Introduction to Spice

[​IMG]Spice products are available in various retail markets, which has attributed to the rapid rise in their popularity. They are readily retailed online, in headshops, gas stations, and other businesses that are in the public eye. The packaging and the marketing schemes associated with the sales of these products are innocuous upon appearance. The containers and packets will display the products intended use as incense, herbal blends, and potpourri, which entail a legal necessity to state "not for human consumption" in order to avoid potential legal liability from users.[1] On the back label of many of these products, herbs and plants will be listed to further incite confidence in the marketing scheme. These usually include: Canavalia maritima, Nymphaea caerulea, Scutellaria nana, Pedicularis densiflora, Leonotis leonurus, Zornia latifolia, Nelumbo nucifera, and Leonurus sibiricus. [2]

The inadvertent and fallible association of Spice-products as a "legal alternative" and "drug-test safe alternative" to cannabis have given these products a grey-market appeal and a stark rise in popularity among drug tested cannabis users. However, in recent years, due to changes in state law and federal laws, the products have lost legal status in different stages. In the evolution of this new synthetic drug phenomena, these have been loosely referred to as "generations" or "waves" in the product lines due to the rapid removal and reintroduction of the products in retail settings, and the products have continued to evolve as laws change in country, states, and regions throughout the world. The first generation of synthetic cannabinoids included the brand known as "Spice." In the consideration of current legality, these products are in their "third generation" and quickly evolving to a "fourth generation" to maintain legal standing in the face of recent legislation throughout the world. In the consideration of drug testing, these companies are currently able to screen for first and second generation products rapidly.[3]

The primary constituents of the first wave of spice products included: Spice Silver, Spice Gold, Spice Diamond, Yucatan Fire, K2 (and variations), Happy Shaman Herbs, and Smoke. The first products of Spice brand contained the C8 homologues such as CP‐47,497 and the aminoalkylindole JWH‐018. These potent cannabimimetics were discovered as the culprits of the pharmacological effects as the research done on these chemicals have proven them to be full agonist of both the CB1 and CB2 cannabinoid receptors. Within a few years of production, these chemicals were soon accompanied by many others readily available to replace chemicals deemed illegal throughout the years.

"Spice" products were quickly produced into spin-off variations. Retailers carried their own regional brands along side of popular ones. These retailers evolved due to the popularity of these products. The market shifted into private gas stations, which expose underage people inadvertently. With the popularity of these products quickly rising and problems beginning to surface, dangerous notions have started to form about the drug and its chemical make-up. Due to the highly unspecific nature of the chemicals contained, the unresearched nature of the chemicals, and the highly variable implementation onto the herbal blends, the products have an inherent dangers that have become a reality in many instances. Medical emergencies and poison control center alerts have increased dramatically in the recent years with "Spice"-type products. This fact has come to public light with the many instances of medical emergencies and attributed deaths blamed on the "Spice"-products. With minors having access in many instances to these products, more negative media has been given to these products. As more research is done, credence has been given to the inherit dangers of the unresearched chemicals.

Photo by Lynsay Holst, Kansas City Missouri Police Department[4]

Spice as a brand

[IMG="http://upload.wikimedia.org/wikipedia/commons/thumb/e/e3/Spice_drug.jpg/220px-Spice_drug.jpg"]http://upload.wikimedia.org/wikipedia/commons/thumb/e/e3/Spice_drug.jpg/220px-Spice_drug.jpg[/IMG] Spice was the first commercial brand of synthetic marijuana that went on sale in Europe in 2004, manufactured by a company called The Psyche Deli in London, UK. The Psyche Deli was not willing to directly ship to the US at the time, so it was a difficult to find this brand of synthetic cannabinoid blends in the US. The brand was more common to the European market, but the "K2" brand was surging in popularity in the US soon after.

Working largely through intermediaries, online and in person, they give only a website address on their products. The site has now disappeared, but official company records show that Psyche Deli does exist. Its two shareholders and directors are Richard Creswell and Paul Galbraith. The scant and tardy accounts give some idea of the size and growth of the business: assets rose from £65,000 in 2006 to £899,000 in 2007. More recently, the Psyche Deli has been sold to a Dutch “head shop”, De Sjamaan; the owners have moved to the Netherlands, too.[5]

In the peak of popularity in 2009, the Medicines and Healthcare Products Regulatory Agency (MHRA) of Vauxhall, London sent the Psyche Deli a letter in regards to their product requiring a license to be filed for. Regardless, sales continued with no signs of enforcement. This required the UK government to eventually consider banning the chemicals used in these products. [6]

For further information on the origin of the Spice brand, please visit this Financial Times article outlining the history along with interviews from people involved.

Commonly known products of Spice were Spice Gold, Spice Arctic, and Spice Diamond.

Spice as a category of drugs

Note: This Wiki is written for the general term of "branded herbal blend products." The "Spice as a Brand" covers the specifics of the brand. The rest of the article, unless otherwise specified, refers to the general products available on the market and not Psyche Deli's Spice Brand Herbal Blends specifically.

