Racetams are often misleadingly described as nootropic supplements. Despite a lack of effectiveness and safety data and FDA warnings, they are being promoted as “smart drugs” that anyone can buy online. However, many users are not told that racetams are not supplements but unapproved drugs. Read on as we compare the risks of four closely related nootropics in this class.
What are Racetams?
Overview
Racetams are a class of drugs that have the same chemical backbone (a pyrrolidone nucleus).
PIracetam is the “original” racetam. It was discovered in the late 1960s. Since then, more than twenty derivatives have been synthesized. These piracetam-like compounds have been poorly researched and vary in potency and potential mode of action [1].
The exact mechanisms of how each racetam works is not understood. Racetams research is extremely limited. Much of what we know about the racetam comes from animal studies.
Proper scientific evidence is lacking to determine the effectiveness and safety of any racetam.
Despite this, some companies advertise racetams as smart drugs and nootropic compounds. They’ve been marketed for boosting the production of neurotransmitters. Some claim it may make people feel more energetic and focused. These claims are unsubstantiated.
FDA Status & Warnings
In 2003, piracetam failed the new dietary ingredient (NDI) filing, which is a process used to determine the safety of novel ingredients on the market. It did not meet the definition of a supplement.
Instead, the FDA classified piracetam as a new, unapproved drug. The same goes for all subsequent racetams.
The FDA recently issued warnings to several companies that were illegally producing and selling racetams [2, 3].
In the warning, the FDA reinstates that all racetams, including piracetam, are new unapproved drugs since they are not generally recognized as safe and effective for the labeled uses among experts.
Despite this, racetams like piracetam continue to be sold online.
The 2019 Hermitage Company case is a serious warning to all such companies. It involves a man from Hermitage, Pennsylvania, who pleaded guilty to a charge of conspiracy. He was importing and selling illegal drugs manufactured in Russia and China via his website. Piracetam and phenylpiracetam were on the list of the illegal drugs under his belt [4].
This poses a major risk to public health. The production of these drugs goes against important laws and regulations. It leads to the sale of dangerous, adulterated, and misbranded compounds to consumers.
Uses of Racetams Lacking Evidence
All racetams – including aniracetam, piracetam, oxiracetam, pramiracetam, and phenylpiracetam – are classified by the FDA as unapproved new drugs.
Evidence is lacking to support any of the uses listed below.
We strongly advise against taking racetams until their safety and effectiveness have been determined in large clinical trials.
1) Aniracetam
In rats, aniracetam did not affect acetylcholine activity in the brain [5].
Another rat experiment suggested that it may increase serotonin and dopamine in the brain via cholinergic pathways in the prefrontal cortex. They also suspect it may impact cortisol activity via GABA. How this might affect human behavior is unknown [6, 7].
Some researchers are looking at its effects on anxiety, depression, memory damage, and learning impairments in animal models, but findings have been inconclusive [8, 9].
The only recent research study, published in 2014, concluded that aniracetam does not alter cognition or behavior in mice. They tested repeated doses of aniracetam on several measures of learning, memory, and cognitive function and found no effect of this drug [10].
2) Oxiracetam
There is a lack of safety and effectiveness data on oxiracetam in people and particularly in elderly patients with brain disorders.
Most of the “evidence” comes from a low-quality study from the early 80s. In the study, the authors claimed that oxiracetam exhibited improvements in “the memory factor” in 60 elderly patients with mental disorders. Their findings have not been replicated [11].
In the only other human study from 1993, a group of Italian researchers gave a single dose of aniracetam along with an amnesia-inducing drug (scopolamine) to 12 healthy volunteers. Oxiracetam seemed to improve overall test performance, but it’s impossible to draw reliable conclusions from such a small sample size [12].
Similarly, oxiracetam is theorized to reduce drug-induced amnesia in mice. One research group suggested that it may slow the decrease of acetylcholine in the cortex and hippocampus in mice with this experimental condition. But a direct effect hasn’t been established [13].
In animals, oxiracetam increases long-term potentiation (LTP) in the hippocampus, similar to aniracetam. This mechanism hasn’t been explored in humans [14].
