unit 11 - hallucinogens

Question 1

behavioral, cognitive and physiological effects of hallucinogenic drugs

Answer 1

• The main effect of most hallucinogens is on thought, perception and mood
• There is only minimal intellectual or memory impairment
• Stupor or psychomotor stimulation is not an integral part of the action of most hallucinogenic drugs
• Autonomic side effects are not disabling
• For most hallucinogens there is less dependence liability compared to many other classes of abused drugs

Question 2

hallucionogens

Answer 2

drugs that alter consciousness by distorting primarily auditory and visual perception but can affect any sensory system.
- also affect judgment, orientation, memory, and emotions.
In short, despite profound alterations in perception, adverse effects are minimal and hallucinogens are not addictive.

Question 3

hallucination

Answer 3

the experience of a sensation in the absence of a provoking stimulus.

Question 4

chemical structure of some hallucinogenic drugs

Answer 4

There is wide diversity in the chemical characteristics of hallucinogenic drugs. Many hallucinogens have chemical structures like those of natural neurotransmitters (acetylcholine-, serotonin-, or catecholamine-like). The indole ring structure is a common feature of very powerful hallucinogens.
[Almost all hallucinogens contain nitrogen and are classified as alkaloids.]

Question 5

classification for psychedelic drugs

Answer 5

cholinergic/anticholinergic, catecholamine-like psychedelic drugs, serotonin-like psychedelic drugs, psychedelic anesthetic drugs, marijuana

Question 6

cholinergic/anticholinergic drugs

Answer 6

muscarine, scopolamine

Question 7

catecholamine-like psychedelic drugs

Answer 7

mescaline, amphetamine derivatives (DOM, MDA, DMA, MDMA, TMA, MDE), Myristin, elemicin

Question 8

serotonin-like psychedelic drugs

Answer 8

• Lysergic acid diethylamide (LSD)
• Dimethyltryptamine (DMT)
• Psilocybin, psilocin, bufotenine
• Ololiuqui (morning glory seeds)
• Harmine

Question 9

psychedelic anesthetic drugs

Answer 9

• Phencyclidine (Sernyl)
  - Ketamine (Ketalar)

Question 10

muscarine

Answer 10

Acts as an agonist at muscarinic receptors.
Also acts as an agonist on GABAA receptors and therefore has neurodepressant action
One of two active ingredients of the mushroom Amanita muscaria or “fly agaric mushroom”
Ingestion of muscarine produces a state best described as delirium (restlessness, ataxia and hallucinations)
Muscarine also produces salivation, nausea, diarrhea, hypotension and shock
Antidote: atropine
The use of Amanita muscaria is becoming increasingly rare in Western culture

Question 11

main psychoactive constituents of muscarine

Answer 11

are the compounds ibotenic acid and muscimol which bind to GABAA receptors.
The mushroom was used as an intoxicant by the peoples of Siberia ,and has a religious significance in these cultures.

Question 12

atropine

Answer 12

is a muscarinic cholinergic receptor blocker.
Atropine can be used to treat certain types of nerve agent and pesticide poisonings.
Atropine occurs naturally in a number of plants of the nightshade family including Jimson weed and Mandrake.

Question 13

structural formulas of acetylcholine and the anticholinergic psychedelic scopolamine

Answer 13

Scopolamine acts by blocking acetylcholine receptors. The shaded portion of each molecule illustrates structural similarities, which presumably contribute to receptor fit.
Scopolamine is found naturally in plants of the Nightshade family.

Question 14

anticholinergic syndrome

Answer 14

psychological effects:
* Euphoria
* Delirium
* Anxiety
* Excitement
* Hallucinations (usually visual, formed, and frightening, with loss of insight)
somatic effects:
* Mydriasis (dilation of the pupils)
* Reduced secretions (saliva, bronchi, and nasal)
* Loss of pupillary light reflexes
* Decreased GI motility
* Blurred vision (loss of accommodation)
* Hyperpyrexia
* Dry, flushed skin
* Tachycardia with hyper/hypotension
* Vasodilation
* Urinary retention
toxic effects
* Myoclonus (muscle contraction)
* Coma
* Extensor posturing
* Respiratory depression
* Seizures
* Circulatory collapse
* Death

Question 15

deadly nightshade

Answer 15

anticholinergic syndrome
- The foliage and berries are extremely toxic when ingested, containing toxins such as atropine and scopolamine which cause delirium and hallucinations.

