Nootropics and Smart Drugs Formulations with Ultrasonics

Smart drugs and nootropic supplements are consumed as “cognitive enhancers” in order to increase cognitive function, brain capacity, concentration, memory and creativity, to boost motivation and mental energy as well as to support brain health. To promote the transport of the bioactive compounds such as nootropics, smart drugs and energizing substances across the blood-brain-barrier (BBB), the molecules should be in a nano-enhanced form. Ultrasonically prepared nano-liposomes, micelles, solid-lipid nanoparticles, nanostructured nano carriers and nano-emulsions are known to increase the bioavailability of bioactive molecules, vitamins and phytochemicals.

Nootropics or smart drugs are brain and body stimulating moleculesso-called cognitive enhancers, which can be distinguished into the following categories racetams, stimulants, adaptogens, cholinergics, serotonergics, dopaminergics, metabolic function smart drugs and more categories.
Interested in those different categories of nootropics? Click here to read more about nootropics and their categorization!

What are Liposomes and Lipid-Based Nanocarriers?

Liposomes and lipid-based nano carriers such as nano-emulsions, nano-suspensions, solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are known as potent drug carrier systems, which delivery bioactive molecules and nutrients to the targeted cell site and result thereby in superior bioavailability and absorption rates.


Ultrasonication is the preferred technique to form liposomes with a high load of bioactive compounds.Liposomes can be categorized as a specific form of nanostructured lipid nanocarriers. Liposomes are spherical vesicles with an aqueous core enclosed by one or more lipid bilayers. Since liposomes offer the capability of encapsulate lipophilic and hydrophilic molecules, they have gained profound acceptance as a highly potent drug delivery system. In its self-assembled, self-closed structure, a liposome can encapsulate multiple bioactive compounds (i.e. nutrients or therapeutic molecules) at once. Its phospholipidic bilayer protects the entrapped bioactive molecules against hydrolysis and oxidative degradation. Since the structure of the liposome’s shell exhibits a significant similarity to mammalian cell, liposomes are capable to transfer bioactive compounds into cells and subcellular sites. Known advantages of liposomal delivery systems include their protections against enzymatic degradation, their low toxicity, high biocompatibility, biodegradability and non-immunogenicity.

Ultrasonication is a fast and reliable technique to produce superior liposomes, nanoliposomes and nano-structured lipid carriers.

UP400St, a 400 watts powerful ultrasonic homogeniser, for the production nano-liposomes.

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Liposomes, niosomes, nanoemulsions, solid-lipid nanoparticles, and nanostructured lipid carriers can be produced by ultrasonic emulsification.

The structural composition of liposomes, niosomes, nanoemulsions, solid-lipid nanoparticles, nanostructured lipid carriers
image: Poonia et al. 2016

Other Lipidic Nano-Carriers

Famotidine-loaded solid-lipid nanoparticles (SLNs) prepared by ultrasonicationLipidic nano-carriers or lipid-based nano-carriers are defined as nano-sized drug / molecule delivery systems, which use lipid structures to encapsulate bioactive molecules in order to obtain improved bioavailability, higher absorption rates, enhanced long-term stability and protection against external degradation factors (e.g. oxidation, hydrolysis). Nanostructured lipid carriers include solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), nanoliposomes, micelles, nanoemulsions,nanosuspensions and lipid nanotubes. The specific chemical composition and its corresponding physicochemical characteristics give each nano-carrier form unique benefits, which make them suitable for specific administration forms (e.g. oral, intravenous, intranasal, transdermal etc.), molecule combinations, loading capacity or time-release formulations.
Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) are defined as solid particles consisting of a lipid matrix in an aqueous phase stabilized by surfactants.
Liposomal and other nano-encapsulated (e.g. SLNs, NLCs) supplements offer a superior bioavailability, which means a very high percentage of the bioactive substance (e.g. vitamin, antioxidant, flavonoid etc.) is absorbed and metabolized by the body’s cells. Only a very small fraction is wasted since it is not absorbed but excreted by the body. This makes nano-liposomal formulations very potent, efficacious and reliable since nearly all of the bioactive molecules are delivered to the destination cells.