In mice, oxiracetam is hypothesized to increase memory test scores. Scientists are giving it to animals immediately after a learning experience “post-trial” to see if it can facilitate the formation of long-term memory. Their findings can’t be applied to humans [15, 16, 17].
On the other hand, oxiracetam did not impact the animals’ learning response in tests performed over the first 24 hr of receiving the drug [18].
Additionally, it appears to improve scores in maze memory tests only in untrained mice [19].
Dosage is also an area of research. One animal study suggests that it may have some arousing effect at low and high doses, but not at the midline mark. This hasn’t been tested in humans [20].
Researchers are investigating whether oxiracetam activates enzymes implicated in learning and memory processes (Protein Kinase C) [21, 22].
Dementia
Research has yet to determine whether oxiracetam impacts dementia in elderly patients. Based on the available data, it should not be used since it is an unapproved drug with unknown safety and efficacy [11, 23].
In one low-quality study from the early 90s, patients with forms of dementia or multiple strokes, high daily doses of oxiracetam (1,600 mg/kg) appeared to improve quality of life and scores on neuropsychological tests after 12 weeks [24].
However, some participants withdrew from the study due to tolerability and compliance issues. One had a mini stroke (ischaemic attack). No larger, better-designed follow up studies were carried out.
Additionally, a couple of old analyses had suggested the potential of oxiracetam in affecting social function and verbal fluency in stroke and primary dementia patients. But modern research hasn’t verified any of these proposed effects [25, 26, 27].
In test tubes, scientists are investigating if oxiracetam can affect the production of ATP [28].
In the late 80s, scientists were exploring the effects of oxiracetam injections on the offspring of pregnant mice. They wanted to know if oxiracetam can improve learning and cognitive development in mice, but these studies were soon abandoned due to safety concerns [29].
Oxiracetam and Nicotine
Nicotine is an addictive substance that naturally occurs as a liquid alkaloid in many plants of the nightshade family. It’s what gets people addicted to cigarettes.
The cognitive effects of nicotine are an area of research. But with the exception of nicotine replacement therapy for smoking cessation, the risks far outweigh any potential benefits.
Nonetheless, some researchers were curious to understand the combined effects of nicotine and oxiracetam in lab animals. In the early 90s, they gave this combination to mice tested in both passive and active avoidance tests (active test – are tests aligned for depressive symptoms. Passive tests – are a short and long term memory assessment) [30, 31].
The combination of the two drugs improved passive avoidance more than either drug separately, and in the active avoidance test, the combination (with low dose nicotine) showed stronger effects than nicotine alone [32].
These experiments were later abandoned due to limited medical value and high health risks.
Proposed Mechanism
Scientists investigated the following pathways on which oxiracetam may hypothetically act:
- Signaling efficiency in hippocampal cells [14].
- Neuron signaling efficiency and the release of glutamate and D-aspartic acid in the brain [33].
- Positive modulation of AMPA sensitive glutamate receptors in neurons [34].
- Release of glutamate and acetylcholine in the hippocampus [35].
- Choline uptake in the hippocampus [36].
None of these mechanisms have been explored in humans.
3) Pramiracetam
Pramiracetam, similar to piracetam, has gone through some tests in animals with drug-induced amnesia. No proper human data are available, though.
In one old study on 24 healthy volunteers, a single pramiracetam dose appeared to reduce drug-induced amnesia in younger and older subjects. These findings haven’t been replicated [37].
It was also tested for improving cognitive abilities and memory in small, old studies of young men suffering from head trauma. Proper clinical have never verified these findings [38].
In mice, pre-administration of pramiracetam seemed to suppress drug-induced amnesia [39].
Another older, small study of 35 healthy elderly people suggested that pramiracetam may have some effect on memory loss. However, the authors stressed that the relationship between memory and emotions are complex and that the way pramiracetam and memory training affect them has yet to be determined [40].
4) Phenylpiracetam
Phenylpiracetam is popularly thought to cross the blood-brain barrier because of the additional phenyl group, but there is no research to prove this claim.
As with all other racetams, its safety and efficacy in humans are unknown.