"Spice" primarily falls under the category of synthetic cannabinoids as the lacing ingredient in the herbal blends. The synthetic cannabinoids include many different drugs of various types and structure. They are agonist capable of binding to the CB1 and/or CB2 receptors of the brain. It is attributed to being an "herbal product" based on the marketing by the companies, but the "Spice" drugs should be known specifically as a designer drug using research chemicals known as synthethic cannabinoids to generate the desired effects. These chemicals are many and vary greatly among products of brands (and even the same brands contain different blends). One blend may contain many chemicals, so the user must be aware of this. The user must also be aware of the consideration that potency and consistency is highly variable among brands, packs, and even down to the material within the package. [7]

Spice chemicals and generations

Synthetic cannabinoids can be classified into eight general groups, based on the type of chemical substitution made to alter the original substance. This chart lists the cannabinoid groups, the chemical substitution characterized by the class, and non-exhaustive lists of the substances (and their trade names) included in each group. Note that some substances do not fit within the classes and are listed as such. This table was created using language from Kansas HB 2049 (2011), Nebraska LB 19 (2011) and North Carolina SB 7 (2011). The table was created from the substances available (or potentially available) in 2011. Since then, many other chemicals have been proposed, synthesized, and used in the production of "Spice" products. This list will be updated over time.