Ultrasonic Formulation of Stimulating Molecules with Highest Bioavailability

Ultrasonic nano-emulsification and nano-encapsulation makes nootropic and psychoactive molecules water-soluble and thereby highly absorbable and bioavailable. A higher absorption rate as well as increased bioavailability and biocompatibility make the bioactive substance more potent and may enable it to cross the blood-brain-barrier.

Ultrasonic encapsulation of pharmaceutical substances in solid lipid nanoparticles (SLNs)

Ultrasonic Preparation of Solid-Lipid Nanoparticles
(Kumar et al. 2019)

Ultrasonic Formulation of Nootropics

  • Liposomes
  • Nano-Emulsions
  • Micelles
  • Solid-Lipid Nanoparticles (SLN)
  • Nanostructured Lipid Carriers (NLC)
  • Inclusion Complex (e.g. cyclodextrin)
  • Niosomes
Ultrasonic processor UIP2000hdT (2kW) with stirred batch reactor

Ultrasonic homogenizer UIP2000hdT (2kW) with continuously stirred batch reactor

There are manifold brain health and capacity supporting molecules, nutrients and phytochemicals, which can be extracted and/or formulated into nano-enhanced supplements, such as liquids, tinctures, capsules, nasal sprays, fortified food products etc.

Most known nootropics are substances of the racetam class, such as piracetam, aniracetam, oxiracetam, pramiracetam and phenylpiracetam. Many Racetams are lipophilic (=fat-soluble). Using ultrasonic treatment, the fat-soluble racetam is encapsulated in a nano-enhanced form such as nano-emulsions, liposomes, solid-lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs). These nano-enhanced formulations turn the water-repellant, fat-soluble racetam into a water-soluble product. Since the blood stream in the human body is water-based nano-enhanced water-soluble formulations offer a significantly higher bioavailability.

Ultrasonically Nano-Enhanced Smart Drugs

The ultrasonic encapsulation and nano-formulation technology enables for the preparation of highly bioavailable supplements and therapeutics. Bioactive molecules which benefit from being ultrasonically formulated into a liposomal or other nano-structured lipid carrier system include vitamins, antioxidants, flavonoids, botanical extracts, minerals, amino acids and peptides.

  • Vitamins and antioxidants, which can be either extracted from a natural source or be synthesized, include vitamin C, B vitamins, glutathione, resveratrol, CoQ10 (ubiquinone), etc.
  • Herbal and botanical molecules such as CBD, THC, CBG (cannabis), green tea catechins (e.g. EGCG), nicotine, caffeine, ashwagandha, berberine, kratom etc.
  • Fungi / mushroom extracts such as astragalus, lion‘s mane, turkey tail, chaga, psilocybin (magic mushrooms), etc.
  • Amino acids such as creatine, glycine, 5-HTP (5-hydroxytryptophan), phenylalanine, L-theanine (an amino acid analogue found in tea), GABA (gamma-aminobutyric acid), taurine, N-acetylcysteine (NAC), L-tyrosine, etc.
  • Minerals such as magnesium chelates (e.g. magnesium threonate, magnesium orotate) can be ultrasonically encapsulated as nano-particulates into liposomes.
  • Nutrients, peptides, and other molecules such as alpha-GPC, melatonin, choline (choline bitartrate, choline chloride), (racemic) ketamine, omega-3 fatty acids (EPA, DHA), α-lipoic acid (ALA), selegiline (L-deprenyl), centrophenoxine, oxytocin, methylene blue, etc.

The nano-enhanced liposomal formulation of bioactive molecules and nutrients offers a superior bioavailability and may enable the targeted substances to cross the blood brain barrier. The encapsulation prevents the bioactive molecules against acid-induced hydrolysis in the stomach and enzymatic degradation throughout the gastrointestinal tract, so that a high percentage of the nutrient is transported undamaged to the targeted site of cells.

