Psychopharmacology and Memory Loss

Example: Flunitrazepam
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Flunitrazepam (generic name) aka Rohypnol (brand name) aka Roffies
(street name) is a majorly abused pharmaceutical, which has a wide variety of
side effects. However, the main reason for its abuse is due to its potency in
causing anterograde amnesia[2].

Pharmaceuticals have been known to cause side effects of dizziness and cognitive impairment. Many of these drugs share the common property of causing memory loss, specifically anterograde amnesia[1], through acting on the encoding phase of memory creation and retention. This is the first possible step where memory failure may occur. These drugs prevent the brain from interpreting the sensory information, which is usually received by sensory organs through the thalamus. Oddly enough, most of these drugs do not act exclusively on the thalamus; instead, there is a wide spectrum of drugs that act throughout the brain on many different types of receptors to achieve memory loss. Some major drugs, such as benzodiazepines, act on GABA receptors[1], and have different effects when combined with other pharmaceuticals[2], while others act indirectly to GABA receptors using other various pathways.

1. Benzodiazepines

In the modern world of pharmaceuticals there have been many medications discovered and created to treat and manage diseases and symptoms alike, and many of these medications result in desired and undesired interference with the memory process. The memory process is usually interfered with in an early stage of memory formation, known as the input stage[1]. This stage is also sometimes called the encoding stage of memory. In this stage the sensory information picked up by our body's sensory receptors is unable to be transformed into short-term memory(STM), thus inducing anterograde amnesia causing the target to be unable to form accurate memories.

The most famous and thoroughly studied pharmaceuticals to induce such an effect are the class of drugs known as benzodiazepines. Benzodiazepines have been used for pre-anesthesia effects, for anxiety purposes, and even stress control. A major class break within the benzodiazepine category is sedative hypnotic benzodiazepines and non-sedative hypnotic benzodiazepines[1]. The sedative quality of benzodiazepines is dependent on how powerful the drug is at inducing loss of consciousness along with it's anterograde amnesia effects. Benzodiazepines all act on the central nervous system(CNS) via receptors on GABA-mediated chloride ion channels leading to increased GABAnergic firing, which in turn induces hyper-polarization of the neuronal cell leading to a depression of the CNS[1]. In particular there is an observed influence that benzodiazepines have on the hippocampus and amygdala, which is thought to be the reason for the anterograde amnesia effects[1].

1.1 Flunitrazepam

Drug Comparison Trials
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"Percentage Frequency of Any Degree of Amnesia
at the Times Shown Following Various Doses of 3
Benzodiazepines Administered Orally[1]."

Flunitrazepam is a sedative hypnotic benzodiazepine and has been shown to be one of the most effective at causing anterograde amnesia as compared in a dosage dependent manner to other benzodiazepines (see trials)[1]. Once taken, it has a very fast time frame of activation in its GABAnergic binding mechanisms; and the potent and rapid effect does not diminish its ability to last in the host for an, at least, average amount of time[2].Flunitrazepam, unlike other sedative hypnotic benzodiazepines, is able to, at higher doses, greatly affect psychomotor performance resulting in delayed reaction time an balance[3]. This effect is experienced in addition to the amnesiac effects that all benzodiazepines cause. The greater effect on psychomotor performance is thought to be attributed to the higher potency effects of Flunitrazepam as compared dose dependently to other benzodiazepines[3]. Flunitrazepam's potency as a sedative hypnotic benzodiazepine is well documented but what cannot be under stressed is exactly how little Flunitrazepam can produce anterograde amnesic effects. It has been known to disrupt memory loss in extremely small increments[5]; as little as .5mg of Flunitrazepam will cause amnesia in four out of five people within the hour[1].

A powerful, yet little known secondary effect of Flunitrazepam use, is that it causes extreme risky behavior and has been known to cause exacerbate violent behaviors in many people and along with it's powerful memory erasure effects, has become illegal in many countries around the world[2]. Many different drugs cause risky decision making at many different doses but Flunitrazepam seems to affect decision making in a different manner than other common drugs like alcohol. At high doses both drugs may cause risky decision making but Flunitrazepam seems to affect decision making by causing a loss of memory leading to a failure of grasping the STM learning abilities gained with experience producing an over all less predictable action, otherwise known as risky decision making[3]. The risky decision making is also attributed in part by Flunitrazepam causing impulsivity. It's been shown using delay discounting in pigeons that higher doses of Flunitrazepam lead to faster decisions being made regardless of reinforcers[4]. This impulsivity along with the tendency for risky decisions and lowered risk aversion makes Flunitrazepam a dangerous but effective drug in a whole different and separate manner from simply it's amnesic properties, adding to its illegal substance abuse.

1.1.1 Alcoholic Interactions

Additive Effects of Flunitrazepam & Alcohol
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"Dose-effects of drug coadministration on locomotor activity. Mice were monitored for
their locomotor activity in a 3 h recording session to create a baseline activity curve.[6]."
This shows that the strongest effects created were that of the highest alcohol dosage in combination
with the highest Flunitrazepam dosage.

