Toxicity LD 50 = 14 mg 17gm, 1 gm respectively not estimated

Potency 100 to 200 times than psilocin

1% as potent as LSD Difficult ,due to different route of administration

Onset of action 30-40 min 30-40 min 5 min

Duration 8-12 hr 2-6 hr 15 -30 min"businessman's trip"

Classes

– Indolealkylamines (similar to 5-HT)– Phenylalkylamines (similar to nor-ep)– Anticholinergics (Deliriants)– Miscellaneous category

Phenylalkylamines(Phenylethylamine)

Norepinephrine

OHNH2HO

HO

Dopamine

NH2HO

HO

Mescaline

NH2O

OO

CH3

H3C

H3C Weak hallucinogenic Dose (orally) = 350 mg1000-5000 times less

potent than LSDNauseating with bitter

taste ??Tea, smoked, ingested

Duration 6-12 hr.

Peyote Coctus

CH3

NH2

Amphetamine

Modification of mescaline structure that produce both stimulant and hallucinogenic effects.

Mescaline

NH2O

OO

CH3

H3C

H3C

N

CH3

CH3O

O

H

MDMAMethylenedioxymethamphetamine

Ecstacy, XTC, love or hug drugWidespread among teenagersCommon in ravesDose = 125 mgPills or pure crystals dissolved in waterOnset of action 30 min -1 hrDuration 3-6 hrPurity issue??? 42.22 celeciousAuthentication problem???

Ecstacy, XTC, love or hug drugNeurotoxicWidespread among teenagers in ravesDose = 125 mgPills or pure crystals dissolved in waterOnset of action =30 min -1 hrDuration = 3-6 hrPurity issue ??? Authentication???

Bad trip

RAVES

Neuropharmacology Presynaptic releasing agent of serotonin, norepinephrine, and

dopamine. High affinity for 5-HT receptor specially 5-HT 2. Binds with less affinity to DA 1 and 2 and NE receptors. long term use cause serotonin neurotoxicity and memory

impairment which is directed to the dose administered.

Symptoms Oral effects include xerostomia, bruxism and dry mouth. (characteristic).

Classes

– Indolealkylamines (similar to 5-HT)– Phenylalkylamines (similar to nor-ep)– Anticholinergics (Deliriants)– Miscellaneous category

Anticholinergic Hallucinogenic Atropine and scopolamine block acetylcholine receptors in the

brain muscarinic receptors. In low doses they are used for a variety of medical purposes.

atropine, if administered rapidly after exposure, is an antidote for nerve gas.

Anticholinergic hallucinogens produce such physiological effects as dry mouth, blurred vision (mydriasis), loss of motor control, and increased heart rate and body temperature

They can be fatal as they cause respiratory failure at doses only slightly higher than the effective dose

Datura stramonium Atropa Belladonna Henbane

Classes

– Indolealkylamines (similar to 5-HT)– Phenylalkylamines (similar to nor-ep)– Anticholinergics (Deliriants)– Miscellaneous category

DissociativeNon-classical

NMDA receptor antagonistse.g. Ketamine, PCPκ-opioid receptor agonistse.g. Ibogaine, Salvinorin A

Β-carbolinesClassical

Act as 5-HT2 antagonists and some members have MAO inhibition

activitye.g. Harmine, Harmoline

Less potent than DMT

CannabinoidNon-classical

Miscellaneous

CB-1 receptor antagonists

e.g. Dronabinol

Designer Drugs

– Structurally altered or functional analog of a controlled substance that has been designed to mimic the pharmacological effects of the original drug, while avoiding classification as illegal and/or detection in standard drug tests. Designer drugs include psychoactive substances (club drugs) or bath salts.

– Tested on animals with no expectation of potency and unexpected side-effects

– Synthesized in underground labs (no Q.C).

List of Designer Drugs (psychedelics)

Lysergamidese.g. 1-Acetyl LSD

Tryptaminese.g. psilacetin or 4-

acetoxy-DMT

Phenethylaminese.g. 3C-E

N

NCH3

O

N

CH3

H3C

1-Acetyl LSD

O

N

N CH3H3C

H

4- Acetoxy DMTPsilacetin

OO

3C-E

NH2O

OO

Solvents!!! 2015

References

– Mehling R, Triggle DJ. Hallucinogens. Infobase Publishing; 2009. book

– Foye WO. Foye's principles of medicinal chemistry. Lemke TL, Williams DA, editors. Lippincott Williams & Wilkins; 2008. book

– Maisto SA, Galizio M, Connors GJ. Drug use and abuse. Cengage Learning; 2014. book

– Rivera-García MT, López-Rubalcava C, Cruz SL. Preclinical characterization of toluene as a non-classical hallucinogen drug in rats: participation of 5-HT, dopamine and glutamate systems. Psychopharmacology. 2015 Oct 1;232(20):3797-808.

– Canezin J, Cailleux A, Turcant A, Le Bouil A, Harry P, Allain P. Determination of LSD and its metabolites in human biological fluids by high-performance liquid chromatography with electrospray tandem mass spectrometry. Journal of Chromatography B: Biomedical Sciences and Applications. 2001 Dec 5;765(1):15-27.

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