Column 1 Column 2
Tetrahydrocannabinols Tetrahydrocannabinols naturally contained in a plant of the genus cannabis (cannabis plant), as well as synthetic equivalents of the substances contained in the plant, or in the resinous extractives of cannabis and/or synthetic substances, derivatives, and their isomers with similar chemical structure and pharmacological activity such as the following: Delta-1 cis or trans tetrahydrocannabinol and their optical isomers; Delta-6 cis or trans tetrahydrocannabinol and their optical isomers; Delta-3,4 cis or trans tetrahydrocannabinol, and its optical isomers.
Naphthoylindoles Any compound containing a 3-(1-naphthoyl)indole structure with substitution at the nitrogen atom of the indole ring by an alkyl, haloalkyl, alkenyl, cycloalkylmethyl, cycloalkylethyl, 1-(N-methyl-2-piperidinyl)methyl or 2-(4-morpholinyl)ethyl group, whether or not further substituted in the indole ring to any extent and whether or not substituted in the naphthyl ring to any extent. Examples and their trade names include: 1-Pentyl-3-(1-naphthoyl)indole, a.k.a. JWH-018 or AM-678
  • 1-Butyl-3-(1-napthoyl)indole, a.k.a. JWH-073
  • 1-Pentyl-3-(4-methoxy-1-naphthoyl)indole, a.k.a. JWH-081
  • 1-[2-(4-morpholinyl)ethyl]-3-(1-naphthoyl)indole, a.k.a. JWH-200
  • 1-Propyl-2-methyl-3-(1-naphthoyl)indole, a.k.a. JWH-015
  • 1-Hexyl-3-(1-naphthoyl)indole, a.k.a. JWH-019
  • 1-Pentyl-3-(4-methyl-1-naphthoyl)indole, a.k.a. JWH-122
  • 1-Pentyl-3-(4-ehtyl-1-naphthoyl)indole, a.k.a. JWH-210
  • 1-Pentyl-3-(4-chloro-1-naphthoyl)indole, a.k.a. JWH-398
  • 1-(5-fluoropentyl)-3-(1-naphthoyl)indole, a.k.a. AM-2201
Naphthylmethylindoles Any compound containing a H-indol-3-yl-(1-naphthyl)methane structure with substitution at the nitrogen atom of the indole ring by an alkyl, haloalkyl, alkenyl, cycloalkylmethyl, cycloalkylethyl, 1-(N-methyl-2-piperidinyl)methyl or 2-(4-morpholinyl)ethyl group, whether or not further substituted in the indole ring to any extent and whether or not substituted in the naphthyl ring to any extent. Examples and their trade names include:
  • 1-Pentyl-1H-indol-3-yl-(1-naphthyl)methane, a.k.a. JWH-175
  • 1-Pentyl-1H-3-yl-(4-methyl-1-naphthyl)methane, a.k.a. JWH-184
Naphthoylpyrroles Any compound containing a 3-(1-naphthoyl)pyrrole structure with substitution at the nitrogen atom of the pyrrole ring by a alkyl, haloalkyl, alkenyl, cycloalkylmethyl, cycloalkylethyl or 2-(4-morpholinyl)ethyl group, whether or not further substituted in the pyrrole ring to any extent and whether or not substituted in the naphthyl ring to any extent. Examples and their trade names include:
[*](5-(2-fluorophenyl)-1-pentylpyrrol-3-yl)-naphthalen-1-ylmethanone, a.k.a. JWH-307[/LIST]
Naphthylideneindenes or Naphthylmethylindenes Any compound containing a naphthylideneindene structure with substitution at the 3-position of the indene ring by a alkyl, haloalkyl, alkenyl, cycloalkylmethyl, cycloalkylethyl, 1-(N-methyl-2-piperidinyl)methyl or 2-(4-morpholinyl)ethyl group, whether or not further substituted in the indene ring to any extent and whether or not substituted in the naphthyl ring to any extent. Examples and their trade names include:
  • E-1-[1-(1-Naphthalenylmethylene)-1H-inden-3-yl]pentane, a.k.a. JWH-176
Phenylacetylindoles Any compound containing a 3-phenylacetylindole structure with substitution at the nitrogen atom of the indole ring by a alkyl, haloalkyl, alkenyl, cycloalkylmethyl, cycloalkylethyl, 1-(N-methyl-2-piperidinyl)methyl or 2-(4-morpholinyl)ethyl group, whether or not further substituted in the indole ring to any extent and whether or not substituted in the phenyl ring to any extent. Examples and their trade names include:
  • 1-(2-cyclohexylethyl)-3-(2-methoxypheylacetyl)indole, a.k.a. RCS-8
  • 1-Pentyl-3-(2-methoxyphenylacetyl)indole, a.k.a. JWH-250
  • 1-Pentyl-3-(2-methylphenylacetyl)indole, a.k.a. JWH-251
  • 1-Pentyl-3-(2-chlorophenylacetyl)indole, a.k.a. JWH-203
Cyclohexylphenols Any compound containing a 2-(3-hydroxycyclohexyl)phenol structure with substitution at the 5-position of the phenolic ring by a alkyl, haloalkyl, alkenyl, cycloalkylmethyl, cycloalkylethyl, 1-(N-methyl-2-piperidinyl)methyl or 2-(4-morpholinyl)ethyl group, whether or not substituted in the cyclohexyl ring to any extent. Examples and their trade names include:
  • 5-(1,1-dimethylheptyl)-2-[(1R,3S)-3-hydroxycyclohexyl]-phenol, a.k.a. CP 47,497
  • 5-(1,1-dimethyloctyl)-2-[(1R,3S)-3-hydroxycyclohexyl]-phenol, a.k.a. Cannabicyclohexanol or CP 47,497 C8 homologue
  • 5-(1,1-dimethylheptyl)-2-[(1R,2R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-phenol, a.k.a. CP 55,490
Benzoylindoles Any compound containing a 3-(benzoyl)indole structure with substitution at the nitrogen atom of the indole ring by a alkyl, haloalkyl, alkenyl, cycloalkylmethyl, cycloalkylethyl, 1-(N-methyl-2-piperidinyl)methyl or 2-(4-morpholinyl)ethyl group, whether or not further substituted in the indole ring to any extent and whether or not substituted in the phenyl ring to any extent. Examples and their trade names include:
  • 1-Pentyl-3-(4-methoxybenzoyl)indole, a.k.a. RCS-4
  • 1-(5-fluoropentyl)-3-(2-iodobenzoyl)indole, a.k.a. AM-694
  • (4-Methoxyphenyl)-[2-methyl-1-(2-(4-morpholinyl)ethyl)indol-3-y]methanone, a.k.a. WIN-48,098 or Pravadoline
Other Unclassified Synthetic Cannabinoids
  • (6aR,10aR)-9-(hydroxymethyl)-6,6-dimethyl-3-(2-methyloctan-2-yl)-6a,7,10,10a-tetrahydrobenzo[c]chromen-1-ol, a.k.a. HU-210
  • (6aS,10aS)-9-(hydroxymethyl)-6,6-dimethyl-3-(2-methyloctan-2-yl)-6a,7,10,10a-tetrahydrobenzo[c]chromen-1-ol, a.k.a. Dexanabinol or HU-211
  • 2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl-1-naphthalenylmethanone, a.k.a. WIN 55,212-2

-Table from the National Conference of State Legislators on the first wave bans.[8]

First generation chemicals

On March 1, 2011, the United States Drug Enforcement Agency (DEA) moved to control five synthetic cannabinoid chemicals (JWH-018, JWH-073, JWH-200, CP-47,497 and CP-47,497-C8 homologue).[9] This affected the market at the time since these were the primary ingredients in the products prior to the federal ban. Along with more stringent state-wide bans occurring in the United States, a new generation of chemicals were introduced. Prior to this introduction, the products that contained JWH-018, JWH-073, JWH-200, CP-47,497, and HU-210 are known as "First Generation" Spice production. This is a generic term given to the first wave of banned products in the US (and generally around the world as the US followed suit with other nations banning synthetic drugs). [10][11][12]

List of "First Generation" Spice chemicals:
  • JWH-018
  • JWH-073
  • JWH-200
  • CP-47,497
  • CP-47,497-C8
  • HU-210 (rarely used due to its innate inability to be smoked)

Second generation chemicals

[IMG="http://www.drugs-forum.com/forum/attachment.php?attachmentid=33058&stc=1&d=1369020246"]http://www.drugs-forum.com/forum/attachment.php?attachmentid=33058&stc=1&d=1369020246[/IMG] Due to recent legislative action throughout the world, much of the chemicals being sold and used in the products were changed to other analogs that would bypass the explicit bans imposed by the governments. These chemicals evolved into further analogs of the Napthoylindoles. At this point in time, the products branched into many different chemicals of many different sorts. The danger of the "Spice" products increased greatly due to this fact. Many of the chemicals being used at this point had a very low dosage (~500 micrograms), and it was more easily able to overdose the user from the producers' own mistakes.