Excursus: Ultrasonic Extraction of Phyto-Chemicals

Sonication is the superior technology to release bioactive molecules from plants, fungi and bacteria. Ultrasonic extraction is a non-thermal method, whose working principle is based on acoustic cavitation. Acoustic / ultrasonic cavitation creates mechanical shear and turbulences, which perforate and disrupt cell walls and membranes and promotes mass transfer. Thereby, sonication releases the bioactive substances from the cell interior and transfers it to the solvent (e.g. water, ethanol, glycerine, vegetable oil etc. ).
Learn more about ultrasonic extraction of bioactive molecules from botanicals!

High-Performance Ultrasonicators for Nootropic Formulations

Hielscher Ultrasonics’ systems are reliable machines used in the pharmaceutical and supplement production to formulate high-quality nootropics and smart drugs, which range from nano-emulsions to liposomes, nanostructured lipid carriers, solid-lipid nanoparticles, and inclusions complexes that are loaded with vitamins, antioxidants, flavonoids, peptides, polyphenols and other bioactive compounds and provide highest bioavailability, great stability and functionality. To meet its customers’ demands, Hielscher supplies ultrasonicators from the compact hand-held lab homogenizer and bench-top ultrasonicators to fully industrial ultrasonic systems for the production of high-volumes of nootropics and smart drug formulations. Ultrasonic formulating processes can be run as batch or as continuous inline process using an ultrasonic flow-through reactor. A broad range of ultrasonic sonotrodes (probes) and reactor vessels are available to ensure an optimal setup for your liposome production. The robustness of Hielscher’s ultrasonic equipment allows for 24/7 operation under heavy duty in demanding environments and ensure a long-life cycle of the ultrasonicators.
Hielscher's industrial processors of the hdT series can be comfortable and user-friendly operated via browser remote control.The precise control over all important process parameters such as amplitude, pressure, temperature and sonication time make the ultrasonic process reliable and reproducible. Hielscher Ultrasonics knows of the importance of continuously high product quality and supports supplement and therapeutics manufacturers to implement process standardisation and GMP (Good Manufacturing Practices) by intelligent software and automatic data recording. Our digital ultrasonic homogenizers automatically record all ultrasonic process parameters on a built-in SD-card. Digital touch displays and browser remote control allow for continuous process monitoring and enable to adjust the process parameters precisely whenever required. This facilitates process monitoring and quality control significantly.
The table below gives you an indication of the approximate processing capacity of our ultrasonicators:

Batch VolumeFlow RateRecommended Devices
1 to 500mL10 to 200mL/minUP100H
10 to 2000mL20 to 400mL/minUP200Ht, UP400St
0.1 to 20L0.2 to 4L/minUIP2000hdT
10 to 100L2 to 10L/minUIP4000hdT
n.a.10 to 100L/minUIP16000
n.a.largercluster of UIP16000

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Hielscher Ultrasonics manufactures high-performance ultrasonic homogenizers for dispersion, emulsification and cell extraction.

High-power ultrasonic homogenizers from lab to pilot and industrial scale.

Literature / References

Facts Worth Knowing

Nootropics and Smart Drugs

The termnootropicis derived from the Ancient Greek words νόος (nóos), which stands formindand τροπή (tropḗ), which has the meaningturning”. Nootropics, also known as smart drugs, are “mind turning” substances, i.e. bioactive substances that affect the brain by increasing cognitive function, particularly intelligence, executive functions, memory, creativity, alertness, and motivation. They are used as cognitive enhancers or as brain doping. Popular nootropics include racetams. The first synthesised racetam form was derived from GABA and is known as piracetam, which is considered as non-toxic and long-term investigated. Aniracetam, oxiracetam, pramiracetam and phenylpiracetam are structurally similar to piracetam, but exhibit higher stimulating potencies. Newer racetam forms such as coluracetam, fasoracetam, nefiracetam, or noopept do not have structural similarities to piracetam.
Some nootropics can have psychedelic or psycho-active/psychotropic effects, too and affect mental processes, e.g. perception, consciousness, cognition, responsiveness, mood and emotions.