Flunitrazepam is a majorly abused drug for its potency and is often mixed with other substances for illegal abuse. In fact it was reported that one in four driver caught for driving under the influence was also intoxicated with Flunitrazepam[2]. The alcohol greatly increases the effects of the Flunitrazepam on the CNS further depressing it by increasing inhibition. It is thought that the GABA neuron's benzodiazepine receptors undergo a conformational change in the presence of alcohol and this increases the receptors affinity for benzodiazepines leading to the stronger inhibitory effect[6]. The mixture of alcohol and Flunitrazepam is not only used recreationally but has also become the reputable "date-rape drug" for it's effectiveness in causing partial anterograde memory loss[2] and also due to the fact that the alcohol-Flunitrazepam combination is intensified in women[7] resulting in much more powerful memory loss. There are a number of other symptoms that are intensified by alcohol use along with Flunitrazepam other than memory loss including: psychomotor skills such as, balance and reaction time, along with locomotor skills, such as hand-eye coordination and limb control[6].

1.1.2 Withdrawal

Flunitrazepam usage has been linked to tolerance development and substance dependence[6],[8]. It has been shown that verbal and nonverbal memory, and motor control are all affected even after up to six months abstinence from the drugs; However, visuospatial skills and attention concentration hasn't been shown to be affected[8]. Flunitrazepam's withdrawal appears in the form of these cognitive deficits months after it's been stopped[8]. However, Flunitrazepam as also been shown to not create tolerance and addiction with chronic use versus acute use and it also seems to not change it's effects with chronic usage[4]. This array of mixed results in possible addiction to Flunitrazepam is worrying because of its use as a model for other benzodiazepines. With benzodiazepines being one of the most abundantly prescribed medications being used for everything from pre-anesthetics to psychotic treatments , any long term harms of the medications needs to be established so they may be used appropriately for future uses.

1.2 Triazolam

Triazolam is another sedative hypnotic benzodiazepine medication but Triazolam, sold as Valium, is much more legal than Flunitrazepam due to lower side effect occurrences[9]. This drug acts similarly by also increasing GABAnergic inhibition to depress the CNS. Recorded effects of acute Triazolam use include effects simliar to other benzodiazepines such as amnesic memory, loss of psychomotor control, as well as depressed locomotor functions resulting in an overall sedation effect[9]. Triazolam's effect on memory was shown to be more specified and targeted than a general sedative mechanism of action; it was shown to effect memory not only due to the sedation effect but also due to targeting memory formation its self[9]. It was also found that Triazolam's effect on memory may be appropriately followed through with other benzodiazepines as well[9]. Positron emission tomography (PET) scans have been used on adults to measure regional cerebral blood flow (rCBF) pre and post treatment with triazolam[10].The PET scans showed a decrease of rCBF in the post-treatment group in specific brain regions: anterior cingulate cortex, cerebellum, and precuneus[10]. These areas of the brain have been known to be the areas were the encoding (aka input) step of the memory process occurs. Triazolam along with other benzodiazepines was temporally shown to interfere with memory encoding via PET scans[10].

Additive Effects of Lorazepam & Alcohol
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This shows that the strongest effects created
were that of the highest alcohol dosage in combination
with the highest Lorazepam dosage[10].

1.3 Lorazepam

Lorazepam is a non-sedative hypnotic benzodiazepine that has been known to cause impairment on explicit memory tests involving encoding of new information and its retrieval[11]. Like other benzodiazepines Lorazepam interferes the same way, disrupting encoding of memory. It has also been shown to cause psychomotor and mood interference[12], as well as depression in arousal[13]. Lorazepam has also been shown to be a model for benzodiazepines in combination with alcohol resulting in impaired memory and cognitive deficits[11]. The effects are enhancing similar to that of Flunitrazepam, however not to the same extent. The effects of Lorazepam and alcohol are shown in the table to the right. As shown the most severely decreased with use of both barbiturates[11]. An interesting note on Lorazepam as compared to Flunitrazepam is that the explicit cognitive deficit results in impairment of memory accuracy as well as speed as shown with explicit recall tests[11]. One explanation for this might be attributed to Lorazepam and alcohol's psychoactive natures differing in combination compared to Flunitrazepam and alcohol's combination, though this hypothesis does not have enough scientific evidence.

2. Non-Benzodiazepines

This category of drugs encompasses everything that is simply not a benzodiazepine, and yet still acts on memory in one way or another. The included drugs range in legality, safety, availability, composition, routes of administration, uses, etc. Due to the overwhelming amount of information to be covered, the categories have been divided further into imidazopyridines (specifically ones that show similar memory amnesic effects but act on different receptors than benzodiazepines), opiates (commonly used for pain relive, they act on a different set of receptors to create secondary effects of memory/consciousness loss), stimulants (mainly illegal and used for "highs", the evidence for memory loss is fragile), and anesthesia (used legitimately to render full or regionalized paralysis/numbness and unconsciousness, many have been known to case memory interference).