Only a couple of low-quality human studies and animal findings have been published, mostly in Russian.
In one Russian study, phenylpiracetam daily for one year seemed to improve functional and cognitive parameters in stroke patients (dose was 400 mg/day). This study has several limitations and leaves us with more questions than answers. The full-text article is available only in Russian and the study design is unclear, including whether a placebo group was included or not [41].
In three studies with similar limitations, phenylpiracetam (200 mg/day) was claimed to improve neurological and psychological symptoms in individuals with diseases of the brain and in epilepsy patients. The study specifics are not available and it’s impossible to draw any conclusions [42, 43, 44].
A Risk Comparison of the Most Well-Known Racetams
Warning
Keep in mind that the safety profile of racetams is relatively unknown, given their unapproved drug status, reported risks, and a lack of well-designed clinical studies.
Thus, the list of side effects below, compiled based on the existing data [45, 46, 47] is not a definite one.
Scientific reviews point out that unapproved nootropics, including racetams, can be much more dangerous and harmful for brain health than usually thought. They also suggest that people with a history of mental or substance use disorders might be particularly vulnerable to their adverse effects [45].
Comparison
Piracetam
- Psychomotor agitation
- Dysphoria
- Tiredness
- Dizziness
- Memory loss
- Headache
- Diarrhea
Read more about Piracetam.
Aniracetam
- Anxiety
- Uneasiness
- Insomnia
- Headaches
- Vertigo
- Diarrhea
- Strong rashes
Learn more about Aniracetam.
Oxiracetam
- Sleep disturbance
- Overexcitability
- Nausea
- Headaches
- High blood pressure
- Constipation or diarrhea
Read more about Oxiracetam.
Pramiracetam
- Headaches
- Dizziness
- Insomnia
There’s little data on it in general, especially in humans.
Learn more about Pramiracetam.
Phenylpiracetam
- Headaches
- Insomnia
- Irritability and sensory overload
- Heightened anger and aggressiveness
- Possible suicidal thoughts
Read more about Phenylpiracetam.
Other Side Effects & Overdose
If you have been exposed to racetams and experience poisoning, urgently contact a poison control center near you (call 1-800-222-1222).
Racetams may have anti-clotting effects, which can be particularly risky for people who are already on blood-thinning drugs.
Headache, fatigue, foggy thinking, extreme irritability, and faintness are all possible symptoms of racetams overdose.
Dosing
There is no safe dosage for any type of racetam, since all racetams are unapproved new drugs that pose a significant safety risk.
Below is a summary of the dosages used in scientific research, outlined for informational purposes. We highly advise against the use of racetams.
Aniracetam: 100 mg – 1,500 mg/day. Seems to be rapidly absorbed and quickly metabolized by the body [48].
Oxiracetam: 1,200 – 2,400 mg. May be more bioavailable and stay in the body longer. Estimated bioavailability ranges from 68 to 82 percent [49].
Pramiracetam: 1,200 mg/day.
Phenylpiracetam: 200 – 600 mg/day.
Hypothetical Effects on Acetylcholine
While both oxiracetam and aniracetam (100 mg/kg) didn’t modify choline concentrations in any tested brain region, they did slow a scopolamine drug-induced decrease of acetylcholine. Oxiracetam did so in the hippocampus and cortex (but not striatum) at doses of 50 and 100mg/kg. Higher and lower doses were ineffective. Aniracetam (100 and 300 mg/kg) reduced acetylcholine decrease in the hippocampus only [13].
Independent of increasing acetylcholine concentrations, oxiracetam appears to increase acetylcholine utilization in the cortex and hippocampus at 100 – 300 mg/kg injections [36].
Repeated daily doses of oxiracetam were noted to increase acetylcholine utilization by 31% relative to the control, and appears to be more potent and prolonged than Piracetam [36].
Injections of both piracetam and oxiracetam increase choline uptake in the hippocampus [36].
Oxiracetam may not have an effect on GABA or Serotonin levels in the brain [35].
Piracetam, Aniracetam, Oxiracetam, and Pramiracetam may inhibit steroid synthesis in the body [50, 51, 52, 53].