Question 16

anticholinergic syndrome mnemonic

Answer 16

The anticholinergic syndrome is so well known that there is a mnemonic to remember it by:
–mad as a hatter
–blind as a bat
–red as a beet
–hot as a hare
–dry as a bone

Mydriasis is the dilation of the pupil.

We are most interested in the altered mental states.

Question 17

phencyclidine (PCP)

Answer 17

also known as angel dust, causes hallucinations, distorted perceptions of sounds, and sometimes violent behavior. Pharmacologically, PCP works primarily as an NMDA receptor antagonist.
- dissociative anesthetics

Question 18

ketamine

Answer 18

sold under the brand name Ketalar among others, is a medication mainly used for starting and maintaining anesthesia. It induces a trance-like state while providing pain relief, sedation and even memory loss. It also is an NMDA receptor antagonist and is known for producing hallucinations.
- dissociative anesthetics

Question 19

phencyclidine and ketamine (slide 28)

Answer 19

were developed to be anesthetics. They are called dissociative anesthetics because people report having a sense of “detachment” from their bodies or “disconnectedness” with the environment while on the drugs. Phencyclidine did not work so well and was replaced by ketamine which has some limited usefulness.

Question 20

signs and symptoms of PCP intoxication - low dose

Answer 20

low dose - anticipated effects
- dreamy, carefree state, mood elevation, heightened or altered perception
negative effects
- impaired judgement, mood swings, panic, partial amnesia

Question 21

signs and symptoms of PCP intoxication - moderate dose

Answer 21

anticipated effects
- inebriation, dissociation, depersonalization, perceptual distortions, diminished pain sensitivity
negative side effects
- ataxia, motor impairment, confusion, disorientation, preoccupation with abnormal body sensations, amnesia, exaggerated mood swings, panic

Question 22

signs and symptoms of PCP intoxication - high dose

Answer 22

all of the anticipated effects + hallucinations
negative side effects
- catatonia, delirium, drooling, severe motor impairment, psychotic behavior, hypertensive crisis, amnesia

Question 23

binding site for PCP

Answer 23

thought to be located inside the cation channel of the NMDA-receptor complex
- PCP is a non-competitive antagonist (binds in a location different from glutamate itself). Recall that this is where the anesthetics typically bind to the NMDA receptor. The inhibition of glutamate transmission in the frontal cortex is thought to be the mechanism for producing hallucinations.

Question 24

ventral tegmental to nucleus accumbens projection and reward

Answer 24

Despite some untoward effects, many people like the effects of PCP and Ketamine. PCP and Ketamine appear to have rewarding effects by activating a reward pathway in the brain that has been known for decades: the Medial Forebrain Bundle connecting the Ventral Tegmental Area (VTA) to the Nucleus accumbens (NA).

The VTA contains dopamine neurons and, when activated, will release DA into the nucleus accumbens which has rewarding properties. For example, experimental animals will press levers in Skinner boxes to activate stimulating electrodes placed in the MFB to mimic increased neural activity from the VTA to NA.

Question 25

6-hydroxydopamine lesions of the nucleus accumbens block PCP-induced locomotor activation

Answer 25

Rats were injected bilaterally in the nucleus accumbens either with the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA) or with vehicle. At least 14 days later, the animals were given saline, PCP, D-amphetamine, or caffeine intraperitoneally (doses are shown under each drug). 6-OHDA lesions of the nucleus accumbens significantly antagonized the locomotor activating effects of PCP and amphetamine, but not that of caffeine.