2.1 Imidazopyridines

Zolpidem and Zopiclone are both sedative hypnotic non-benzodiazepines medications that fall under the category of imidazopyridines. These drugs are structurally, and so physically, completely unrelated to benzodiazepines but seem to cause memory impairment in the encoding process of memory storage like benzodiazepines[1]. Although with these drugs the memory impairment is anterograde amnesia, it seems to be much more on a dose dependent scale such where .75mg of Triazolam is equal to 7.5mg of Zopiclone is equal to 10mg of Zolpidem in terms of equal sedation effects[1]. This class of drugs represents the vast number of non-benzodiazepine medications that cause anterograde amnesia as a side effect. These drugs cause similar amnesic symptoms but by acting on different receptors in different parts of the brain.

2.2 Stimulants

Stimulants encompass a set of mainly illegal drugs that act on the nervous system to create a type of various "highs" for the user where they appear to believe they have enhanced and improved abilities. These drugs are generally highly addictive and detrimental to development and growth of the nervous system as well as to neuronal activity in general[14]. Though their effects on cognitive processes is well determined the narrow scope of effects on memory isn't understood very well. Regardless their have been findings that allow conclusions to be made of many stimulants and their effects on memory.

Illegal Substances
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Many stimulants are considered dangerous and illegal in many parts of the world. Their
stimulating effects come hand in hand with detrimental and sometimes permanent brain damage.

2.2.1 Cocaine

Cocaine use has been linked to memory loss only as a byproduct of overall neurological depression due to lack of blood flow, and this is evident due to the return of cognitive functions, including memory encoding, once a period of abstinence is observed[14]. Chronic users of cocaine may be prone to more severe cognitive decifits due to loss of blood flow, via constriction of coronary and cerebral blood vessels, for to long leading to the death of neurons; however, the damage led to impairment in memory storage capabilities instead of learning[17]. This places cocaine as one of the rarer drugs that causes the inability to form new LTMs instead of interrupting the memory process at the encoding stage.

2.2.2 Heroin

Heroin is another illegal substance that seems to follow a very selective effect on the brain and as a result seems to mainly affect the impulse control of the person, along with their learning patterns and behaviors, commonly resulting in habituation[14]. Heroin seems to target selective neurons in the brain to create effects of impulse behaviors but do not affect attention, reasoning, memory, or other cognitive abilities[18]. Impulsive behavior leads to an eradicate and dangerous environment and these neurological changes may cause heroin related violent behavior.

2.2.3 Amphetamine/Methamphetamine

Methamphetamines are known to induce a semi-permanent loss of dopamine (DA) transporters in the caudate and putamen brain regions along with loss in the orbitofrontal and dorsolateral prefrontal cortices[15]. This loss has been linked to decreased rates of learning and retention of information indicative of interference in the encoding to STM part of the memory process hinting showing as anterograde amnesia or overall decreased psychological functionality[14]. Amphetamines have been consistently creating a long list of results from studies, ranging from enhancing effects, null effects, and deteriorating effects, when it comes to memory effects of their usage; but one thing that has been consistently found is a loss of accuracy in the memory[9].

2.2.4 Cannabis

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Cannabis creates very bipolar sets of effects for users and non-users. Common users of cannabis seem to increase CBF in the frontal cortex with more uses but novice users see a decrease in CBF with more uses[14]. There is also a consensus that heavy cannabis users see a overall decrease in neurophysiological activity, particularly in the dorsolateral prefrontal cortex (DLPFC); however, a surprising fact occurs that the deficit in mental abilities, especially episodic memory, persists after use up to 28 days later[16]. Due to lack of consensus evidence of long term cannabis use being harmful in a greater than 28 day period of time, cannabis use cannot be declared to cause permanent memory problems; however, the evidence is clear that STM loss is evident with cannabis long term uses along with symptoms of psychosis[16].

2.2.5 Alcohol

Alcohol is one of the few stimulants mentioned that is legal (with restrictions). Alcohol has already been mentioned to interact in additive effects with benzodiazepines to create stronger more influential cognitive deficits in memory and further cause anterograde amnesia and other alcohol related memory issues. However, the superadditive effects of alcohol is also present in use with other stimulants. A prime example is the use of cocaine along with alcohol. It has been shown that this combination of stimulants leads to neurobehavioral impairment that persists about a month after use[14].

2.3 Anesthesia

Anesthetic Example: Isofurane
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Anesthesia is and has been used legally by medical practitioners around the world as a part of surgery to numb the patient or a region of the patient's body. Isofurane has been considered one of the safer anesthetics around. Anesthetics such as Isofurane act on thier appropriate receptors on GABAnergic neurons to producing inhibiting effects in the body quite similar to benzodiazepines[19]. However, Isofurane has now been considered a drug that causes cognitive deficits even with proper care and usage. Most prominently the anesthetic creates a memory deficit due to a loss of stem cells in the hippocampus which then decreased the number of neuronal stem cells, and thus neurons, in the dentate gyrus[19]. Loss of cells in the hippocampus leaves room damage to the retrieval phase of memory.In addition to this memory centered effect it was also shown that younger rats treated with Isofurane suffered learning deficits due to the inability to correctly encode STM and thus LTM memories thus impairing the ability to learn[19]. This effect was also shown to increase with age and so the younger rats treated with the Isofurane, suffering deficits, would progressively become worse due to lack of neurogenesis over time[19].

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