Racetams are known as the original type of smart drug with piracetam as the first synthesised racetam an known as the first nootropic ever. Piracetam is a molecule in the racetams group with the chemical name 2-oxo-1-pyrrolidine acetamide. It is a derivative of the neurotransmitter GABA (gamma-aminobutyric acid). Piracetam is a drug molecule with a pyrrolidone core, which is commonly prescribed to patients with Alzheimer’s or pre-dementia symptoms. However, piracetam and other racetams are also used by healthy adults in order to intensify the chemical synaptic transmission between brain cells. Racetams can thereby heighten the general IQ, memory and learning functions, mental clarity and motivation. Other molecules in the class of racetam are e.g. pramiracetam, oxiracetam, аnԁ aniracetam.
Since racetams are falling into the category of not-controlled substances in the USA or many other countries in the world, racetams can be purchased as OTC (over-the-counter) supplements without prescription. Racetams are considered as non-toxic and general side effects include head aches, which are a result of racetams depletion of choline in the brain. Therefore, users often combine their racetam dose with a choline supplement (e.g. choline bitartrate. Overdoses of racetams have mostly only light side-effects, which are similar to the consumption of excessive caffeine.


Stimulating substances such as caffeine and nicotine are smart drugs widely spread in the world’s population. Caffeine and nicotine are legal psychostimulants, whilst the use of stimulant’s subclass of amphetamines is illegal. The class of stimulants includes almost any molecule that promotes general wakefulness and alertness, reduce the feeling of tiredness and drowsiness and increases at the same time brain function and intelligence quotient (IQ). The anti-narcolepsy drug Modafinil is one of the most prominent medical drugs, which is used by healthy individuals as “off-label cognitive enhancer” to boost cognitive function. Another off-label used drug is methylphenidate, a medication administered to treat Attention Deficit Hyperactivity Disorder (ADHD) and used by healthy individuals as cognitive enhancer.
Click here to learn more about the ultrasonic extraction of caffeine and nicotine!


Adaptogenic substances are phyto-chemical compounds, i.e. plant-derived molecules, which are administered in order to strengthen the body’s response and immune system to stressful situations. Adaptogens can be described as “stressing” compounds, which provoke the body to adapt to maintaining or regaining homeostasis (equilibrium between the body’s metabolic processes). The main route of adaptogenic action affects the hypothalamic–pituitary–adrenal (HPA axis) in response to stimulation by external stress. Almost all adaptogens fall into the class of not-controlled drugs, which can be purchased as over-the-counter (OTC) supplements. Most popular and widely consumed adaptogens are e.g. ginseng, gingerol (ginger), ashwagandha, eleutherococcus senticosus (Siberian ginseng), rhodiola rosea (Arctic root), schisandra chinensis, kava kava, passion flower, St. Johns Wort, and scutellaria baicalensis (Chinese skullcap).
Is Cannabis An Adaptogen? Cannabis has gotten major attention during the last years, mostly for its anti-inflammatory and relaxing compounds cannabidiol (CBD) and cannabigerol (CBG). Even cannabinoids are non-toxic plant-derived compounds and have proven stress-reducing effects on the body, cannabis and cannabinoids are not officially classified as adaptogenic substances. But since CBD, CBG and true adaptogenics show similarities in their function and effects, they are often used in combination in order to amplify the efficiency of the cannabinoid as well as the adaptogen.
Whilst adaptogens have health-promoting and stress-reducing effects, they show only small effects as cognitive enhancers, “per se”. Cognitive enhancement from adaptogens is mainly achieved by balancing-out the body’s stress response, resiliency and overall health, rather than directly initiating the growth of new brain cells or neural connections.
Click here to learn more about the ultrasonic extraction of adaptogens from botanicals!