List of "Second Generation" chemicals:

Third generation chemicals

[​IMG]This is the "current generation" which has been slowly attacked by state bans in the US. Yet the list continues to grow daily as more chemicals become synthesized by international research chemical vendors.

Using Spice

Ways of administration:

Spice blends are typically (if not always) smoked as normally one would smoke cannabis. The plant materials contained within the various spice blends all very in type and consistency, so the material burns differently. The taste and overall qualities of spice is variable as well where brands typically sell flavors to suit the buyers preference. The taste is strong and resembles that of potpourri.

Effects of Spice

The effects are HIGHLY variable and must be understood to be independent in each and every experience. Spice-products can be dangerous, and results can vary greatly from user to user. Each product contains different chemicals, and each can have a different effect upon the user. This is a generality of the expected and documented cases of use with these products. This is not an expected result.

Desired effects:
  • Euphoria
  • Laughter
  • A feeling of comfort/relaxation
  • Creative thought process
  • Music appreciation and deeper understanding
  • Sensual/Sexual Sensitvity
  • Muscle relaxation / Bodily pleasure
  • Pain Reduction
  • Increased Appetite
  • Increased awareness
Side effects:

These synthetic drugs can be extremely dangerous and addictive due to the highly variable nature of the contents and unresearched overall interactions and health issues. Improper use of the the drugs could be life-threatening and can include:
  • Discomfort
  • Severe agitation and anxiety. (Panic Attack)
  • Fast, racing heartbeat and higher blood pressure.
  • Nausea and vomiting.
  • Muscle spasms, seizures, and tremors.
  • Intense hallucinations and psychotic episodes.
  • Suicidal and other harmful thoughts and/or actions
General timeline: 10 minutes to an hour. (Depends on the chemicals in the blend)

Combinations with Spice

Due to the potency and the highly unknown nature of these drugs, it is not recommended to combine drugs with Spice products for harm prevention. Although it is done commonly, extreme care and low dosing should always be taken if one is to combine this drug with other substances.

Different Uses for Spice

Generally "Spice"-products smoked as a recreational drug for its own given effects. Some people will claim it to be a working substitute for cannabis despite its distinct differences in effects profile. It is also used in order to substitute cannabis for necessity such as drug tests and probation. The drug has earned its reputation for being able to avoid legal issues for the most part (although not exactly the truth in many considerations). These are the generic uses for the drug in the long run, since the drug has not been researched or implemented for practical for medical use, unlike cannabis.

Pharmacology of Spice

The pharmacology and pharmacokinetics of the "Spice" family of drugs cannot be discussed directly as each brand and series of products carries multiple, various chemicals in its production. The unspecific nature of the drugs makes it difficult discuss the particulars of pharmacology as a whole. Details regarding toxicology, binding affinity, and receptor interactions must be discussed on a per-chemical basis. All of the information regarding the drug's interaction in the human body will specified based on the specific synthetic cannabinoid's research. It is recommended to research the family of drugs and the chemicals listed throughout the article for more direct information on the subject of pharmacology.

For a classifying list of numerous synthetic cannabinoid binding affinities and other information, please visit the ACMD report on the major cannabinoid agonists.

In the pharmacology section, the research currently known research for JWH-018 is displayed. This does NOT represent any chemicals that are different than JWH-018, as they may or may not be toxic. Spice generations have changed, and most products do NOT contain JWH-018 at the present time. The data displayed also shall require further long term research to be done to determine the true safety of the JWH-018 chemical.


ADME is an abbreviation in pharmacokinetics and pharmacology for absorption, distribution, metabolism, and excretion, and describes the disposition of a pharmaceutical compound within an organism. The four criteria all influence the drug levels and kinetics of drug exposure to the tissues and hence influence the performance and pharmacological activity of the compound as a drug. In the case of these studies, the potential or real toxicity of the compound is taken into account (ADME-Tox or ADMET).

JHW-018 ADME-Tox

JWH-018 (1-pentyl-3-(1-naphthoyl)indole) is a synthetic aminoalkylindole cannabinoid agonist which acts at both the CB1 and CB2 receptors, with a moderate selectivity for the CB2 receptor. It is covered by US patent #7241799. This section will cover the recent data developed for the toxicology and interactions in rats with this drug.