Question 26

activation of reward systems

Answer 26

Therefore, by increasing the activity of VTA dopaminergic neurons, PCP, and Ketamine, increase DA release into the NAc creating “reward”. In addition, rats will self-administer PCP directly into the nucleus accumbens (NAc), also suggesting direct rewarding properties that might not have anything to do with DA release. It may be that PCP, and possibly Ketamine, do both: stimulate the VTA to release DA directly into the nucleus accumbens AND act directly on the nucleus accumbens

Question 27

cannabinoids possess

Answer 27

a three-membered ring structure. Cannabinoids have unique chemical structures that can only be found in the cannabis plant. They are generally accepted as the active ingredients of cannabis. The most commonly known cannabinoid is tetrahydrocannabinol (THC). Because of its psychotropic effect, THC is often referred to as the active constituent of cannabis. However, more than 70 different cannabinoids have been identified. These compounds have chemical structures related to THC, but their biological effects are different with little or no psychotropic potential. The point is that cannabinoids are ring structures that interact with a receptor and mimic the action of an endogenous ligand.

Question 28

source and most active component of marijuana

Answer 28

derived from the plant Cannabis sativa In 1964 it was shown that virtually all of the pharmacological activity of MJ is due to (-)delta-9-tetrahydrocannabinol (THC) The MJ plant is either male or female and the most concentrated THC comes from the resin glands of the female flower

Question 29

pharmacokinetics marijuana

Answer 29

Smoking is highly effective in delivering THC – Within seconds it reaches the brain and blood levels peak about the time smoking is complete THC is reasonably well absorbed from the GI tract but systemic delivery is unreliable because of the first pass effect Metabolites are excreted in both the feces (2/3) and urine (1/3)

Question 30

psychological effects of marijuana

Answer 30

Stages of Intoxication 1. - The Buzz is a transient stage where body, head, arms and legs tingle and there is a feeling of light headedness with a dry mouth and throat and a feeling of thirst 2. - The High produces euphoria and physical and mental excitement 3. - With a sufficiently high dose in the stage of Stoned the senses may be heightened and distorted with a relaxed, peaceful calm - May experience synesthesia - Loss of normal sense of time - Light aversion - With the peak of intoxication hallucinations may be experienced - Withdrawn and difficulty in interacting with others - Reflective with metaphysical or philosophical thoughts 4. - When Coming Down there may be hunger (“munchies”) and craving for sweet food and drink - Sleep with colorful dreams

Question 31

dose-related effects of marijuana

Answer 31

Low Dose (2 mg*) * Reduces anxiety * Mild euphoria (a little giddy) Medium Dose (5 mg) * Things become very amusing * Difficulty in completing thoughts * Slowing of perception of time * Increased awareness of internal state High Dose (10-15 mg) * Perceptual changes * Afterimages * Quiet * Slowing of time and movement * Seeing images with eyes closed * Marked motor impairment; may be unable to move

Question 32

acute toxicity of marijuana

Answer 32

- Vomiting, dizziness and headache - Possible intense fear and panic-like attack

Question 33

withdrawal syndrome of marijuana

Answer 33

- Decreased appetite - Sleep-related difficulties - Weight loss - Psychological changes including anger, aggression, irritability, restlessness, strange dreams

Question 34

chronic toxicity? marijuana

Answer 34

- Concerns about persisting cognitive deficits and increased mental illness - Conflicting opinions and studies - Lack of prospective studies and data

Question 35

concerns with marijuana

Answer 35

Memory impairments Amotivational state Paranoia Lung and respiratory disease Cardiac arrhythmias Younger and younger users

Question 36

pharmacodynamics of marijuana

Answer 36

Two types of THC receptors– CB-1 and CB-2 Both are G-protein coupled receptors CB-1 are the receptors in the brain Rimonbant is a CB-1 receptor antagonist THC receptors are mostly on nerve axons and terminals of nearly every type of neurotransmitter This suggests that CB receptor agonists act to modulate release Most of the effects of agonist action at CB-1 receptors is to inhibit release The effects of CB-1 agonist on axon terminals may be through affecting N-Type calcium channels

Question 37

rimonobant

Answer 37

anorectic antiobesity drug that was first approved in Europe in 2006 but was withdrawn worldwide in 2008 due to serious psychiatric side effects, including suicide; it was never approved in the United States. It was the first CB-1 anatagonist.