Cholinergic substances are chemical compounds which mimic the action of acetylcholine and/or butyrylcholine. Choline-based smart drugs are consumed for their effects on memory, attention, and mood regulation. Acetylcholine is one of the major neurotransmitters in the brain. It is also an essential component for the proper functioning of the peripheral nervous system. Choline can be taken as supplement, but is also present in food, e.g. egg yolks and soybeans are particularly rich in choline.
Sulbutiamine (which is commercially available as OTC (over the counter ) drug under the brand name Arcalion) is a synthetic derivative of thiamine (vitamin B1), which crosses the blood-brain barrier and is able to increase thiamine levels in the brain. Known to improve memory and to overcome weakness and fatigue while reducing psycho-behavioral inhibition, sulbutiamine is also used by athletes. Sulbutiamine is classified as a cholinergic smart drug since this substance acts as cholinergic regulator within the hippocampus. When used at therapeutic dosages, no serious side effects have been observed.


Serotonin, or 5-hydroxytryptamine (5-HT), is monoamine neurotransmitter that contributes to and controls mood (well-being, happiness), and modulates sleep, appetite, cognition, learning, memory, the reward system and numerous physiological processes such as vomiting and vasoconstriction. Serotonin is produced within the body by exposure to sunlight. Natural serotonergic (serotonin-promoting or releasing) compounds, such as L-tryptophan, are also present in food sources.


Dopaminergics are smart drug substances that affect levels of dopamine within the brain. Dopamine is a hormone and a neurotransmitter that plays several important roles in the brain and body. For example, the dopamine pathway is responsible for the good feelings and biochemical signalling of positive feedback in regards to pleasant experiences such as tasty food, sex, positive social engagement, etc.
Dopamine is available as medication under the brand names of Intropin, Dopastat, and Revimine, among others, which are mainly used as a stimulant drug in the treatment of severe low blood pressure, slow heart rate, and cardiac arrest.
Dopaminergic smart drugs are dopamine boosters used to overcome low dopamine levels, which are generally associated with low energy levels, a lack of motivation, anhedonia (inability to feel pleasure), apathy, depression, addictive behaviours, poor memory and reduced learning performance. Common dopaminergic smart drugs are L-tyrosine, Yohimbine and selegilin (a MAO inhibitor). Dopamine boosters promote attention and alertness by either increasing the efficacy of dopamine within the brain, or inhibiting the enzymes that break dopamine down.

Other categories of smart drugs, cognitive enhancers, and nootropics include glycinergics, adenosinergics, adrenergics, cannabinoidergics, GABAergics, histaminergics, melatonergics, monoaminergics, and opioidergics.
The group of “-ergic” nootropics are substances that modulate a specific system in the body and brain.The specific system is integrated in the first part of the term. For example, glycinergics directly modulate the glycine system in the body and brain, adenosinergics directly modulate the adenosine system in the body and brain, dopaminergics act on the dopamine system and so on.

Inclusion Complexes

An inclusion compound is a complex in which one chemical substancethe so calledhost” – has a cavity into which another moleculethe so calledguest” – is included.
Cyclodextrins are the most commonly used host compounds, since they can form inclusion complex with a wide variety of solid, liquid and gaseous compounds. Guest compounds range from polar reagents such as acids, amines, small ions (e.g. ClO4- , SCN-, halogen anions) to highly apolar aliphatic and aromatic hydrocarbons and rare gases. Inclusion complexes can be synthesized either in solution or in the crystalline state. Ultrasonic complexation of cyclodextrin-based inclusion complexes is a very reliable and efficient method to produce loaded inclusion complexes, which offer a high stability and increased bioavailability. Water is commonly used as solvent, although dimethyl sulfoxide and dimethyl formamide are alternative solvents to be used.
Besides the inclusion of pharmaceutical / nutraceutical compounds, cyclodextrin is also used as host compounds for fragrance molecules to achieve a higher stability and a slow-release action.
Read more about ultrasonically produced inclusion complexes!

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