CYP450 Inhibition Assay

CYP Inhibition Assays are tests designed to determine which CYP enzymes are responsible for metabolism of a given substance. They are commonly conducted to determine the risk of enzyme induction, inhibition, or interference of any other sort.

The results regarding the inhibition of CYP450 shows that JWH-018 has the capacity to directly interact with the metabolism of other drugs.


The prediction of clinical relevance of competitive CYP inhibition:
Ki > 1 - Likely
1 > Ki > 0.1 - Possible
0.1 > Ki - Remote

If dose is 5 mg then I = 3 µM (theoretical max that assumes 5 mg by IV injection and 5 L blood vol.)
Ki = 0.5 times IC50
IC50s that pose a potential for drug-drug interaction are highlighted above ( <60 µM )

The inhibition of Cytochrome P450 (CYP) enzymes may cause severe interactions with other drugs if co-administered. This interaction is caused by the increase of plasma drug levels due to inhibition of the key metabolic breakdown of the co-administered drugs and perhaps the drug itself. JWH-018 was shown to inhibit some of these key CYPs. Further studies will be needed to be performed to further characterize the drug interaction properties of JWH-018. However, it should be noted that if the human Cmax level is found to be near the Ki for inhibition of the recommended CYPs a drug interaction is likely.

It should be noted that many drugs inhibit CYPs. Classic examples include the bioactive compounds found in grapefruit juice and anti-epileptic drugs such as Phenytoin.

hERG Binding Assay

[/IMG]hERG (human Ether-à-go-go Related Gene) is a gene which encodes for a potassium (K+) channel specific to cardiac neurons. Due to the sensitivity of this particular K+ channel to drug binding, as well as the importance of this channel in maintaining the resting membrane potential in cardiac tissues, affinity examinations are usually required of new drugs to determine their ability to bind to this channel before they are allowed to be administered to humans due to the potential and likely risk of hERG channel binding.

In the late 1990s a number of drugs, approved by the FDA (the U.S. Department of Health and Human Services Food and Drug Administration) and available on the market, had to be withdrawn from sale in the US when it was discovered they were implicated in deaths caused by heart malfunction. It is now known that a side effect of these drugs was the blocking of hERG channels in heart cells. This caused prolongation of "action potentials"—the electrical pulses responsible for controlling heart muscle cells. With proper control of the rate of heartbeat lost, dangerous arrhythmias could develop, which lead in some cases to death. The hERG test is used to screen drug candidates for possible cardiac issues.

This is an example of the typical ECG recording showing what’s called the “QT interval,” shown in blue, which lasts for longer than it should do if these channels are disrupted. This is known as “Long QT Syndrome,” which is associated with fainting and can lead to sudden death.

In the associated data, the percent concentration-response for the concentration (µM) vs. percent inhibition is displayed. The overall percent inhibition are displayed at various concetrations in the chart listed.

In the case of this study, the the IC50 for JWH-018 was found to be >100 µM. Using the same I/Ki ratio as the FDA prescribes for CYPs, the IC50 needs to be >30 µM for the potential for there to be an issue with hERG to exist; therefore, JWH-018 is negative for hERG.

Cytotoxicity Assay

Cytotoxicity is the quality of being toxic to cells. Cytotoxicity assays are widely used by the pharmaceutical industry to screen for cytotoxicity in new drug candidates. Cytotox examinations look for cell death and cell damage as the result of drug adminstration. These tests measure specific materials which leak from cell membranes following rupture.


JWH-018 has been shown not to cause direct cell-death due to not being cytotoxic at low-concetrations. JWH-018 showed no cytotoxicity up to 250 μM in HepG2. The cytotoxicity IC50 has been shown to correlate with the LD50 in rodent toxicity. These results are also consistent with the other cell based assays.

GreenScreen HC Genotoxicity Assay

Genotoxicity is the toxic affect on genetic material (ie. DNA). Genotoxic substances are known to be potentially mutagenic or carcinogenic, specifically those capable of causing genetic mutation and of contributing to the development of tumors. The GreenScreen HC with and without S9 (metabolism) gentoxicity assay is an assay that measures the potential of a compound to be genotoxic and be potentially mutagenic and/or carcinogenic. Genotoxic compounds are compounds which in various ways damage the information stored in chromosomes. Since cancer can arise as a consequence of exposure to genotoxins all new chemicals such as pharmaceuticals and consumer products that come into contact with humans have to be tested for genotoxicity.

The accuracy of GreenScreen HC reflects its unique combination of high sensitivity (ability to correctly identify genotoxins) and high specificity (ability to correctly identify non-genotoxins). Existing in vitro mammalian tests have low specificity, i.e. their false positive rate is high whilst bacterial tests suffer from poor sensitivity, i.e. their false negative rate is high. Validation studies have shown that GreenScreen HC identifies all mechanistic classes of direct acting genotoxins including aneugens, topoisomerase inhibitors and DNA synthesis inhibitors. It can significantly reduce the number of ‘problem compounds’ in preclinical development, thus minimizing the need for expensive and time consuming mechanistic studies.