Question 38

cannabinoid receptors in brain

Answer 38

High levels of binding are seen in the basal ganglia (including the substantia nigra pars reticulata, globus pallidus, entopeduncular nucleus, and caudate putamen), the hippocampal formation, the molecular layer of the cerebellum, and the olfactory bulbs.

Question 39

two sub-types of cannabinoid receptor

Answer 39

Both cannabinoid receptor subtypes are seven transmembrane G-protein-coupled receptors. These figures allow you to see some physical differences between the two. The most important thing for us is that the CB1 receptors are in the CNS and the CB2 receptors are almost entirely in the periphery. - CB-1 receptors are on axons nerve terminals with few present on dendrites and cell bodies; most abundant G-protein coupled receptors in the brain - CB-2 receptors on surface of immune cells

Question 40

endogenous ligands of cannabinoid receptors

Answer 40

- There are two endogenous ligands for CB receptors: AEA (anandamide) and 2-AG (2-arachidonoylglycerol). - The name Anandamide (AEA) is derived from the Sanskrit word ananda which means joy, bliss or delight. - The two endogenous cannabinoids are Anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Anandamide was the first endocannabinoid compound to be identified. It has a pharmacology similar to THC even though its structure is quite different. Anandamide binds to the central (CB1) cannabinoid receptor about the same potency as THC at the CB1 receptor. The CB1 receptors are the receptors in the brain and are located on the presynaptic terminal and function to inhibit neurotransmission via presynaptic inhibition-induced reduction in Ca++ input. Note how the precursor for AEA and 2-AG are made in the postsynaptic neuron!

Question 41

synthesis, action and degradation of 2-AG and AEA

Answer 41

It is not necessary to know the synthetic pathwaysfor 2-AG or AEA. It is important to be aware that these two neuroactive agents are released from post-synaptic sites and act on pre-synaptic nerve endings. That is, agents these function in a manner that is not typical of other neurotransmitters or neuromodulators. -Conventional neurotransmitters are released from a ‘presynaptic’ cell and activate appropriate receptors on a ‘postsynaptic’ cell. Endocannabinoids, on the other hand, are described as retrograde transmitters because they most commonly travel ‘backward’ against the usual synaptic transmitter flow. They are, in effect, released from the postsynaptic cell and act on the presynaptic cell. Activation of cannabinoid receptors temporarily reduces the amount of conventional neurotransmitter released. This endocannabinoid-mediated system permits the postsynaptic cell to control its own incoming synaptic traffic. The ultimate effect on the endocannabinoid-releasing cell depends on the nature of the conventional transmitter being controlled. For instance, when the release of the inhibitory transmitter GABA is reduced, the net effect is an increase in the excitability of the endocannabinoid-releasing cell. On the converse, when release of the excitatory neurotransmitter glutamate is reduced, the net effect is a decrease in the excitability of the endocannabinoid-releasing cell.

Question 42

retrograde transmission

Answer 42

postsynaptic cell controls its own incoming synaptic traffic

Question 43

therapeutic uses of marijuana

Answer 43

Dronabinol (Marinol) – Synthetic THC in Sesame Oil - Appetite stimulant in AIDS patients - Treatment for nausea and vomiting associated with chemotherapy - Reduce muscle spasms and pain in MS - Reduce intraocular pressure in glaucoma - Antidepressant and analgesic actions are claimed -Neuroprotective effects against effect of head trauma, stroke or ischemic insult

Question 44

cannabidiol (CBD)

Answer 44

CBD is the second most prevalent of the active ingredients of marijuana. CBD is an essential component of medical MJ. CBD can be derived directly from the hemp plant, which is a related to the marijuana plant. There is no evidence of public health related problems associated with the use of pure CBD. The FDA recently approved Epidiolex, which contains CBD for treating childhood epilepsy. Significant safety concern with CBD is when it is sold as a supplement, which is not FDA regulated. Exact legal status is unclear.