Bath salts and plant food

Question 1

What are bath salts?

Answer 1

bath salts are a family of designer stimulant drugs that have become popular alternatives to traditional drugs like cocaine and MDMA

the types in circulation frequently change over time as one becomes illegal, others get invented to avoid being illegal

most have reputation for being dangerous drugs that can harm or kill the user

no clinical testing done of them

since 2010, there has been 100 deaths associated with MDPV use alone

they are easy to obtain and cheap and for the most part, legal until the government catches up to them

Question 2

What determines whether a drug is illegal or not?

Answer 2

often legality of drugs is based on specific chemical structure

therefore if structure is changed sufficiently, it may no longer be considered ‘illegal’

Question 3

what are ‘designer’ drugs? what are some dangers associated with designer drugs?

Answer 3

designer drugs are ones that are always changing the structure to not catch up with the law

dangers associated with designer drugs:

• no acute animal or human testing
• no long term testing
• no idea of the LD50 (value of drug dose required to kill half the tested population)
• the right doses are found by trial and error (i.e. someone takes X amount and dies)
• interesting side effects: a contaminant of a designer opioid drug caused parikinsonism in its users, mow used as investigative tool to induce Parkinsons in animal models

Question 4

what are synthetic cathinones and why did they appear?

Answer 4

caxhinone is a naturally occurring drug found in a plant called KHAT

KHAT was made illegal in many countries due to hospitalization of many users so people started making KHAT derivatives (a synthetic cathininone) early 2000

it appeared available online for purchase in 2007

Question 5

what was one of the first reported components of bath salts?

Answer 5

Mephedrone was one the first reported components of bath salts = 4-methylmethcathinone

Question 6

What is another name for cathinone and its derivatives? what are their structural properties?

Answer 6

cathinone and its derivatives are known as beta detonated amphetamines

ketone group makes it more polar and slower than AMPH to cross the BBB (exception is MDPV and derivatives because of their tertiary amino group)

mephedrone is a semi synthetic derived from caxhinone

some cathinones are structurally similar to amphetamines while others are similar to methamphetamines

Mehylone and MDPV are similar to MDMA

Question 7

What are some cathinone derivates of bath salts?

Answer 7

ephedrine, methylone, MDPV and others

Question 8

in 2013 what were the top 3 drugs of choice of bath salts?

Answer 8

1. alpha-PVP
2. Methylone
3. MDPV

Question 9

what was the drug of choice in 2014?

Answer 9

1. alpha-PVP
2. ethylone
3. methylone

and MDVP moved down 3 spots

shows that drugs can change rapidly year to year with new creations

Question 10

How are bath salts administered?

Answer 10

most common routes are snorting AND injection at the same time through a process called KEYING AND PARACHUTING/BOMBING

keying involves dipping keys into powder and snorting

then parachuting involves wrapping powder in cigarette paper and swallowing it

these two combined provide the rapid onset of sniffing and the delayed onset of injestion for prolonged effects

MDPV, has the high lipophilicity can produce effects with very small doses (as little as 5mg) but tends to have a shorter duration

Question 11

What are the 3M’s?

Answer 11

MEPHEDRONE, METHYLONE AND MDPV

Question 12

what are some of the effects of the 3M’s?

Answer 12

all can produce sympathetic excitation by increasing dopamine and noradrenaline levels
- can produce death from “excited delirium”
which is excess agitation, cardiovascular excitation and death
- linked to ability to increase NORE levels by blocking its transporter

also blocks dopamine transporter

MDPV and its derivatives seem to be stimulants at low doses but produce horrible behaviours at high doses

Question 13

what is the biphasic effect?

Answer 13

MDPV and derivatives act like other cathinones at low doses but at high doses you get bizarre behaviours like self mutilation

Question 14

In what ways do cathinones such as MDPV share behavioural similarities with AMPH?

Answer 14

Mice were trained to press a lever to receive direct electrical stimulation to reward pathway

drugs of abuse will increase this behaviour at low frequencies of sitmulation

methAMPH and MDPV had the same results

in both the animal works harder the less of the drug

Question 15

what is alpha-PVP or Flakka?

Answer 15

Flakka is a second generation bath salt and the new “most dangerous thing ever”

also known as gravel
- very cheap to use $5

introduced when first generation drugs were made illegal

linked to a lot of deaths considering their recent introduction

other chemicals in this family include alpha-PPP and alpha-PBP and they differ from alpha-PVP by the length of their carbon tails

Question 16

what are the properties of flaka and alpha-PVP derivatives?

Answer 16

alpha-PVP Is a derivative of the potent MDPV and its just the removal of the methyelenedioxy ring in MDPV but kept the teritary amine group to cross the bilayer faster

the tertiary nitrogen of the pyrrolidine ring allows them to cross lipids more easily than other cathinones
therefore they tend to be more potent than other cathinones that do lack this group

removal of one methyl group of alpha-PVP gives rise to alpha-PBP and removal of one methyl group from alpha-PBP is alpha-PPP

Question 17

What is the mechanism of action of MDPV and other pyrrolidine ring derivatives?