The GreenScreen HC can also be run with S9 fraction from liver hepatocytes which metabolizes compounds and looks for genotoxic metabolites.

JWH-018 along with its metabolites was found to be negative in both GreenScreen HC and GreenScreen HC S9 (metabolism) genotoxic assays at concentrations up to 75 μg/ml.

Note on the study: the positive cytotoxicity indicated in the GreenScreen HC S9 is likely an anomaly due to the S9 fraction causing interference. It was noted only at the highest concentration. Any cell permeability will show the dye indicating false positive and does not necessarily indicate cell death. This test is not best marker for cytoxicity.

Rat Repeat Toxicity Assay

Repeat dose rat tolerability studies are performed to determine the potential for toxicities of drugs dosed repeatedly (chronically) over 7 days. Repeated dose toxicity testing is used to evaluate chronic toxic effects, primarily effects on various organ systems. Doses are selected to be sub-lethal but still high enough to cause toxic effects. Animals are euthanized after 7 days and organs are checked for visual signs of toxicity.

The rats are Sprague Dawley species mixed between male and female selections. The approximate weights were between 205-230 grams.

Clinical Observations:

Animal weights compared to the control group were also seen to be decreased probably due to the lethargy of the animals.

The largest concern from these studies is the potency of the compound as well as the tachyphylaxis. It is suggested that in vivo efficacy studies in animals be performed to both identify the lowest efficacious dose but also to see if a repeat dose study causes the need for the efficacious dose to rise due to their tachyphylatic properties. If simple scaling is applied using the FDA guidance on suggested human clinical doses, a HED, or human equivalent dose, based upon only the rat tolerability data and using the 0.1 mg/kg dose as a potentially acceptable dose then the HED is 0.016 mg/kg or for a 68 kg human a 1.1 mg dose.

The main observations from these studies was that JWH-018 caused a severe lethargic, unresponsive catatonic state at all doses tested from 0.1mg/kg to 10 mg/kg in the rats. At the upper drug concentration of 10mg/kg there was decreased breathing, and some animal deaths occurred. There is also the observation that only male rats died. It seemed the deaths were related to the catatonia and decreased breathing rather than organ toxicicity.

Another interesting observation was the fact that the male rats were observed to be significantly more sensitive to the effects of JWH-018 than females. Two out of the three male rats died during the high dose 5mg/kg PK study (equivalent HED is .8mg/kg or for a 68kg human a 54.4mg dose).

Rat Pharmacokinetics

Pharmacokinetics is the study of the way the body deals with the absorption, distribution, metabolism, and excretion (ADME) of drugs under investigation expressed in mathematical terms. The effects and the duration of action of the drug are also taken into account. The data obtained from such studies are useful for the design and conduct of subsequent clinical trials.

Pharmacokinetic studies are performed to observe how long the parent drug remains in the blood system after administration, how the drug is absorbed into the tissues and how it is eliminated.

Absorption is the process whereby a substance entering the body is assimilated by it. For proper pharmacokinetics study, it is necessary to know both the rate and the extent to which the active substance or therapeutic moiety are absorbed. They include substances intended to produce / not produce systematic effects.
Distribution is the dispersion or dissemination of substances throughout the fluids and tissues of the body.
Metabolism is the process whereby a substance is irreversibly transformed into metabolites.
Excretion is the elimination of the substance from the body. In rare cases, not all substances are eliminated; some drugs irreversibly accumulate in a tissue in the body.

A rat pharmacokinetic study was performed by bolus IV injection at 5 mg/kg and blood was collected at various time points for 24 hours post-dose. JWH-018 showed a bi-phasic distribution suggesting both distribution and elimination phases. The clearance was consistent of hepatic blood flow rates in a rat of (55 ml/min/kg). The volume of distribution suggests that the drug is well distributed. No accumulation was observed.

JWH-018 distributes well throughout the rat. It is metabolized and eliminated normally and shows a half life of ~2 hours.

The overall results indicate that JWH-018 is distributed well throughout the rat’s tissues. Metabolism and excretion are normal, with a plasma half-life of approximately 2 hours.

Study Information

Study Documentation and Source

Included in the thread is the discussion and the PDF documents showing the source of the ADME-Tox.

The poster was quoted to say:
Much of the summarized information was directly sourced out of the document here.

Words of staff and moderation for Drugs-Forum were also used in this summary.

The dangers of Spice

Spice and synthetic cannabinoids have side effects and dangers with their use and users should be aware of the potential risks associated with Spice before using any synthetic substances. As many Spice-like blends contain various levels and types of synthetic cannabinoids, it must be noted that side effects and overdose levels are different for each compound and the individual user.


Overdose is possible if the user consumes too many synthetic cannabinoids in a very short amount of time or if there is not sufficient tolerance to synthetic cannabinoids. Overdose effects may differ from user to user, however there are signs that can tell if someone has overdosed. Tachycardia or an Arrhythmia can occur when the user's heart rate escalates to rates higher than average (60 to 100 BPM). Panic attacks and high levels of anxiety are common with overdoses due to the unwanted effects of synthetic cannabinoids. Visual and Auditory hallucinations can occur if the cannabinoid receptors are stimulated to levels higher than desired, sometimes triggering a panic attack. A user that appears to be pale, with flushed skin and/or sweating can be experiencing an overdose.

If there are adverse reactions or effects occurring, a user should seek medical attention. Abnormal heart beat with discomfort, pains, or any serious medical issues should be attended to immediately.


Addiction is a very real possibility and has been confirmed with some of these products. The chemicals potential for addiction is variable, but the evidence is there to suggest that some strong cannabimimetic agents have a strong capability to form addiction with withdrawal symptoms in users.

Short term health effects

A report that appears in the April issue of Pediatrics, "Clinical Presentation of Intoxication Due to Synthetic Cannabinoids," describes three teens with signs and symptoms of synthetic marijuana intoxication, including:[13]
  • A 16-year-old who developed altered mental status who had been smoking marijuana containing K2 and ended up overnight in the hospital in a catatonic state
  • An 18-year-old who became agitated, diaphoretic, and aggressive after smoking Spice
  • A 16-year-old who developed altered mental status after smoking Spice
Another very concerning journal published also in Pediatrics gives evidence that K2 (another brand of herbal blend cannabinoid products) was directly linked to Myocardial Infarctions (Heart attacks) in young adults. [14]

From the article:

Long term health effects

Long term effects are yet to be known at this time. There have been some indications of potential problems, but there is not enough solid evidence and research to make any worthwhile statements on the effects from long-term use.

Producing/Growing Spice

In the production of Spice-type products, a synthetic compound is usually added to the smoke-able plant matter by either soaking it through spray and/or by evaporation. Both of these processes can deposit variable quantities of the target compound onto the plant matter due to variations in atmospheric pressure, humidity, temperature, and surface area exposed. This leads to some batches having very little active compound, while others have high dosages capable of creating an overdose condition. These areas of high concentration are known as "hotspots," and they can be very dangerous to the user. Some medical incidents regarding spice-type products have been attributed to hot-spots in the material. The user makes an assumption that dosages are typical between packages (or brands); thereby, incidentally creating an overdose situation from using the same relative weight in plant material without acknowledging the potential of higher concentrations.

Other important factors of concern in production are the improper removal of solvents and usage of acetone could lead to negative impacts on the user's health. It is important to realize the processes of dissolving, volumetric dosing, and distribution onto the plant material is a sensitive operation that requires a competent individual in chemistry. Recent products have been developed and produced by entrepreneurs looking to make money from the rising popularity of the products, and this introduces a lack of quality and safety on the end of the producer. It is important for users to recognize the potential danger in this. The requirement of knowledge to produce these products is light; therefore, allowing many unqualified individuals to enter the market with potentially dangerous products.

The typical plant materials are chosen based on ability to smoke and economics for the producer.

Forms of Spice

Spice is usually considered as a smoke-able blend of plant matter that has been coated with synthetic cannibanoids, or a combination of these substances. Different varieties of "Spice" are sold under various labels such as K2, Spice, Zombie Killer, Funky Green Stuff, Golden Buddha, K3, etc. Each Spice can have markedly different effects, even different packages of the same label, as different chemicals are used, having variable concentrations. Although there are numerous different kinds of Spice, they are all usually manufactured to produce the same sedating effects of cannabinoids.

Included in the new forms of spice are E-Cigarette cartomizers and E-liquid. Spice is also available as pre-packaged joints in certain product lines. Some producers also sell the alkaloids in powder form straight to the consumer in packages.

Legal status of Spice

United Nations

At this point in time, the UN has only published recommendations and reports on synthetic cannabinoids. There have been no laws passed on its legality.


Federal Bans: The Drug Enforcement Administration (DEA) proposed placing five synthetic cannabinoids 1-pentyl-3-(1-naphthoyl)indole (JWH-018), 1-butyl-3-(1-naphthoyl)indole (JWH-073), 1-[2-(4-morpholinyl)ethyl]-3-(1-naphthoyl)indole (JWH-200), 5-(1,1-dimethylheptyl)-2-(3-hydroxycyclohexyl)-phenol (CP-47,497), and 5-(1,1-dimethyloctyl)-2-(3-hydroxycyclohexyl)-phenol (cannabicyclohexanol, CP-47,497 C8 homologue) including their salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible, into Schedule I of the Controlled Substances Act (CSA).

On July 9, 2012, the federal Synthetic Drug Abuse Prevention Act of 2012 was signed into law. The substances above are now banned federally. This does not mean that the state government has not already banned the substances in question. The state legislators have been far more pursuant on banning designer drugs.