Answer 17

MDPV and other pyrrolidine ring derivatives like alpha-PVP have similar actions to cocaine
- MDPV is a potent transporter blocker but does not seem to reverse transporter flux

• also, theres evidence that flakka and its anologues do not induce reversal of transporters

Question 18

What is the mechanism of action of Cathinones without pyrrolidine ring?

Answer 18

cathinones without pyrrolidine ring tend to have similar mechanism of action to the amphetamines –> bind to and inhibit transporters for dopamine, serotonin and NORE
(includes methcathinone and MEPHEDRONE)

transported into the neuron by serotonin transporter (SERT) and other transporters

releases cytoplasmic stores of NT via reversal of transporters and inhibition of VMAT-dependent NT uptake into vesicles

Question 19

How are the effects on transporters measured?

Answer 19

transporters are involved because drugs will inhibit transport of NT’s into nerve terminals by interacting with the transporters

• use of synaptosome preparation –> grinding up brain tissue and nerve endings are sheared off and spontaneously form into sealed vesicle
• transporters are still active and can accumulate neruostramsitter
• and from this we can see how drugs affect this accumulation

Question 20

How do we measure NT transport?

Answer 20

if we add radioactive neurotransmitter to synaptosomes, we can measure how much they accumulate and make a graph out of this to show normal accumulation
- i.e. as dopamine concentration rises, so does the amount of dopamine in the synaptosome, we use this and add a drug to see how drugs affect the curve

Question 21

What if we measure dopamine accumulation In the presence of the drug?

Answer 21

First we look at MAX dopamine that could enter the synaptosome at dopamine = 100%

then we add the drug and see what happens to the overall dopamine inside the synaptosome…

we can see that the transporters are getting affected by drug because they are binding to it and letting less dopamine into the synaptosome and more floating around the outside

Question 22

what is the IC50 concentration of the drug concentration v. accumulation curve?

Answer 22

it is the concentration of the drug that causes 50% decrease in uptake

The more concentration it takes to reach IC50 means that you need more of the drug to get less than 50% of the dopamine within the synaptosome and the drug is not as potent

if the graph is more the right = drug is not as potent

lower numbers = higher potency

higher number = lower potency

Question 23

Which drugs (cocaine, AMPH, MDPV and alpha-PVP) are more potent at Dopamine transporter? (need less)

Answer 23

MDVP (4.1) and alpha-pvp

cocaine and amphetamine have a higher number so they are less potent

Question 24

Which drugs (cocaine, AMPH, MDPV and alpha-PVP) are more potent at SERT transporter? (need less)

Answer 24

cocaine has the least potency at this receptor at 313 while alpha PVP virtually does not even affect SERT

Question 25

what is the DAT/SERT ratio? what does it indiciate

Answer 25

DAT/SERT ratio tells you how dependent the drug can be, if the IC50 DAT is high it means less potent and less dependency (if numerator is higher)

but if numerator is lower it means you will yield a lower number and that means that dependency is higher

the more potent something is at the dopamine receptor means the more risk of addiction

Question 26

How do we know if they reverse the transporter?

Answer 26

We can take the synaptosome and load them with radioactive NT or NT analogue as a substitute for dopamine that can transported by the transporter proteins

then add the drug to the exterior and see if any of the substance that was on the inside ends up on the outside of the synaptosome

Question 27

What are some effects shown experimentally on 5HT and Dopamine from mephedrone?

Answer 27

mephedrone affects both transporters (DAT AND SERT)

4-MEC affects serotonin release but not dopamine release

4-mePPPP works poorly at inhibiting 5-HT and dopamine

efflux ==> pyrrolidine ring structures are probably responsible for the differnce
- all of the chatinones with pyrrolidine structure have this characteristic of little efflux (act more like cocaine)

1st generation drugs like mephadrone and methcathinone act like amphetamines because they reverse the role of transporters (SERT AND DAT), and overtime you can see a shift in higher levels of 5HT and MPP+ (dopamine substitute) outside the synaptosome

Second generation drugs like 4-MEC and 4-MEPPP act like cocaine and do not reverse transporters therefore you don’t see an increase in serotonin or dopamine outside synaptosome

Question 28

what are some medical issues related to cathinone?

Answer 28

symptoms are related to surge in levels of dopamine, norE and serotonin in the periphery and include:

1. hyperthermia (indicated as primary problem in deaths)
2. Rhabdomyolysis (muscle breakdown), kidney failure
3. Tachycardia (elevated HR) that is followed by bradycardia (slowing down of HR), hypertension, chest pain
4. panic attacks, paranoia, suicidal thoughts, confusion and psychosis