For state bans, please visit: http://www.ncsl.org/issues-research/justice/synthetic-cannabinoids-enactments.aspx

Pending Legislation for state bans: http://www.ncsl.org/issues-research/justice/2012-synthetic-cannabinoids-pending-legislation.aspx

More info on synthetic drug bans: http://www.ncsl.org/issues-research/justice/synthetic-drug-threats.aspx


Spice is illegal (a Class B substance) in the UK [15]
Spice is also illegal in :
Austria as of March 2009[16]
Romania as of 15th February 2010 [16]

For current info on laws in other countries: http://www.unodc.org/enl/browse_countries.jsp

For a complete overview of the world and their laws, visit the following link.

History of Spice

Picture is property of Dirk Hanson of Addiction Inbox. [17]

The two main cannabinoid receptors (CB) were discovered in the 1980s. Type CB1 is found mostly in the central nervous system (CNS), while type CB2 is associated with the immune system. Other receptors are believed to exist in the CNS and other tissues. Anandamide, discovered in 1992, was the first identified substance of several closely-related endogenous agonists for these cannabinoid receptors. ∆-9-tetrahydrocannabinol (THC) is the principal naturally-occurring exogenous agonist for CB1 and CB2. Following the isolation of THC in the 1960s, a large series of synthetic exogenous agonists were synthesised. They fall into four major groups: Analogues of THC were developed from the 1960s and include HU-210 — a dibenzopyran (‘HU’ stands for Hebrew University), Nabilone and many others. Some, like Nabilone, have limited therapeutic use, e.g. in treating nausea following chemotherapy. HU-210 is reported to have 100 times the potency of THC.

In the 1970s, Pfizer developed the cyclohexylphenols (CP) series. Examples include CP 59,540, CP 47,497 and their n-alkyl homologs. In the 1990s, J.W. Huffman et al. at Clemson University, USA created a large series of naphthoylindoles, naphthoylpyrroles and related structures (known as JWH compounds — after the name of their inventor). Examples include JWH-015, its n-pentyl homolog JWH-018 and JWH-073 (an alkyl homolog of JWH-018), etc.

Miscellaneous compounds, possibly including fatty acid amides (e.g. oleamide). Although similar in structure to anandamide, the status of oleamide as a cannabinoid receptor agonist is uncertain; it is used as an antislip agent and is a common contaminant from plastics. Examples from all four groups have been reported in Spice and Spice-like samples: CP 47,497 and its homologs; JWH-018 and JWH-073 and oleamide have been reported in Europe; while HU-210 has been only reported in the US. [18]


  1. ^http://www.cbsnews.com/8301-201_162-57479901/many-synthetic-drugs-still-legal-after-bath-salts-ban/
  2. ^http://www.unodc.org/documents/scientific/Synthetic_Cannabinoids.pdf
  3. ^http://www.redwoodtoxicology.com/services/synthetic_cannabinoid_testing.html
  4. ^http://www.nj.com/mercer/index.ssf/2012/04/mercer_county_officials_enforc.html
  5. ^http://www.ft.com/cms/s/0/1721e2da-f8a0-11dd-aae8-000077b07658.html#axzz2TntHzmf5
  6. ^http://www.ft.com/cms/s/0/1721e2da-f8a0-11dd-aae8-000077b07658.html#axzz2TntHzmf5
  7. ^http://www.unodc.org/documents/scientific/Synthetic_Cannabinoids.pdf
  8. ^http://www.ncsl.org/issues-research/justice/synthetic-cannabinoid-chemical-classes.aspx
  9. ^http://jat.oxfordjournals.org/content/early/2012/05/13/jat.bks047.full
  10. ^. Auwärter, V., et al., 'Spice' and other herbal blends: harmless incense or cannabinoid designer drugs? J
    Mass Spectrom, 2009. 44(5): p. 832‐7.
  11. ^Uchiyama, N., et al., Identification of a cannabinoid analog as a new type of designer drug in a herbal
    product. Chem Pharm Bull (Tokyo), 2009. 57(4): p. 439‐41.
  12. ^http://www.unodc.org/documents/scientific/Synthetic_Cannabinoids.pdf
  13. ^Clinical Presentation of Intoxication Due to Synthetic Cannabinoids
    Joanna Cohen, Sephora Morrison, Jeffrey Greenberg, and Mohsen Saidinejad
    Pediatrics peds.2011-1797; published ahead of print March 19, 2012, doi:10.1542/peds.2011-1797
  14. ^Myocardial Infarction Associated With Use of the Synthetic Cannabinoid K2. Pediatrics; originally published online November 7, 2011; Arshid Mir, Adebisi Obafemi, Amy Young and Colin Kane. DOI: 10.1542/peds.2010-3823
  15. ^http://news.bbc.co.uk/1/hi/8427439.stm
  16. ^ a berowid Spice Vault
  17. ^http://addiction-dirkh.blogspot.com/2011/11/marijuana-new-generation.html
  18. ^EMCDDA (2009), Understanding the ‘Spice’ phenomenon, EMCDDA Thematic paper, European Monitoring Centre for Drugs and Drug Addiction (available online).

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